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Biocatalysis in Drug Design: Engineered Reductive Aminases (RedAms) Are Used to Access Chiral Building Blocks with Multiple Stereocenters
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  • Arnau Rué Casamajo
    Arnau Rué Casamajo
    Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester M1 7DN, United Kingdom
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    Orcidhttps://orcid.org/0000-0001-8932-8763
  • Yuqi Yu
    Yuqi Yu
    Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester M1 7DN, United Kingdom
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  • Christian Schnepel
    Christian Schnepel
    School of Engineering Sciences in Chemistry, Biotechnology and Health, Department of Industrial Biotechnology, KTH Royal Institute of Technology, AlbaNova University Center, 11421 Stockholm, Sweden
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    Orcidhttps://orcid.org/0000-0002-4331-2675
  • Charlotte Morrill
    Charlotte Morrill
    Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester M1 7DN, United Kingdom
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  • Rhys Barker
    Rhys Barker
    Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester M1 7DN, United Kingdom
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  • Colin W. Levy
    Colin W. Levy
    Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester M1 7DN, United Kingdom
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  • James Finnigan
    James Finnigan
    Prozomix Ltd, Building 4, West End Ind. Estate, Haltwhistle NE49 9HA, United Kingdom
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  • Victor Spelling
    Victor Spelling
    Early Chemical Development, Pharmaceutical Sciences, Biopharmaceuticals R&D, AstraZeneca, Mölndal, 431 50 Gothenburg, Sweden
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    Orcidhttps://orcid.org/0000-0001-5976-8047
  • Kristina Westerlund
    Kristina Westerlund
    Medicinal Chemistry, Research and Early Development; Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, Mölndal, 431 50 Gothenburg Sweden
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  • Mark Petchey
    Mark Petchey
    Compound Synthesis and Management, Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Mölndal, 431 50 Gothenburg, Sweden
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  • Robert J. Sheppard
    Robert J. Sheppard
    Medicinal Chemistry, Research and Early Development; Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, Mölndal, 431 50 Gothenburg Sweden
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  • Richard J. Lewis
    Richard J. Lewis
    Department of Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, 43183 Mölndal, Sweden
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    Orcidhttps://orcid.org/0000-0001-9404-8520
  • Francesco Falcioni
    Francesco Falcioni
    Early Chemical Development, Pharmaceutical Sciences, Biopharmaceuticals R&D, AstraZeneca, CB21 6GP Cambridge, United Kingdom
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  • Martin A. Hayes
    Martin A. Hayes
    Compound Synthesis and Management, Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Mölndal, 431 50 Gothenburg, Sweden
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    Orcidhttps://orcid.org/0000-0002-2640-8464
  • Nicholas J. Turner*
    Nicholas J. Turner
    Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester M1 7DN, United Kingdom
    *Email: [email protected]
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    Orcidhttps://orcid.org/0000-0002-8708-0781
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Journal of the American Chemical Society

Cite this: J. Am. Chem. Soc. 2023, 145, 40, 22041–22046
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https://doi.org/10.1021/jacs.3c07010
Published October 2, 2023

Copyright © 2023 The Authors. Published by American Chemical Society. This publication is licensed under

CC-BY 4.0 .

Abstract

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Novel building blocks are in constant demand during the search for innovative bioactive small molecule therapeutics by enabling the construction of structure–activity–property–toxicology relationships. Complex chiral molecules containing multiple stereocenters are an important component in compound library expansion but can be difficult to access by traditional organic synthesis. Herein, we report a biocatalytic process to access a specific diastereomer of a chiral amine building block used in drug discovery. A reductive aminase (RedAm) was engineered following a structure-guided mutagenesis strategy to produce the desired isomer. The engineered RedAm (IR-09 W204R) was able to generate the (S,S,S)-isomer 3 in 45% conversion and 95% ee from the racemic ketone 2. Subsequent palladium-catalyzed deallylation of 3 yielded the target primary amine 4 in a 73% yield. This engineered biocatalyst was used at preparative scale and represents a potential starting point for further engineering and process development.

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Introduction

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Chiral amines are common building blocks in the pharmaceutical industry that allow access to a plethora of biologically active compounds. (1−5) They can be used for different applications, from development of small molecule pharmaceuticals (4−8) to more complex therapeutics, such as proteolysis targeting chimeras (PROTACs), (9) or for bioconjugation of peptides or proteins. (10−13) The pharmaceutical industry is constantly looking for innovative ways to produce new bioactive compounds, which has increased the demand for novel building blocks in drug design. (14−20) The wide structural diversity of such compounds facilitates the study of drug properties, such as permeability, potency, or secondary pharmacology. Current synthetic methodologies allow extensive coverage of available chemical space, but there are still opportunities for novel building blocks. (14,21−24) Biocatalysis is a powerful synthetic methodology that can allow access to novel chemistries by exploiting mild reactions conditions, as well as the catalytic nature of the transformation, with high stereoselectivity driven by precise enzyme/substrate interactions. (17,18,25−27)
Importantly, biocatalytic synthesis can play a crucial role in drug discovery since enzymes are tunable catalysts that allow for excellent control of chemoselectivity, regioselectivity and enantioselectivity. (25,28,29) Imine reductases (IREDs) are one emerging platform of biocatalyst (30−34) that perform a variety of reactions, including cyclic imine reduction, (31,35,36) reductive amination (RedAms), (34,37,38) and alkene reduction (EneIRED). (3,39) Interestingly, individual IREDs can behave simultaneously as an IRED, a RedAm, or an EneIRED depending on the substrate used while still maintaining excellent chemoselectivity. (3)

Results and Discussion

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Herein, we address the enzymatic synthesis of a chiral building block (S,S,S)-4, which was required for a medicinal chemistry discovery program and proved to be particularly challenging to obtain by organic synthesis. We initially envisioned directly accessing this primary chiral amine via a RedAm-mediated reductive amination with ammonia. However, although RedAms have been previously shown to use ammonia as the nucleophile, (40) they were found to be inactive with racemic ketone 2. We therefore elected to use allylamine 1, which typically shows high activity with a wide range of different RedAms and should generate a product that could be readily converted to primary amine 4 (Figure 1).

Figure 1

Figure 1. Combined biocatalytic resolution and reductive amination of racemic ketone 2 with allylamine 1 forming (S,S,S)-3, which is a key intermediate for the desired primary amine (S,S,S)-4.

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A metagenomic panel of IREDs and RedAms, (36) containing different biocatalysts, was screened to identify active enzymes capable of converting the substrate ketone 2 to the product 3. A previously reported colorimetric high-throughput screening method (HTS), (36) which operates in the oxidative direction and uses the product of the reaction 3 to identify active enzymes, was initially employed to select enzymes for further characterization.
Any hits obtained from this primary screen were subsequently confirmed by examining the reductive amination of 2 with allylamine 1 in the synthetic direction. In addition, on the basis of previous experience, several other IREDs were selected because of known substrate promiscuity. Two of these IREDs were found to be active; IR-09 and IR-20 exhibited >95% and 47% conversion, respectively.
All biotransformations were performed with glucose and glucose dehydrogenase (GDH) as the NADPH recycling system. For all reactions, formation of alcohol was observed to some extent, likely because of either ketone reduction catalyzed by GDH (41,42) and/or other ketoreductases (KREDs) present in the cell-free extract (CFE). (43,44) Consequently, IR-09 was purified, and reactions were performed with pure IR-09 in the absence of GDH; under these conditions, no alcohol formation was observed, thereby confirming the excellent chemoselectivity of IR-09. (Supplementary Figure S8).
Unfortunately, none of the active enzymes generated the desired diastereomer (S,S,S)-3 (Table 1). In fact, all of the hits preferentially yielded the trans-diastereomers (S,S,R)-3 and (R,R,S)-3 as the major products, as shown by chiral supercritical fluid chromatography (SFC) (Figure 2). For example, IR-09 gave 96% conversion to predominantly a mixture of (S,S,R)-3 and (R,R,S)-3 (expressed as 85% de trans) with a small amount of (R,R,R)-3 of high ee (99%). A phylogenetic tree was constructed to identify further homologues of IR-09 and IR-20 that might possess similar levels of activity but with altered diastereoselectivity. In total, eight homologues of IR-09 were screened and showed some activity, but none exhibited the desired diastereoselectivity.

Figure 2

Figure 2. (a) The four possible reductive amination products (S,S,S)-3, (R,R,R)-3, (S,S,R)-3, and (R,R,S)-3 derived from ketone (±)-2; (b) SFC chromatogram of the stereoisomers.

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Table 1. Active Enzymes for the Reductive Amination of (±)-2 with Allylamine 1a
IREDconversion (%)de trans (%)ee (R,R,R) (%)
IR-09968599
IR-16899399
IR-20473499
IR-615399 
IR-202729299
IR-3612999 
a

All enzymes yielded (S,S,R)-3 and (R,R,S)-3 as the major diastereomers. Reaction conditions: 10 mM rac-2, 10 amine equiv of 1, 4 mg mL–1 of imine reductase cell-free extract (IRED CFE), 0.5 mg mL–1 of glucose dehydrogenase (GDH), 40 mM glucose, 5% v/v of DMSO, 100 mM Tris buffer pH 8. See the Supporting Information Section 4 for equations details.

In order to gain access to the desired diastereomer, we therefore considered engineering one of our active hits. It was decided to initially explore a structure-guided approach in order to alter the stereoselectivity of IR-09.
Clearly, the major challenge for protein engineering of IR-09 was to generate variants with both high kinetic selectivity for the ketone enantiomer [i.e., preference for reaction of (S,S)-2 over (R,R)-2], as well as high stereoselectivity for the reductive amination step [i.e., preference for formation of (S,S,S)-2 over (S,S,R)-2] (Figure 2a). Encouragingly, previous studies have shown that RedAms can be engineered for high kinetic selectivity for racemic amines. (5)
Since IR-09 exhibited higher activity than the other enzyme hits, this enzyme was selected as the backbone for engineering. A structure-guided mutagenesis approach was developed around the principle that the diastereoselectivity and enantioselectivity of the enzyme would be based on the orientation of the substrate in the active site. A crystal structure of IR-09 was available and used to identify activity site residues that could potentially play a key role in determining the stereoselectivity of the reaction.
The crystal structure of IR-09 contained a monomer in the asymmetric unit with the biological dimer being generated through crystallographic symmetry (see the Supporting Information Section 9 for details.). The crystal structure was obtained as a ternary complex with NADPH and N-cyclopropylcyclohexanamine. N-Cyclopropylcyclohexanamine is a considerably smaller ligand than 3, thus AutoDock Vina (45) flexible docking was performed to find a suitable pose for 3. Amino acid residues within 5 Å of the substrate were selected and allowed to freely rotate. Thereafter, the active site containing the imine intermediate was studied, and residues having a potential influence on the orientation of the ligand were identified (Figure 3). W204 was found at a distance of 3.6 Å from the ligand, and a similar situation was observed for M233 and Q234, which were at 3.7 and 3.4 Å, respectively. These observations were consistent with previous experience of corresponding residues in different RedAms. (37) A multiple sequence alignment was performed and used to confirm that these three residues were conserved across all hits and in AspRedAm.

Figure 3

Figure 3. (a) Crystal structure of IRED-09 (purple) in complex with NADPH (pink) and N-cyclopropylcyclohexanamine; there is only one molecule in the asymmetric unit. (b) IR-09 biological dimer. (c) Active site of IR-09 with the imine intermediate of 3 modeled into the active site showing distances (Å) from C4 of the nicotinamide ring of NAPDH and (B) W204 to the electrophilic carbon of the ligand. (d) The view is rotated 180 deg to observe the active site from the opposite perspective and show distances from (B) M233 and (B) Q234 to the ligand.

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As a result of these docking studies, amino acid residues W204, M233, and Q234 were targeted for site-directed mutagenesis (SDM) with either alanine or serine as the initial replacements. W204A and W204S were identified as the most promising variants (Table S2 and Supplementary Figures S10 and S11) since they both gave rise to a partial increase in diastereoselectivity for the cis diastereomer and, most importantly, they both generated the previously unobserved (S,S,S)-enantiomer. Assignment of the absolute configuration of all four diastereomers of 3 was established by visible circular dichroism (VCD) (see the Supporting Information Section 15). Variants M233A and Q234A also exhibited a change in diastereoselectivity, but both of these enzymes continued to favor the formation of the undesired trans diastereomers.
Since both IR-09 W204 variants still generated considerable amounts of the (S,S,R)-enantiomer (Figure 4a), site saturation mutagenesis (SSM) was performed in order to obtain a variant with higher selectivity. Three new variants were identified that generated the (S,S,S)-enantiomer, namely W204L, W204R, and W204G. Among these variants, IR-09 W204R exhibited the highest selectivity for the (S,S,S)-enantiomer, with 45% S,S,S yield. In contrast, W204L resulted in a decrease in enantioselectivity to lower levels than those of either W204A or W204S.

Figure 4

Figure 4. (a) SFC chromatograms comparing the isomer production of IR-09 WT, the best SDM variant, and the best SSM variant (peak at rt = 4.4. min corresponds to the alcohol). (b) Comparison between WT and the best variants for the production of (S,S,S)-3. Conversion to (S,S,S)-3 (%) = (S,S,S) yield × conversion.

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The relative activity of these new variants was also assessed. Previously, all reactions were performed with a large excess of amine (10 equiv). Screening at a lower amine concentration (1 equiv) revealed that IR-09 WT, IR-09 W204S, and IR-09 W204R all exhibited good levels of activity, especially W204R, which yielded 60% conversion (Supplementary Figure S1). Most variants and WT enzymes exhibited similar degrees of enantioselectivity toward the (R,R)- and (S,S)-2 ketone, since the differences between the amount of (S,S,S) and (S,S,R) in comparison with the amount of (R,R,R) and (R,R,S) formed was always below 2%.
IR-09 W204G is clearly selective for the (S,S)-ketone and was the first variant identified to achieve selective reductive amination while simultaneously performing a kinetic resolution of the starting material. Variant W204G yielded an (S,S,S) yield of 56% with 75% conversion (Table 2 and Supplementary Figure S16).
Table 2. Characterization of WT and IR-09 Variants with Respect to Both the Diastereoselectivity and Enantioselectivitya
IR-09conversion (%)de cis (%)ee (S,S,S) (%)S,S,S yield (%)
WT96–85 0
W204L89–478519
W204A92–486421
W204S93–398028
W204G75159656
W204R93–99545
a

Reaction conditions: 10 mM rac-2, 10 amine equiv of 1, 4 mg mL–1 of IRED CFE, 0.5 mg mL–1 of GDH, 40 mM glucose, 5% v/v of DMSO, 100 mM Tris buffer pH 8. See the Supporting Information Section 4 for equation details.

Finally, preparative biotransformations were carried out to assess the scalability of the reductive amination process. IR-09 W204R was selected for a 50 mL scale reaction, which was carried out on an EasyMax system (Mettler Toledo). The reactions resulted in 91% conversion and yielded the same distribution of stereoisomers as the analytical scale reactions [ee of (S,S,S)-3 = 95%]. The product mixture was extracted with methyl tert-butyl ether (MTBE) and subsequently purified by preparative supercritical fluid chromatography (SFC) to yield pure stereoisomers of amine 3, which were characterized by NMR and mass spectrometry (Supplementary Section 15). Finally, deallylation of (S,S,S)-3 was performed with Pd(dba)2 and DPPB in THF for 2 h followed by extraction with EtOAc to yield the target N-tosyl-protected amine product (S,S,S)-4 in 73% yield as a colorless oil (Supporting Information Sections 13 and 16).

Conclusions

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In summary, we have demonstrated that biocatalysis is a powerful tool to enable the production of difficult to access complex chiral amine building blocks for drug design. In this context, structure-guided mutagenesis proved to be a rapid way of tuning the selectivity of the wild-type biocatalyst for the synthesis of a target molecule with multiple stereocenters. Both the stereoselectivity and stereospecificity of the enzyme were further improved by saturating a key active site residue, which enabled reductive amination with concomitant kinetic resolution. The engineered enzyme retained high levels of conversion and selectivity on a preparative scale, thereby showing the potential for further evolution for early chemical development.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c07010.

  • Experimental section, including general information, experimental procedures, enzyme and primers sequences, chromatograms of biotransformations, and characterization of compounds (PDF)

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Author Information

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  • Corresponding Author
  • Authors
    • Arnau Rué Casamajo - Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester M1 7DN, United Kingdom;  Orcidhttps://orcid.org/0000-0001-8932-8763
    • Yuqi Yu - Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester M1 7DN, United Kingdom
    • Christian Schnepel - School of Engineering Sciences in Chemistry, Biotechnology and Health, Department of Industrial Biotechnology, KTH Royal Institute of Technology, AlbaNova University Center, 11421 Stockholm, Sweden;  Orcidhttps://orcid.org/0000-0002-4331-2675
    • Charlotte Morrill - Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester M1 7DN, United Kingdom
    • Rhys Barker - Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester M1 7DN, United Kingdom
    • Colin W. Levy - Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester M1 7DN, United Kingdom
    • James Finnigan - Prozomix Ltd, Building 4, West End Ind. Estate, Haltwhistle NE49 9HA, United Kingdom
    • Victor Spelling - Early Chemical Development, Pharmaceutical Sciences, Biopharmaceuticals R&D, AstraZeneca, Mölndal, 431 50 Gothenburg, Sweden;  Orcidhttps://orcid.org/0000-0001-5976-8047
    • Kristina Westerlund - Medicinal Chemistry, Research and Early Development; Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, Mölndal, 431 50 Gothenburg Sweden
    • Mark Petchey - Compound Synthesis and Management, Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Mölndal, 431 50 Gothenburg, Sweden
    • Robert J. Sheppard - Medicinal Chemistry, Research and Early Development; Cardiovascular, Renal and Metabolism, Biopharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, Mölndal, 431 50 Gothenburg Sweden
    • Richard J. Lewis - Department of Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, 43183 Mölndal, Sweden;  Orcidhttps://orcid.org/0000-0001-9404-8520
    • Francesco Falcioni - Early Chemical Development, Pharmaceutical Sciences, Biopharmaceuticals R&D, AstraZeneca, CB21 6GP Cambridge, United Kingdom
    • Martin A. Hayes - Compound Synthesis and Management, Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Mölndal, 431 50 Gothenburg, Sweden;  Orcidhttps://orcid.org/0000-0002-2640-8464
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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N.J.T. is grateful to the ERC for the award of an Advanced Grant (Grant no. 742987). A.R.C., Y.Y., C.S., and C.M. are supported by the EPSRC, BBSRC, and AstraZeneca (EP/S005226/1).

References

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    Nature Catalysis (2021), 4 (9), 775-782CODEN: NCAACP; ISSN:2520-1158. (Nature Portfolio)
    Abstr.: Enzymic reductive amination, being a direct, selective and green methodol., has attracted significant interest in a short period of time and is emerging as a powerful tool for the synthesis of chiral alkylated amines. The discovery of an increasing no. of imine reductases with reductive aminase (RedAm) activity has enabled mechanistic and substrate profiling studies. However, their potential for com. applications has not been realized. Here, we report the discovery of RedAm activity in an imine reductase enzyme for the direct reductive amination of a cyclic ketone with methylamine. We also investigate engineering the enzyme to access a cis-cyclobutyl-N-methylamine for the manufg. of a late-stage drug candidate, Janus kinase 1 (JAK1) inhibitor abrocitinib. The engineered enzyme, SpRedAm-R3-V6, showed >200-fold improvement in performance over the wild-type enzyme and was successfully used to develop a com. manufg. process with 73% isolated yield at 99.5% purity and high selectivity (>99:1 cis:trans). This process has been successfully used to manuf. multi-metric tons of the amine, demonstrating the potential of RedAm technol. for com. manufg. [graphic not available: see fulltext].
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  5. 5
    Schober, M.; MacDermaid, C.; Ollis, A. A.; Chang, S.; Khan, D.; Hosford, J.; Latham, J.; Ihnken, L. A. F.; Brown, M. J. B.; Fuerst, D.; Sanganee, M. J.; Roiban, G. D. Chiral Synthesis of LSD1 Inhibitor GSK2879552 Enabled by Directed Evolution of an Imine Reductase. Nat. Catal. 2019, 2 (10), 909– 915,  DOI: 10.1038/s41929-019-0341-4
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    Chiral synthesis of LSD1 inhibitor GSK2879552 enabled by directed evolution of an imine reductase
    Schober, Markus; MacDermaid, Chris; Ollis, Anne A.; Chang, Sandy; Khan, Diluar; Hosford, Joseph; Latham, Jonathan; Ihnken, Leigh Anne F.; Brown, Murray J. B.; Fuerst, Douglas; Sanganee, Mahesh J.; Roiban, Gheorghe-Doru
    Nature Catalysis (2019), 2 (10), 909-915CODEN: NCAACP; ISSN:2520-1158. (Nature Research)
    Imine reductases catalyze the reductive amination of aldehydes or ketones with amines to produce chiral amines-a key transformation in the prepn. of fine chems. and active pharmaceutical ingredients. Although significant progress has been recently made in the field, their industrial application has not been demonstrated. Herein, we describe a wild-type imine reductase that was engineered to perform reductive amination with concomitant substrate amine resoln. to give a com. relevant manufg. process to lysine-specific demethylase-1 inhibitor GSK2879552. Three rounds of evolution resulted in an enzyme variant showing a >38,000-fold improvement over wild type. The engineering of a more stable and active enzyme variant enabled process optimization to an economic, high quality and sustainable operating space. Using the evolved enzyme, kilogram quantities of a key intermediate to GSK2879552 were produced in 84% yield, at 99.9% purity and >99.7% enantiomeric excess, with improved process mass intensity.
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  6. 6
    Savile, C. K.; Janey, J. M.; Mundorff, E. C.; Moore, J. C.; Tam, S.; Jarvis, W. R.; Colbeck, J. C.; Krebber, A.; Fleitz, F. J.; Brands, J.; Devine, P. N.; Huisman, G. W.; Hughes, G. J. Biocatalytic Asymmetric Synthesis of Sitagliptin Manufacture. Science (80-.) 2010, 329 (July), 305– 310,  DOI: 10.1126/science.1188934
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    Adams, J. P.; Brown, M. J. B.; Diaz-Rodriguez, A.; Lloyd, R. C.; Roiban, G. D. Biocatalysis: A Pharma Perspective. Adv. Synth. Catal. 2019, 361 (11), 2421– 2432,  DOI: 10.1002/adsc.201900424
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    Biocatalysis: A Pharma Perspective
    Adams, Joseph P.; Brown, Murray J. B.; Diaz-Rodriguez, Alba; Lloyd, Richard C.; Roiban, Gheorghe-Doru
    Advanced Synthesis & Catalysis (2019), 361 (11), 2421-2432CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Biocatalysis over the past few years has matured into an essential tool for modern, cost effective and sustainable pharmaceutical manufg. While some reaction classes are well established, and may even be the option of first intent, other more recently discovered enzyme classes are being rapidly developed both in academia and industry. Notwithstanding this, there are further promising enzymes that require further investment and investigation to allow their future industrial use. We here outline GlaxoSmithKline's perspective on the current status of biocatalysis for pharmaceutical manufg. and provide our views on areas of significant potential.
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    Romero, E.; Jones, B. S.; Hogg, B. N.; Rué Casamajo, A.; Hayes, M. A.; Flitsch, S. L.; Turner, N. J.; Schnepel, C. Enzymatic Late-Stage Modifications: Better Late Than Never. Angew. Chemie - Int. Ed. 2021, 60 (31), 16824– 16855,  DOI: 10.1002/anie.202014931
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    Enzymatic Late-Stage Modifications: Better Late Than Never
    Romero, Elvira; Jones, Bethan S.; Hogg, Bethany N.; Rue Casamajo, Arnau; Hayes, Martin A.; Flitsch, Sabine L.; Turner, Nicholas J.; Schnepel, Christian
    Angewandte Chemie, International Edition (2021), 60 (31), 16824-16855CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Enzyme catalysis is gaining increasing importance in synthetic chem. Nowadays, the growing no. of biocatalysts accessible by means of bioinformatics and enzyme engineering opens up an immense variety of selective reactions. Biocatalysis esp. provides excellent opportunities for late-stage modification often superior to conventional de novo synthesis. Enzymes have proven to be useful for direct introduction of functional groups into complex scaffolds, as well as for rapid diversification of compd. libraries. Particularly important and highly topical are enzyme-catalyzed oxyfunctionalisations, halogenations, methylations, redns., and amide bond formations due to the high prevalence of these motifs in pharmaceuticals. This Review gives an overview of the strengths and limitations of enzymic late-stage modifications using native and engineered enzymes in synthesis while focusing on important examples in drug development.
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  9. 9
    Hendrick, C. E.; Jorgensen, J. R.; Chaudhry, C.; Strambeanu, I. I.; Brazeau, J. F.; Schiffer, J.; Shi, Z.; Venable, J. D.; Wolkenberg, S. E. Direct-to-Biology Accelerates PROTAC Synthesis and the Evaluation of Linker Effects on Permeability and Degradation. ACS Med. Chem. Lett. 2022, 13 (7), 1182– 1190,  DOI: 10.1021/acsmedchemlett.2c00124
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    Direct-to-Biology Accelerates PROTAC Synthesis and the Evaluation of Linker Effects on Permeability and Degradation
    Hendrick, Charles E.; Jorgensen, Jeff R.; Chaudhry, Charu; Strambeanu, Iulia I.; Brazeau, Jean-Francois; Schiffer, Jamie; Shi, Zhicai; Venable, Jennifer D.; Wolkenberg, Scott E.
    ACS Medicinal Chemistry Letters (2022), 13 (7), 1182-1190CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
    A platform to accelerate optimization of proteolysis targeting chimeras (PROTACs) had been developed using a direct-to-biol. (D2B) approach with a focus on linker effects. A large no. of linker analogs-varying length, polarity, and rigidity-were rapidly prepd. and characterized in four cell-based assays by streamlining time-consuming steps in synthesis and purifn. The expansive data set informs on linker structure activity relationships for in-cell E3 ligase target engagement, degrdn., permeability, and cell toxicity. Unexpected aspects of linker SAR were discovered, consistent with literature reports on "linkerol.", and the method dramatically speeds up empirical optimization. Physicochem. property trends emerged, and the platform had the potential to rapidly expand training sets for more complex prediction models. In-depth validation studies were carried out and confirm the D2B platform was a valuable tool to accelerate PROTAC design-make-test cycles.
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  10. 10
    Fryszkowska, A.; An, C.; Alvizo, O.; Banerjee, G.; Canada, K. A.; Cao, Y.; DeMong, D.; Devine, P. N.; Duan, D.; Elgart, D. M.; Farasat, I.; Gauthier, D. R.; Guidry, E. N.; Jia, X.; Kong, J.; Kruse, N.; Lexa, K. W.; Makarov, A. A.; Mann, B. F.; Milczek, E. M.; Mitchell, V.; Nazor, J.; Neri, C.; Orr, R. K.; Orth, P.; Phillips, E. M.; Riggins, J. N.; Schafer, W. A.; Silverman, S. M.; Strulson, C. A.; Subramanian, N.; Voladri, R.; Yang, H.; Yang, J.; Yi, X.; Zhang, X.; Zhong, W. A Chemoenzymatic Strategy for Site-Selective Functionalization of Native Peptides and Proteins. Science (80-.) 2022, 376 (6599), 1321– 1327,  DOI: 10.1126/science.abn2009
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    Rodríguez, D. F.; Moglie, Y.; Ramírez-Sarmiento, C. A.; Singh, S. K.; Dua, K.; Zacconi, F. C. Bio-Click Chemistry: A Bridge between Biocatalysis and Click Chemistry. RSC Adv. 2022, 12 (4), 1932– 1949,  DOI: 10.1039/D1RA08053A
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    Bio-click chemistry: a bridge between biocatalysis and click chemistry
    Rodriguez, Diego F.; Moglie, Yanina; Ramirez-Sarmiento, Cesar A.; Singh, Sachin Kumar; Dua, Kamal; Zacconi, Flavia C.
    RSC Advances (2022), 12 (4), 1932-1949CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
    A review. The fields of click chem. and biocatalysis have rapidly grown over the last two decades. The development of robust and active biocatalysts and the widespread use of straightforward click reactions led to significant interactions between these two fields. Therefore the name bio-click chem. seems to be an accurate definition of chemoenzymic reactions cooperating with click transformations. Bio-click chem. can be understood as the approach towards mols. of high-value using a green and sustainable approach by exploiting the potential of biocatalytic enzyme activity combined with the reliable nature of click reactions. This review summarizes the principal bio-click chem. reactions reported over the last two decades, with a special emphasis on small mols. Contributions to the field of bio-click chem. are manifold, but the synthesis of chiral mols. with applications in medicinal chem. and sustainable syntheses will be esp. highlighted.
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    Pessatti, T. B.; Terenzi, H.; Bertoldo, J. B. Protein Modifications: From Chemoselective Probes to Novel Biocatalysts. Catalysts 2021, 11 (12), 1466,  DOI: 10.3390/catal11121466
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    Protein Modifications: From Chemoselective Probes to Novel Biocatalysts
    Pessatti, Tomas Bohn; Terenzi, Hernan; Bertoldo, Jean Borges
    Catalysts (2021), 11 (12), 1466CODEN: CATACJ; ISSN:2073-4344. (MDPI AG)
    Chem. reactions can be performed to covalently modify specific residues in proteins. When applied to native enzymes, these chem. modifications can greatly expand the available set of building blocks for the development of biocatalysts. Nucleophilic canonical amino acid sidechains are the most readily accessible targets for such endeavors. A rich history of attempts to design enhanced or novel enzymes, from various protein scaffolds, has paved the way for a rapidly developing field with growing scientific, industrial, and biomedical applications. A major challenge is to devise reactions that are compatible with native proteins and can selectively modify specific residues. Cysteine, lysine, N-terminus, and carboxylate residues comprise the most widespread naturally occurring targets for enzyme modifications. In this review, chem. methods for selective modification of enzymes will be discussed, alongside with examples of reported applications. We aim to highlight the potential of such strategies to enhance enzyme function and create novel semisynthetic biocatalysts, as well as provide a perspective in a fast-evolving topic.
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    Boutureira, O.; Bernardes, G. J. L. Advances in Chemical Protein Modification. Chem. Rev. 2015, 115 (5), 2174– 2195,  DOI: 10.1021/cr500399p
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    Advances in Chemical Protein Modification
    Boutureira, Omar; Bernardes, Goncalo J. L.
    Chemical Reviews (Washington, DC, United States) (2015), 115 (5), 2174-2195CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review. Transition metal-free and -mediated approaches are covered.
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    Fryszkowska, A.; Devine, P. N. Biocatalysis in Drug Discovery and Development. Curr. Opin. Chem. Biol. 2020, 55, 151– 160,  DOI: 10.1016/j.cbpa.2020.01.012
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    Biocatalysis in drug discovery and development
    Fryszkowska, Anna; Devine, Paul N.
    Current Opinion in Chemical Biology (2020), 55 (), 151-160CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)
    A review. Enzyme catalysis, enabled by advances in protein engineering and directed evolution, is beginning to transform chem. synthesis in the pharmaceutical industry. This review presents recent examples of the creative use of biocatalysis to enable drug discovery and development. We illustrate how increased access to novel biotransformations and the rise of cascade biocatalysis allowed fundamentally new syntheses of novel medicines, representing progress toward more sustainable pharmaceutical manufg. Finally, we describe the opportunities and challenges the industry must address to ensure the redn. to practice of biotechnol. innovations to develop new therapies in a faster, more economical, and environmentally benign way.
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    Devine, P. N.; Howard, R. M.; Kumar, R.; Thompson, M. P.; Truppo, M. D.; Turner, N. J. Extending the Application of Biocatalysis to Meet the Challenges of Drug Development. Nat. Rev. Chem. 2018, 2 (12), 409– 421,  DOI: 10.1038/s41570-018-0055-1
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    Brown, D. G.; Boström, J. Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?. J. Med. Chem. 2016, 59 (10), 4443– 4458,  DOI: 10.1021/acs.jmedchem.5b01409
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    Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?
    Brown, Dean G.; Bostrom, Jonas
    Journal of Medicinal Chemistry (2016), 59 (10), 4443-4458CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A review. An anal. of chem. reactions used in current medicinal chem. (2014), three decades ago (1984), and in natural product total synthesis has been conducted. The anal. revealed that of the current most frequently used synthetic reactions, none were discovered within the past 20 years and only two in the 1980s and 1990s (Suzuki-Miyaura and Buchwald-Hartwig). This suggests an inherent high bar of impact for new synthetic reactions in drug discovery. The most frequently used reactions were amide bond formation, Suzuki-Miyaura coupling, and SNAr reactions, most likely due to com. availability of reagents, high chemoselectivity, and a pressure on delivery. The authors show that these practices result in overpopulation of certain types of mol. shapes to the exclusion of others using simple PMI plots. The authors hope that these results will help catalyze improvements in integration of new synthetic methodologies as well as new library design.
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    Saldívar-González, F. I.; Aldas-Bulos, V. D.; Medina-Franco, J. L.; Plisson, F. Natural Product Drug Discovery in the Artificial Intelligence Era. Chem. Sci. 2022, 13 (6), 1526– 1546,  DOI: 10.1039/D1SC04471K
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    Natural product drug discovery in the artificial intelligence era
    Saldivar-Gonzalez, F. I.; Aldas-Bulos, V. D.; Medina-Franco, J. L.; Plisson, F.
    Chemical Science (2022), 13 (6), 1526-1546CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    Natural products (NPs) are primarily recognized as privileged structures to interact with protein drug targets. Their unique characteristics and structural diversity continue to marvel scientists for developing NP-inspired medicines, even though the pharmaceutical industry has largely given up. High-performance computer hardware, extensive storage, accessible software and affordable online education have democratized the use of artificial intelligence (AI) in many sectors and research areas. The last decades have introduced natural language processing and machine learning algorithms, two subfields of AI, to tackle NP drug discovery challenges and open up opportunities. In this article, we review and discuss the rational applications of AI approaches developed to assist in discovering bioactive NPs and capturing the mol. "patterns" of these privileged structures for combinatorial design or target selectivity.
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    Ertl, P. Substituents of Life: The Most Common Substituent Patterns Present in Natural Products. Bioorg. Med. Chem. 2022, 54, 116562  DOI: 10.1016/j.bmc.2021.116562
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    Substituents of life: The most common substituent patterns present in natural products
    Ertl, Peter
    Bioorganic & Medicinal Chemistry (2022), 54 (), 116562CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    Comparison of substituents present in natural products with the substituents found in av. synthetic mols. reveals considerable differences between these two groups. The natural products substituents contain mostly oxygen heteroatoms, are structurally more complex, often contg. double bonds and are rich in stereocenters. Substituents found in synthetic mols. contain nitrogen and sulfur heteroatoms, halogenes and more arom. and particularly heteroarom. rings. The characteristics of substituents typical for natural products identified here can be useful in the medicinal chem. context, for example to guide the synthesis of natural product-like libraries and natural product-inspired fragment collections. The results may be used also to support compd. derivatization strategies and the design of pseudo-natural natural products.
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    Volochnyuk, D. M.; Ryabukhin, S. V.; Moroz, Y. S.; Savych, O.; Chuprina, A.; Horvath, D.; Zabolotna, Y.; Varnek, A.; Judd, D. B. Evolution of Commercially Available Compounds for HTS. Drug Discovery Today 2019, 24 (2), 390– 402,  DOI: 10.1016/j.drudis.2018.10.016
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    Evolution of commercially available compounds for HTS
    Volochnyuk, Dmitriy M.; Ryabukhin, Sergey V.; Moroz, Yurii S.; Savych, Olena; Chuprina, Alexander; Horvath, Dragos; Zabolotna, Yuliana; Varnek, Alexandre; Judd, Duncan B.
    Drug Discovery Today (2019), 24 (2), 390-402CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)
    A review. Over recent years, an industry of compd. suppliers has grown to provide drug discovery with screening compds.: it is estd. that there are over 16 million compds. available from these sources. Here, we review the chem. space covered by suppliers' compd. libraries (SCL) in terms of compd. physicochem. properties, novelty, diversity, and quality. We examine the feasibility of compiling high-quality vendor-based libraries avoiding complicated, expensive compd. management activity, and compare the resulting libraries to the ChEMBL data set. We also consider how vendors have responded to the evolving requirements for drug discovery.
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    Tomberg, A.; Boström, J. Can Easy Chemistry Produce Complex, Diverse, and Novel Molecules?. Drug Discovery Today 2020, 25 (12), 2174– 2181,  DOI: 10.1016/j.drudis.2020.09.027
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    Can easy chemistry produce complex, diverse, and novel molecules
    Tomberg, Anna; Bostroem, Jonas
    Drug Discovery Today (2020), 25 (12), 2174-2181CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)
    A review. Statements, such as you need to break free from amide-formations to improve mol. properties and novel chem. leads to novel biol. are frequently encountered in the medicinal chem. community. To verify whether truth lies in such preconceptions, we investigated whether complex, diverse, and novel mols. can be made by easy chem. By analyzing the AstraZeneca screening collection, we conclude that novelty, diversity, and mol. complexity is currently not compromised by the use of the most popular reaction, amide bond formation, mainly because of a recent steady increase in unique amines available. Easy chem. allows speedy access to a broad chem. space, facilitating progress in projects, and opens the possibility of synthesis automation and new technologies, such as DNA-encoded libraries.
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    France, S. P.; Lewis, R. D.; Martinez, C. A. The Evolving Nature of Biocatalysis in Pharmaceutical Research and Development. JACS Au 2023, 3 (3), 715– 735,  DOI: 10.1021/jacsau.2c00712
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    The Evolving Nature of Biocatalysis in Pharmaceutical Research and Development
    France, Scott P.; Lewis, Russell D.; Martinez, Carlos A.
    JACS Au (2023), 3 (3), 715-735CODEN: JAAUCR; ISSN:2691-3704. (American Chemical Society)
    A review. Biocatalysis is a highly valued enabling technol. for pharmaceutical research and development as it can unlock synthetic routes to complex chiral motifs with unparalleled selectivity and efficiency. This perspective aims to review recent advances in the pharmaceutical implementation of biocatalysis across early and late-stage development with a focus on the implementation of processes for preparative-scale syntheses.
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    Benkovics, T.; Peng, F.; Phillips, E. M.; An, C.; Bade, R. S.; Chung, C. K.; Dance, Z. E. X.; Fier, P. S.; Forstater, J. H.; Liu, Z.; Liu, Z.; Maligres, P. E.; Marshall, N. M.; Salehi Marzijarani, N.; McIntosh, J. A.; Miller, S. P.; Moore, J. C.; Neel, A. J.; Obligacion, J. V.; Pan, W.; Pirnot, M. T.; Poirier, M.; Reibarkh, M.; Sherry, B. D.; Song, Z. J.; Tan, L.; Turnbull, B. W. H.; Verma, D.; Waldman, J. H.; Wang, L.; Wang, T.; Winston, M. S.; Xu, F. Diverse Catalytic Reactions for the Stereoselective Synthesis of Cyclic Dinucleotide MK-1454. J. Am. Chem. Soc. 2022, 144 (13), 5855– 5863,  DOI: 10.1021/jacs.1c12106
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    22
    Diverse Catalytic Reactions for the Stereoselective Synthesis of Cyclic Dinucleotide MK-1454
    Benkovics, Tamas; Peng, Feng; Phillips, Eric M.; An, Chihui; Bade, Rachel S.; Chung, Cheol K.; Dance, Zachary E. X.; Fier, Patrick S.; Forstater, Jacob H.; Liu, Zhijian; Liu, Zhuqing; Maligres, Peter E.; Marshall, Nicholas M.; Salehi Marzijarani, Nastaran; McIntosh, John A.; Miller, Steven P.; Moore, Jeffrey C.; Neel, Andrew J.; Obligacion, Jennifer V.; Pan, Weilan; Pirnot, Michael T.; Poirier, Marc; Reibarkh, Mikhail; Sherry, Benjamin D.; Song, Zhiguo Jake; Tan, Lushi; Turnbull, Ben W. H.; Verma, Deeptak; Waldman, Jacob H.; Wang, Lu; Wang, Tao; Winston, Matthew S.; Xu, Feng
    Journal of the American Chemical Society (2022), 144 (13), 5855-5863CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    As practitioners of org. chem. strive to deliver efficient syntheses of the most complex natural products and drug candidates, further innovations in synthetic strategies are required to facilitate their efficient construction. These aspirational breakthroughs often go hand-in-hand with considerable redns. in cost and environmental impact. Enzyme-catalyzed reactions have become an impressive and necessary tool that offers benefits such as increased selectivity and waste limitation. These benefits are amplified when enzymic processes are conducted in a cascade in combination with novel bond-forming strategies. In this article, we report a highly diastereoselective synthesis of MK-1454, a potent agonist of the stimulator of interferon gene (STING) signaling pathway. The synthesis begins with the asym. construction of two fluoride-bearing deoxynucleotides. The routes were designed for max. convergency and selectivity, relying on the same benign electrophilic fluorinating reagent. From these complex subunits, four enzymes are used to construct the two bridging thiophosphates in a highly selective, high yielding cascade process. Crit. to the success of this reaction was a thorough understanding of the role transition metals play in bond formation.
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    McIntosh, J. A.; Liu, Z.; Andresen, B. M.; Marzijarani, N. S.; Moore, J. C.; Marshall, N. M.; Borra-Garske, M.; Obligacion, J. V.; Fier, P. S.; Peng, F.; Forstater, J. H.; Winston, M. S.; An, C.; Chang, W.; Lim, J.; Huffman, M. A.; Miller, S. P.; Tsay, F. R.; Altman, M. D.; Lesburg, C. A.; Steinhuebel, D.; Trotter, B. W.; Cumming, J. N.; Northrup, A.; Bu, X.; Mann, B. F.; Biba, M.; Hiraga, K.; Murphy, G. S.; Kolev, J. N.; Makarewicz, A.; Pan, W.; Farasat, I.; Bade, R. S.; Stone, K.; Duan, D.; Alvizo, O.; Adpressa, D.; Guetschow, E.; Hoyt, E.; Regalado, E. L.; Castro, S.; Rivera, N.; Smith, J. P.; Wang, F.; Crespo, A.; Verma, D.; Axnanda, S.; Dance, Z. E. X.; Devine, P. N.; Tschaen, D.; Canada, K. A.; Bulger, P. G.; Sherry, B. D.; Truppo, M. D.; Ruck, R. T.; Campeau, L. C.; Bennett, D. J.; Humphrey, G. R.; Campos, K. R.; Maddess, M. L. A Kinase-CGAS Cascade to Synthesize a Therapeutic STING Activator. Nat. 2022 6037901 2022, 603 (7901), 439– 444,  DOI: 10.1038/s41586-022-04422-9
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    Ertl, P.; Altmann, E.; Mckenna, J. M. The Most Common Functional Groups in Bioactive Molecules and How Their Popularity Has Evolved over Time. J. Med. Chem. 2020, 63 (15), 8408– 8418,  DOI: 10.1021/acs.jmedchem.0c00754
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    The Most Common Functional Groups in Bioactive Molecules and How Their Popularity Has Evolved over Time
    Ertl, Peter; Altmann, Eva; McKenna, Jeffrey M.
    Journal of Medicinal Chemistry (2020), 63 (15), 8408-8418CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    The concept of functional groups (FGs), sets of connected atoms that can det. the intrinsic reactivity of the parent mol. and in part are responsible for the overall properties of the mol., form a foundation within modern medicinal chem. In this Article, we analyze the occurrence of various FGs in mols. described in the medicinal chem. literature over the last 40 years and show how their development and utilization over time has varied. The popularity of various FGs has not evolved randomly, but instead, clear patterns of use are evident. Various factors influencing these patterns, including the introduction of new synthetic methods, novel techniques, and strategies applied in drug discovery and the better knowledge of mol. properties affecting the success of candidate development, are discussed.
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    Young, R. J.; Flitsch, S. L.; Grigalunas, M.; Leeson, P. D.; Quinn, R. J.; Turner, N. J.; Waldmann, H. The Time and Place for Nature in Drug Discovery. J. Am. Chem. Soc. 2022, 2 (11), 2400– 2416,  DOI: 10.1021/jacsau.2c00415
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    The Time and Place for Nature in Drug Discovery
    Young, Robert J.; Flitsch, Sabine L.; Grigalunas, Michael; Leeson, Paul D.; Quinn, Ronald J.; Turner, Nicholas J.; Waldmann, Herbert
    JACS Au (2022), 2 (11), 2400-2416CODEN: JAAUCR; ISSN:2691-3704. (American Chemical Society)
    A review. The case for a renewed focus on Nature in drug discovery is reviewed; not in terms of natural product screening, but how and why biomimetic mols., esp. those produced by natural processes, should deliver in the age of artificial intelligence and screening of vast collections both in vitro and in silico. The declining natural product-likeness of licensed drugs and the consequent physicochem. implications of this trend in the context of current practices are noted. To arrest these trends, the logic of seeking new bioactive agents with enhanced natural mimicry is considered; notably that mols. constructed by proteins (enzymes) are more likely to interact with other proteins (e.g., targets and transporters), a notion validated by natural products. Nature's finite no. of building blocks and their interactions necessarily reduce potential nos. of structures, yet these enable expansion of chem. space with their inherent diversity of phys. characteristics, pertinent to property-based design. The feasible variations on natural motifs are considered and expanded to encompass pseudo-natural products, leading to the further logical step of harnessing bioprocessing routes to access them. Together, these offer opportunities for enhancing natural mimicry, thereby bringing innovation to drug synthesis exploiting the characteristics of natural recognition processes. The potential for computational guidance to help identifying binding commonalities in the route map is a logical opportunity to enable the design of tailored mols., with a focus on "org./biol." rather than purely "synthetic" structures. The design and synthesis of prototype structures should pay dividends in the disposition and efficacy of the mols., while inherently enabling greener and more sustainable manufg. techniques.
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    Bauer, R. A.; Wurst, J. M.; Tan, D. S. Expanding the Range of ‘Druggable’ Targets with Natural Product-Based Libraries: An Academic Perspective. Curr. Opin. Chem. Biol. 2010, 14 (3), 308– 314,  DOI: 10.1016/j.cbpa.2010.02.001
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    Expanding the range of druggable' targets with natural product-based libraries: an academic perspective
    Bauer, Renato A.; Wurst, Jacqueline M.; Tan, Derek S.
    Current Opinion in Chemical Biology (2010), 14 (3), 308-314CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)
    A review. Existing drugs address a relatively narrow range of biol. targets. As a result, libraries of drug-like mols. have proven ineffective against a variety of challenging targets, such as protein-protein interactions, nucleic acid complexes, and antibacterial modalities. In contrast, natural products are known to be effective at modulating such targets, and new libraries are being developed based on underrepresented scaffolds and regions of chem. space assocd. with natural products. This has led to several recent successes in identifying new chem. probes that address these challenging targets.
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    Newman, D. J.; Cragg, G. M. Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019. J. Nat. Prod. 2020, 83 (3), 770– 803,  DOI: 10.1021/acs.jnatprod.9b01285
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    27
    Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019
    Newman, David J.; Cragg, Gordon M.
    Journal of Natural Products (2020), 83 (3), 770-803CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
    This review is an updated and expanded version of the five prior reviews that were published in this journal in 1997, 2003, 2007, 2012, and 2016. For all approved therapeutic agents, the time frame has been extended to cover the almost 39 years from the first of Jan. 1981 to the 30th of Sept. 2019 for all diseases worldwide and from ∼1946 (earliest so far identified) to the 30th of Sept. 2019 for all approved antitumor drugs worldwide. As in earlier reviews, only the first approval of any drug is counted, irresp. of how many "biosimilars" or added approvals were subsequently identified. As in the 2012 and 2016 reviews, we have continued to utilize our secondary subdivision of a "natural product mimic", or "NM", to join the original primary divisions, and the designation "natural product botanical", or "NB", to cover those botanical "defined mixts." now recognized as drug entities by the FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or synthetic variations using their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over the time frame from 1946 to 1980, of the 75 small mols., 40, or 53.3%, are N or ND. In the 1981 to date time frame the equiv. figures for the N* compds. of the 185 small mols. are 62, or 33.5%, though to these can be added the 58 S* and S*/NMs, bringing the figure to 64.9%. In other areas, the influence of natural product structures is quite marked with, as expected from prior information, the anti-infective area being dependent on natural products and their structures, though as can be seen in the review there are still disease areas (shown in Table 2) for which there are no drugs derived from natural products. Although combinatorial chem. techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are still able to identify only two de novo combinatorial compds. (one of which is a little speculative) approved as drugs in this 39-yr time frame, though there is also one drug that was developed using the "fragment-binding methodol." and approved in 2012. We have also added a discussion of candidate drug entities currently in clin. trials as "warheads" and some very interesting preliminary reports on sources of novel antibiotics from Nature due to the abs. requirement for new agents to combat plasmid-borne resistance genes now in the general populace. We continue to draw the attention of readers to the recognition that a significant no. of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated"; thus we consider that this area of natural product research should be expanded significantly.
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  28. 28
    Yao, P.; Xu, Z.; Yu, S.; Wu, Q.; Zhu, D. Imine Reductase-Catalyzed Enantioselective Reduction of Bulky α,B-Unsaturated Imines En Route to a Pharmaceutically Important Morphinan Skeleton. Adv. Synth. Catal. 2019, 361 (3), 556– 561,  DOI: 10.1002/adsc.201801326
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    28
    Imine Reductase-Catalyzed Enantioselective Reduction of Bulky α,β-Unsaturated Imines en Route to a Pharmaceutically Important Morphinan Skeleton
    Yao, Peiyuan; Xu, Zefei; Yu, Shanshan; Wu, Qiaqing; Zhu, Dunming
    Advanced Synthesis & Catalysis (2019), 361 (3), 556-561CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The morphinan skeleton is an important sub-structure in many medicines such as dextromethorphan, and can be constructed from 1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (1-benzyl-OHIQ) derivs. 1-Benzyl-3,4,5,6,7,8-hexahydroisoquinolines (1-benzyl-HHIQs), the precursors of 1-benzyl-OHIQs, constitute a type of bulky α, β-unsatd. imines. Until now, the application of imine reductases (IREDs) to α, β-unsatd. imines has only rarely been reported. In this study, through evaluation of 48 IREDs, both enantiomers of 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (1-(4-methoxybenzyl)-OHIQ) were obtained in high yield and excellent optical purity. Among the enzymes, the most steric hindrance-tolerant IRED from Sandarearacinus amylolyticus (IR40) was able to convert various Ph substituted 1-benzyl-HHIQ to the corresponding 1-benzyl-OHIQ derivs. with excellent enantiomeric excess. These results provide an effective route to synthesize these important compds. via enantioselective redn. of bulky α, β-unsatd. imine precursors, which can be readily prepd. from 2-(1-cyclohexenyl)ethylamine and corresponding aryl acetic acids.
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    Arnold, F. H. Directed Evolution: Bringing New Chemistry to Life. Angew. Chemie - Int. Ed. 2018, 57 (16), 4143– 4148,  DOI: 10.1002/anie.201708408
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    Directed evolution: Bringing new chemistry to life
    Arnold, Frances H.
    Angewandte Chemie, International Edition (2018), 57 (16), 4143-4148CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Directed evolution mimics evolution by artificial selection, and is accelerated in the lab. setting by focusing on individual genes expressed in fast-growing microorganisms. We start with existing proteins (sourced from Nature or engineered), introduce mutations, and then screen for the progeny proteins with enhanced activity (or other desirable traits). We use the improved enzymes as parents for the next round of mutation and screening, recombining beneficial mutations as needed, and continuing until we reach the target level of performance. Thus, the evolution of Nature's enzymes can lead to the discovery of new reactivity, transformations not known in biol., and reactivity inaccessible by small-mol. catalysis.
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  30. 30
    Aleku, G. A.; Man, H.; France, S. P.; Leipold, F.; Hussain, S.; Toca-Gonzalez, L.; Marchington, R.; Hart, S.; Turkenburg, J. P.; Grogan, G.; Turner, N. J. Stereoselectivity and Structural Characterization of an Imine Reductase (IRED) from Amycolatopsis Orientalis. ACS Catal. 2016, 6 (6), 3880– 3889,  DOI: 10.1021/acscatal.6b00782
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    30
    Stereoselectivity and structural characterization of an imine reductase (IRED) from Amycolatopsis orientalis
    Aleku, Godwin A.; Man, Henry; France, Scott P.; Leipold, Friedemann; Hussain, Shahed; Toca-Gonzalez, Laura; Marchington, Rebecca; Hart, Sam; Turkenburg, Johan P.; Grogan, Gideon; Turner, Nicholas J.
    ACS Catalysis (2016), 6 (6), 3880-3889CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    Imine reductase AoIRED from A. orientalis (Uniprot R4SNK4) catalyzes the NADPH-dependent redn. of a wide range of prochiral imines and iminium ions, predominantly with (S)-selectivity and with ee's of up to >99%. AoIRED displays up to 100-fold greater catalytic efficiency for 2-methyl-1-pyrroline (2MPN) compared to other IREDs, such as the enzyme from Streptomyces sp. GF3546, which also exhibits (S)-selectivity, and thus, AoIRED is an interesting candidate for preparative synthesis. AoIRED exhibits unusual catalytic properties, with inversion of stereoselectivity obsd. between structurally similar substrates, and also, in the case of 1-methyl-3,4-dihydroisoquinoline, for the same substrate, dependent on the age of the enzyme after purifn. The structure of AoIRED was detd. in an "open" apo-form, revealing a canonical dimeric IRED fold in which the active site is formed between the N- and C-terminal domains of participating monomers. Co-crystn. with NADPH gave a "closed" form in complex with the cofactor, in which a relative closure of domains, and assocd. loop movements, resulted in a much smaller active site. A ternary complex was also obtained by cocrystn. with NADPH and 1-methyl-1,2,3,4-tetrahydroisoquinoline, and it revealed a binding site for the (R)-amine product, which placed the chiral carbon within 4 Å of the putative location of the C4 atom of NADPH that delivers hydride to the C:N bond of the substrate. The ternary complex permitted structure-informed mutation of the active site, resulting in mutants including Y179A, Y179F, and N241A, of altered activity and stereoselectivity.
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    Gilio, A. K.; Thorpe, T. W.; Heyam, A.; Petchey, M. R.; Pogrányi, B.; France, S. P.; Howard, R. M.; Karmilowicz, M. J.; Lewis, R.; Turner, N.; Grogan, G. A Reductive Aminase Switches to Imine Reductase Mode for a Bulky Amine Substrate. ACS Catal. 2023, 13 (3), 1669– 1677,  DOI: 10.1021/acscatal.2c06066
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    A Reductive Aminase Switches to Imine Reductase Mode for a Bulky Amine Substrate
    Gilio, Amelia K.; Thorpe, Thomas W.; Heyam, Alex; Petchey, Mark R.; Pogranyi, Balazs; France, Scott P.; Howard, Roger M.; Karmilowicz, Michael J.; Lewis, Russell; Turner, Nicholas; Grogan, Gideon
    ACS Catalysis (2023), 13 (3), 1669-1677CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    Imine reductases (IREDs) catalyze the asym. redn. of cyclic imines, but also in some cases the coupling of ketones and amines to form secondary amine products in an enzyme-catalyzed reductive amination (RedAm) reaction. Enzymic RedAm reactions have typically used small hydrophobic amines, but many interesting pharmaceutical targets require that larger amines be used in these coupling reactions. Following the identification of IR77 from Ensifer adhaerens as a promising biocatalyst for the reductive amination of cyclohexanone with pyrrolidine, we have characterized the ability of this enzyme to catalyze couplings with larger bicyclic amines such as isoindoline and octahydrocyclopenta(c)pyrrole. By comparing the activity of IR77 with redns. using sodium cyanoborohydride in water, it was shown that, while the coupling of cyclohexanone and pyrrolidine involved at least some element of reductive amination, the amination with the larger amines likely occurred ex situ, with the imine recruited from soln. for enzyme redn. The structure of IR77 was detd., and using this as a basis, structure-guided mutagenesis, coupled with point mutations selecting improving amino acid sites suggested by other groups, permitted the identification of a mutant A208N with improved activity for amine product formation. Improvements in conversion were attributed to greater enzyme stability as revealed by X-ray crystallog. and nano differential scanning fluorimetry. The mutant IR77-A208N was applied to the preparative scale amination of cyclohexanone at 50 mM concn., with 1.2 equiv of three larger amines, in isolated yields of up to 93%.
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    Montgomery, S. L.; Pushpanath, A.; Heath, R. S.; Marshall, J. R.; Klemstein, U.; Galman, J. L.; Woodlock, D.; Bisagni, S.; Taylor, C. J.; Mangas-Sanchez, J.; Ramsden, J. I.; Dominguez, B.; Turner, N. J. Characterization of Imine Reductases in Reductive Amination for the Exploration of Structure-Activity Relationships. Sci. Adv. 2020, 6 (21), eaay9320  DOI: 10.1126/sciadv.aay9320
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    Grogan, G. Synthesis of Chiral Amines Using Redox Biocatalysis. Curr. Opin. Chem. Biol. 2018, 43, 15– 22,  DOI: 10.1016/j.cbpa.2017.09.008
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    Synthesis of chiral amines using redox biocatalysis
    Grogan, Gideon
    Current Opinion in Chemical Biology (2018), 43 (), 15-22CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)
    Chiral amines feature in a large no. of small mol. pharmaceuticals, and thus methods for their asym. synthesis are of considerable interest. Biocatalytic approaches have come to the fore in recent years as these offer advantages of superior atom economy, mild reaction conditions and excellent stereoselectivity. Advances in redox cofactor process technol. have meant that oxidoreductase enzymes in particular now have growing potential as industrial catalysts for amine formation. In this review we survey recent developments in the discovery and application of oxidoreductase enzymes for amine prodn., including Monoamine Oxidases (MAOs), engineered and natural Amine Dehydrogenases (AmDHs), Imine Reductases (IREDs) and Reductive Aminases (RedAms), in addn. to their application in enzyme cascades.
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    Sharma, M.; Mangas-Sanchez, J.; France, S. P.; Aleku, G. A.; Montgomery, S. L.; Ramsden, J. I.; Turner, N. J.; Grogan, G. A Mechanism for Reductive Amination Catalyzed by Fungal Reductive Aminases. ACS Catal. 2018, 8 (12), 11534– 11541,  DOI: 10.1021/acscatal.8b03491
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    A mechanism for reductive amination catalyzed by fungal reductive aminases
    Sharma, Mahima; Mangas-Sanchez, Juan; France, Scott P.; Aleku, Godwin A.; Montgomery, Sarah L.; Ramsden, Jeremy I.; Turner, Nicholas J.; Grogan, Gideon
    ACS Catalysis (2018), 8 (12), 11534-11541CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
    Reductive aminases (RedAms) catalyze the asym. reductive amination of ketones with primary amines to give secondary amine products. RedAms have great potential for the synthesis of bioactive chiral amines; however, insights into their mechanism are currently limited. Comparative studies on reductive amination of cyclohexanone with allylamine in the presence of RedAms, imine reductases (IREDs), or NaBH3CN support the distinctive activity of RedAms in catalyzing both imine formation and redn. in the reaction. Structures of AtRedAm from Aspergillus terreus, in complex with NADPH and ketone and amine substrates, along with kinetic anal. of active-site mutants, reveal modes of substrate binding, the basis for the specificity of RedAms for redn. of imines over ketones, and the importance of domain flexibility in bringing the reactive participants together for the reaction. This information is used to propose a mechanism for their action and also to expand the substrate specificity of RedAms using protein engineering.
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    Zumbrägel, N.; Machui, P.; Nonnhoff, J.; Gröger, H. Enantioselective Biocatalytic Reduction of 2 H-1,4-Benzoxazines Using Imine Reductases. J. Org. Chem. 2019, 84 (3), 1440– 1447,  DOI: 10.1021/acs.joc.8b02867
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    Enantioselective Biocatalytic Reduction of 2 H-1,4-Benzoxazines Using Imine Reductases
    Zumbragel Nadine; Machui Paul; Nonnhoff Jannis; Groger Harald
    The Journal of organic chemistry (2019), 84 (3), 1440-1447 ISSN:.
    A biocatalytic reduction of 2 H-1,4-benzoxazines using imine reductases is reported. This process enables a smooth and enantioselective synthesis of the resulting cyclic amines under mild conditions in aqueous media by means of a catalytic amount of the cofactor NADPH as hydride source as well as glucose as the reducing agent used in stoichiometric amounts for in situ cofactor recycling. Several substrates were studied, and the 3,4-dihydro-2 H-1,4-benzoxazines were obtained with up to 99% ee. In addition, the efficiency of this reduction process based on imine reductases as catalysts has been demonstrated for one 2 H-1,4-benzoxazine on an elevated laboratory scale running at a substrate loading of 10 g L(-1) in the presence of a tailor-made whole-cell catalyst.
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    Marshall, J. R.; Yao, P.; Montgomery, S. L.; Finnigan, J. D.; Thorpe, T. W.; Palmer, R. B.; Mangas-Sanchez, J.; Duncan, R. A. M.; Heath, R. S.; Graham, K. M.; Cook, D. J.; Charnock, S. J.; Turner, N. J. Screening and Characterization of a Diverse Panel of Metagenomic Imine Reductases for Biocatalytic Reductive Amination. Nat. Chem. 2021, 13 (2), 140– 148,  DOI: 10.1038/s41557-020-00606-w
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    Screening and characterization of a diverse panel of metagenomic imine reductases for biocatalytic reductive amination
    Marshall, James R.; Yao, Peiyuan; Montgomery, Sarah L.; Finnigan, James D.; Thorpe, Thomas W.; Palmer, Ryan B.; Mangas-Sanchez, Juan; Duncan, Richard A. M.; Heath, Rachel S.; Graham, Kirsty M.; Cook, Darren J.; Charnock, Simon J.; Turner, Nicholas J.
    Nature Chemistry (2021), 13 (2), 140-148CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)
    Finding faster and simpler ways to screen protein sequence space to enable the identification of new biocatalysts for asym. synthesis remains both a challenge and a rate-limiting step in enzyme discovery. Biocatalytic strategies for the synthesis of chiral amines are increasingly attractive and include enzymic asym. reductive amination, which offers an efficient route to many of these high-value compds. Here we report the discovery of over 300 new imine reductases and the prodn. of a large (384 enzymes) and sequence-diverse panel of imine reductases available for screening. We also report the development of a facile high-throughput screen to interrogate their activity. Through this approach we identified imine reductase biocatalysts capable of accepting structurally demanding ketones and amines, which include the preparative synthesis of N-substituted β-amino ester derivs. via a dynamic kinetic resoln. process, with excellent yields and stereochem. purities.
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    Aleku, G. A.; France, S. P.; Man, H.; Mangas-Sanchez, J.; Montgomery, S. L.; Sharma, M.; Leipold, F.; Hussain, S.; Grogan, G.; Turner, N. J. A Reductive Aminase from Aspergillus Oryzae. Nat. Chem. 2017, 9 (10), 961– 969,  DOI: 10.1038/nchem.2782
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    A reductive aminase from Aspergillus oryzae
    Aleku, Godwin A.; France, Scott P.; Man, Henry; Mangas-Sanchez, Juan; Montgomery, Sarah L.; Sharma, Mahima; Leipold, Friedemann; Hussain, Shahed; Grogan, Gideon; Turner, Nicholas J.
    Nature Chemistry (2017), 9 (10), 961-969CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)
    Reductive amination is one of the most important methods for the synthesis of chiral amines. Here we report the discovery of an NADP(H)-dependent reductive aminase from Aspergillus oryzae (AspRedAm, Uniprot code Q2TW47) that can catalyze the reductive coupling of a broad set of carbonyl compds. with a variety of primary and secondary amines with up to >98% conversion and with up to >98% enantiomeric excess. In cases where both carbonyl and amine show high reactivity, it is possible to employ a 1:1 ratio of the substrates, forming amine products with up to 94% conversion. Steady-state kinetic studies establish that the enzyme is capable of catalyzing imine formation as well as redn. Crystal structures of AspRedAm in complex with NADP(H) and also with both NADP(H) and the pharmaceutical ingredient (R)-rasagiline are reported. We also demonstrate preparative scale reductive aminations with wild-type and Q240A variant biocatalysts displaying total turnover nos. of up to 32,000 and space time yields up to 3.73 g l-1 d-1.
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  1. Godwin A. Aleku. Imine Reductases and Reductive Aminases in Organic Synthesis. ACS Catalysis 2024, 14 (19) , 14308-14329. https://doi.org/10.1021/acscatal.4c04756
  2. Chenming Huang, Li Zhang, Tong Tang, Haijiao Wang, Yingqian Jiang, Hanwen Ren, Yitian Zhang, Jiali Fang, Wenhe Zhang, Xian Jia, Song You, Bin Qin. Application of Directed Evolution and Machine Learning to Enhance the Diastereoselectivity of Ketoreductase for Dihydrotetrabenazine Synthesis. JACS Au 2024, 4 (7) , 2547-2556. https://doi.org/10.1021/jacsau.4c00284
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  • Abstract

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    Figure 1

    Figure 1. Combined biocatalytic resolution and reductive amination of racemic ketone 2 with allylamine 1 forming (S,S,S)-3, which is a key intermediate for the desired primary amine (S,S,S)-4.

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    Figure 2

    Figure 2. (a) The four possible reductive amination products (S,S,S)-3, (R,R,R)-3, (S,S,R)-3, and (R,R,S)-3 derived from ketone (±)-2; (b) SFC chromatogram of the stereoisomers.

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    Figure 3

    Figure 3. (a) Crystal structure of IRED-09 (purple) in complex with NADPH (pink) and N-cyclopropylcyclohexanamine; there is only one molecule in the asymmetric unit. (b) IR-09 biological dimer. (c) Active site of IR-09 with the imine intermediate of 3 modeled into the active site showing distances (Å) from C4 of the nicotinamide ring of NAPDH and (B) W204 to the electrophilic carbon of the ligand. (d) The view is rotated 180 deg to observe the active site from the opposite perspective and show distances from (B) M233 and (B) Q234 to the ligand.

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    Figure 4

    Figure 4. (a) SFC chromatograms comparing the isomer production of IR-09 WT, the best SDM variant, and the best SSM variant (peak at rt = 4.4. min corresponds to the alcohol). (b) Comparison between WT and the best variants for the production of (S,S,S)-3. Conversion to (S,S,S)-3 (%) = (S,S,S) yield × conversion.

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  • References

    This article references 45 other publications.

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      There is no corresponding record for this reference.
    7. 7
      Adams, J. P.; Brown, M. J. B.; Diaz-Rodriguez, A.; Lloyd, R. C.; Roiban, G. D. Biocatalysis: A Pharma Perspective. Adv. Synth. Catal. 2019, 361 (11), 2421– 2432,  DOI: 10.1002/adsc.201900424
      7
      Biocatalysis: A Pharma Perspective
      Adams, Joseph P.; Brown, Murray J. B.; Diaz-Rodriguez, Alba; Lloyd, Richard C.; Roiban, Gheorghe-Doru
      Advanced Synthesis & Catalysis (2019), 361 (11), 2421-2432CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Biocatalysis over the past few years has matured into an essential tool for modern, cost effective and sustainable pharmaceutical manufg. While some reaction classes are well established, and may even be the option of first intent, other more recently discovered enzyme classes are being rapidly developed both in academia and industry. Notwithstanding this, there are further promising enzymes that require further investment and investigation to allow their future industrial use. We here outline GlaxoSmithKline's perspective on the current status of biocatalysis for pharmaceutical manufg. and provide our views on areas of significant potential.
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    8. 8
      Romero, E.; Jones, B. S.; Hogg, B. N.; Rué Casamajo, A.; Hayes, M. A.; Flitsch, S. L.; Turner, N. J.; Schnepel, C. Enzymatic Late-Stage Modifications: Better Late Than Never. Angew. Chemie - Int. Ed. 2021, 60 (31), 16824– 16855,  DOI: 10.1002/anie.202014931
      8
      Enzymatic Late-Stage Modifications: Better Late Than Never
      Romero, Elvira; Jones, Bethan S.; Hogg, Bethany N.; Rue Casamajo, Arnau; Hayes, Martin A.; Flitsch, Sabine L.; Turner, Nicholas J.; Schnepel, Christian
      Angewandte Chemie, International Edition (2021), 60 (31), 16824-16855CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Enzyme catalysis is gaining increasing importance in synthetic chem. Nowadays, the growing no. of biocatalysts accessible by means of bioinformatics and enzyme engineering opens up an immense variety of selective reactions. Biocatalysis esp. provides excellent opportunities for late-stage modification often superior to conventional de novo synthesis. Enzymes have proven to be useful for direct introduction of functional groups into complex scaffolds, as well as for rapid diversification of compd. libraries. Particularly important and highly topical are enzyme-catalyzed oxyfunctionalisations, halogenations, methylations, redns., and amide bond formations due to the high prevalence of these motifs in pharmaceuticals. This Review gives an overview of the strengths and limitations of enzymic late-stage modifications using native and engineered enzymes in synthesis while focusing on important examples in drug development.
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    9. 9
      Hendrick, C. E.; Jorgensen, J. R.; Chaudhry, C.; Strambeanu, I. I.; Brazeau, J. F.; Schiffer, J.; Shi, Z.; Venable, J. D.; Wolkenberg, S. E. Direct-to-Biology Accelerates PROTAC Synthesis and the Evaluation of Linker Effects on Permeability and Degradation. ACS Med. Chem. Lett. 2022, 13 (7), 1182– 1190,  DOI: 10.1021/acsmedchemlett.2c00124
      9
      Direct-to-Biology Accelerates PROTAC Synthesis and the Evaluation of Linker Effects on Permeability and Degradation
      Hendrick, Charles E.; Jorgensen, Jeff R.; Chaudhry, Charu; Strambeanu, Iulia I.; Brazeau, Jean-Francois; Schiffer, Jamie; Shi, Zhicai; Venable, Jennifer D.; Wolkenberg, Scott E.
      ACS Medicinal Chemistry Letters (2022), 13 (7), 1182-1190CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)
      A platform to accelerate optimization of proteolysis targeting chimeras (PROTACs) had been developed using a direct-to-biol. (D2B) approach with a focus on linker effects. A large no. of linker analogs-varying length, polarity, and rigidity-were rapidly prepd. and characterized in four cell-based assays by streamlining time-consuming steps in synthesis and purifn. The expansive data set informs on linker structure activity relationships for in-cell E3 ligase target engagement, degrdn., permeability, and cell toxicity. Unexpected aspects of linker SAR were discovered, consistent with literature reports on "linkerol.", and the method dramatically speeds up empirical optimization. Physicochem. property trends emerged, and the platform had the potential to rapidly expand training sets for more complex prediction models. In-depth validation studies were carried out and confirm the D2B platform was a valuable tool to accelerate PROTAC design-make-test cycles.
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    10. 10
      Fryszkowska, A.; An, C.; Alvizo, O.; Banerjee, G.; Canada, K. A.; Cao, Y.; DeMong, D.; Devine, P. N.; Duan, D.; Elgart, D. M.; Farasat, I.; Gauthier, D. R.; Guidry, E. N.; Jia, X.; Kong, J.; Kruse, N.; Lexa, K. W.; Makarov, A. A.; Mann, B. F.; Milczek, E. M.; Mitchell, V.; Nazor, J.; Neri, C.; Orr, R. K.; Orth, P.; Phillips, E. M.; Riggins, J. N.; Schafer, W. A.; Silverman, S. M.; Strulson, C. A.; Subramanian, N.; Voladri, R.; Yang, H.; Yang, J.; Yi, X.; Zhang, X.; Zhong, W. A Chemoenzymatic Strategy for Site-Selective Functionalization of Native Peptides and Proteins. Science (80-.) 2022, 376 (6599), 1321– 1327,  DOI: 10.1126/science.abn2009
      There is no corresponding record for this reference.
    11. 11
      Rodríguez, D. F.; Moglie, Y.; Ramírez-Sarmiento, C. A.; Singh, S. K.; Dua, K.; Zacconi, F. C. Bio-Click Chemistry: A Bridge between Biocatalysis and Click Chemistry. RSC Adv. 2022, 12 (4), 1932– 1949,  DOI: 10.1039/D1RA08053A
      11
      Bio-click chemistry: a bridge between biocatalysis and click chemistry
      Rodriguez, Diego F.; Moglie, Yanina; Ramirez-Sarmiento, Cesar A.; Singh, Sachin Kumar; Dua, Kamal; Zacconi, Flavia C.
      RSC Advances (2022), 12 (4), 1932-1949CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
      A review. The fields of click chem. and biocatalysis have rapidly grown over the last two decades. The development of robust and active biocatalysts and the widespread use of straightforward click reactions led to significant interactions between these two fields. Therefore the name bio-click chem. seems to be an accurate definition of chemoenzymic reactions cooperating with click transformations. Bio-click chem. can be understood as the approach towards mols. of high-value using a green and sustainable approach by exploiting the potential of biocatalytic enzyme activity combined with the reliable nature of click reactions. This review summarizes the principal bio-click chem. reactions reported over the last two decades, with a special emphasis on small mols. Contributions to the field of bio-click chem. are manifold, but the synthesis of chiral mols. with applications in medicinal chem. and sustainable syntheses will be esp. highlighted.
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    12. 12
      Pessatti, T. B.; Terenzi, H.; Bertoldo, J. B. Protein Modifications: From Chemoselective Probes to Novel Biocatalysts. Catalysts 2021, 11 (12), 1466,  DOI: 10.3390/catal11121466
      12
      Protein Modifications: From Chemoselective Probes to Novel Biocatalysts
      Pessatti, Tomas Bohn; Terenzi, Hernan; Bertoldo, Jean Borges
      Catalysts (2021), 11 (12), 1466CODEN: CATACJ; ISSN:2073-4344. (MDPI AG)
      Chem. reactions can be performed to covalently modify specific residues in proteins. When applied to native enzymes, these chem. modifications can greatly expand the available set of building blocks for the development of biocatalysts. Nucleophilic canonical amino acid sidechains are the most readily accessible targets for such endeavors. A rich history of attempts to design enhanced or novel enzymes, from various protein scaffolds, has paved the way for a rapidly developing field with growing scientific, industrial, and biomedical applications. A major challenge is to devise reactions that are compatible with native proteins and can selectively modify specific residues. Cysteine, lysine, N-terminus, and carboxylate residues comprise the most widespread naturally occurring targets for enzyme modifications. In this review, chem. methods for selective modification of enzymes will be discussed, alongside with examples of reported applications. We aim to highlight the potential of such strategies to enhance enzyme function and create novel semisynthetic biocatalysts, as well as provide a perspective in a fast-evolving topic.
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    13. 13
      Boutureira, O.; Bernardes, G. J. L. Advances in Chemical Protein Modification. Chem. Rev. 2015, 115 (5), 2174– 2195,  DOI: 10.1021/cr500399p
      13
      Advances in Chemical Protein Modification
      Boutureira, Omar; Bernardes, Goncalo J. L.
      Chemical Reviews (Washington, DC, United States) (2015), 115 (5), 2174-2195CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
      A review. Transition metal-free and -mediated approaches are covered.
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    14. 14
      Fryszkowska, A.; Devine, P. N. Biocatalysis in Drug Discovery and Development. Curr. Opin. Chem. Biol. 2020, 55, 151– 160,  DOI: 10.1016/j.cbpa.2020.01.012
      14
      Biocatalysis in drug discovery and development
      Fryszkowska, Anna; Devine, Paul N.
      Current Opinion in Chemical Biology (2020), 55 (), 151-160CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)
      A review. Enzyme catalysis, enabled by advances in protein engineering and directed evolution, is beginning to transform chem. synthesis in the pharmaceutical industry. This review presents recent examples of the creative use of biocatalysis to enable drug discovery and development. We illustrate how increased access to novel biotransformations and the rise of cascade biocatalysis allowed fundamentally new syntheses of novel medicines, representing progress toward more sustainable pharmaceutical manufg. Finally, we describe the opportunities and challenges the industry must address to ensure the redn. to practice of biotechnol. innovations to develop new therapies in a faster, more economical, and environmentally benign way.
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    15. 15
      Devine, P. N.; Howard, R. M.; Kumar, R.; Thompson, M. P.; Truppo, M. D.; Turner, N. J. Extending the Application of Biocatalysis to Meet the Challenges of Drug Development. Nat. Rev. Chem. 2018, 2 (12), 409– 421,  DOI: 10.1038/s41570-018-0055-1
      There is no corresponding record for this reference.
    16. 16
      Brown, D. G.; Boström, J. Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?. J. Med. Chem. 2016, 59 (10), 4443– 4458,  DOI: 10.1021/acs.jmedchem.5b01409
      16
      Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?
      Brown, Dean G.; Bostrom, Jonas
      Journal of Medicinal Chemistry (2016), 59 (10), 4443-4458CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A review. An anal. of chem. reactions used in current medicinal chem. (2014), three decades ago (1984), and in natural product total synthesis has been conducted. The anal. revealed that of the current most frequently used synthetic reactions, none were discovered within the past 20 years and only two in the 1980s and 1990s (Suzuki-Miyaura and Buchwald-Hartwig). This suggests an inherent high bar of impact for new synthetic reactions in drug discovery. The most frequently used reactions were amide bond formation, Suzuki-Miyaura coupling, and SNAr reactions, most likely due to com. availability of reagents, high chemoselectivity, and a pressure on delivery. The authors show that these practices result in overpopulation of certain types of mol. shapes to the exclusion of others using simple PMI plots. The authors hope that these results will help catalyze improvements in integration of new synthetic methodologies as well as new library design.
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    17. 17
      Saldívar-González, F. I.; Aldas-Bulos, V. D.; Medina-Franco, J. L.; Plisson, F. Natural Product Drug Discovery in the Artificial Intelligence Era. Chem. Sci. 2022, 13 (6), 1526– 1546,  DOI: 10.1039/D1SC04471K
      17
      Natural product drug discovery in the artificial intelligence era
      Saldivar-Gonzalez, F. I.; Aldas-Bulos, V. D.; Medina-Franco, J. L.; Plisson, F.
      Chemical Science (2022), 13 (6), 1526-1546CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
      Natural products (NPs) are primarily recognized as privileged structures to interact with protein drug targets. Their unique characteristics and structural diversity continue to marvel scientists for developing NP-inspired medicines, even though the pharmaceutical industry has largely given up. High-performance computer hardware, extensive storage, accessible software and affordable online education have democratized the use of artificial intelligence (AI) in many sectors and research areas. The last decades have introduced natural language processing and machine learning algorithms, two subfields of AI, to tackle NP drug discovery challenges and open up opportunities. In this article, we review and discuss the rational applications of AI approaches developed to assist in discovering bioactive NPs and capturing the mol. "patterns" of these privileged structures for combinatorial design or target selectivity.
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    18. 18
      Ertl, P. Substituents of Life: The Most Common Substituent Patterns Present in Natural Products. Bioorg. Med. Chem. 2022, 54, 116562  DOI: 10.1016/j.bmc.2021.116562
      18
      Substituents of life: The most common substituent patterns present in natural products
      Ertl, Peter
      Bioorganic & Medicinal Chemistry (2022), 54 (), 116562CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
      Comparison of substituents present in natural products with the substituents found in av. synthetic mols. reveals considerable differences between these two groups. The natural products substituents contain mostly oxygen heteroatoms, are structurally more complex, often contg. double bonds and are rich in stereocenters. Substituents found in synthetic mols. contain nitrogen and sulfur heteroatoms, halogenes and more arom. and particularly heteroarom. rings. The characteristics of substituents typical for natural products identified here can be useful in the medicinal chem. context, for example to guide the synthesis of natural product-like libraries and natural product-inspired fragment collections. The results may be used also to support compd. derivatization strategies and the design of pseudo-natural natural products.
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    19. 19
      Volochnyuk, D. M.; Ryabukhin, S. V.; Moroz, Y. S.; Savych, O.; Chuprina, A.; Horvath, D.; Zabolotna, Y.; Varnek, A.; Judd, D. B. Evolution of Commercially Available Compounds for HTS. Drug Discovery Today 2019, 24 (2), 390– 402,  DOI: 10.1016/j.drudis.2018.10.016
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      Evolution of commercially available compounds for HTS
      Volochnyuk, Dmitriy M.; Ryabukhin, Sergey V.; Moroz, Yurii S.; Savych, Olena; Chuprina, Alexander; Horvath, Dragos; Zabolotna, Yuliana; Varnek, Alexandre; Judd, Duncan B.
      Drug Discovery Today (2019), 24 (2), 390-402CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)
      A review. Over recent years, an industry of compd. suppliers has grown to provide drug discovery with screening compds.: it is estd. that there are over 16 million compds. available from these sources. Here, we review the chem. space covered by suppliers' compd. libraries (SCL) in terms of compd. physicochem. properties, novelty, diversity, and quality. We examine the feasibility of compiling high-quality vendor-based libraries avoiding complicated, expensive compd. management activity, and compare the resulting libraries to the ChEMBL data set. We also consider how vendors have responded to the evolving requirements for drug discovery.
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    20. 20
      Tomberg, A.; Boström, J. Can Easy Chemistry Produce Complex, Diverse, and Novel Molecules?. Drug Discovery Today 2020, 25 (12), 2174– 2181,  DOI: 10.1016/j.drudis.2020.09.027
      20
      Can easy chemistry produce complex, diverse, and novel molecules
      Tomberg, Anna; Bostroem, Jonas
      Drug Discovery Today (2020), 25 (12), 2174-2181CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)
      A review. Statements, such as you need to break free from amide-formations to improve mol. properties and novel chem. leads to novel biol. are frequently encountered in the medicinal chem. community. To verify whether truth lies in such preconceptions, we investigated whether complex, diverse, and novel mols. can be made by easy chem. By analyzing the AstraZeneca screening collection, we conclude that novelty, diversity, and mol. complexity is currently not compromised by the use of the most popular reaction, amide bond formation, mainly because of a recent steady increase in unique amines available. Easy chem. allows speedy access to a broad chem. space, facilitating progress in projects, and opens the possibility of synthesis automation and new technologies, such as DNA-encoded libraries.
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    21. 21
      France, S. P.; Lewis, R. D.; Martinez, C. A. The Evolving Nature of Biocatalysis in Pharmaceutical Research and Development. JACS Au 2023, 3 (3), 715– 735,  DOI: 10.1021/jacsau.2c00712
      21
      The Evolving Nature of Biocatalysis in Pharmaceutical Research and Development
      France, Scott P.; Lewis, Russell D.; Martinez, Carlos A.
      JACS Au (2023), 3 (3), 715-735CODEN: JAAUCR; ISSN:2691-3704. (American Chemical Society)
      A review. Biocatalysis is a highly valued enabling technol. for pharmaceutical research and development as it can unlock synthetic routes to complex chiral motifs with unparalleled selectivity and efficiency. This perspective aims to review recent advances in the pharmaceutical implementation of biocatalysis across early and late-stage development with a focus on the implementation of processes for preparative-scale syntheses.
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    22. 22
      Benkovics, T.; Peng, F.; Phillips, E. M.; An, C.; Bade, R. S.; Chung, C. K.; Dance, Z. E. X.; Fier, P. S.; Forstater, J. H.; Liu, Z.; Liu, Z.; Maligres, P. E.; Marshall, N. M.; Salehi Marzijarani, N.; McIntosh, J. A.; Miller, S. P.; Moore, J. C.; Neel, A. J.; Obligacion, J. V.; Pan, W.; Pirnot, M. T.; Poirier, M.; Reibarkh, M.; Sherry, B. D.; Song, Z. J.; Tan, L.; Turnbull, B. W. H.; Verma, D.; Waldman, J. H.; Wang, L.; Wang, T.; Winston, M. S.; Xu, F. Diverse Catalytic Reactions for the Stereoselective Synthesis of Cyclic Dinucleotide MK-1454. J. Am. Chem. Soc. 2022, 144 (13), 5855– 5863,  DOI: 10.1021/jacs.1c12106
      22
      Diverse Catalytic Reactions for the Stereoselective Synthesis of Cyclic Dinucleotide MK-1454
      Benkovics, Tamas; Peng, Feng; Phillips, Eric M.; An, Chihui; Bade, Rachel S.; Chung, Cheol K.; Dance, Zachary E. X.; Fier, Patrick S.; Forstater, Jacob H.; Liu, Zhijian; Liu, Zhuqing; Maligres, Peter E.; Marshall, Nicholas M.; Salehi Marzijarani, Nastaran; McIntosh, John A.; Miller, Steven P.; Moore, Jeffrey C.; Neel, Andrew J.; Obligacion, Jennifer V.; Pan, Weilan; Pirnot, Michael T.; Poirier, Marc; Reibarkh, Mikhail; Sherry, Benjamin D.; Song, Zhiguo Jake; Tan, Lushi; Turnbull, Ben W. H.; Verma, Deeptak; Waldman, Jacob H.; Wang, Lu; Wang, Tao; Winston, Matthew S.; Xu, Feng
      Journal of the American Chemical Society (2022), 144 (13), 5855-5863CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      As practitioners of org. chem. strive to deliver efficient syntheses of the most complex natural products and drug candidates, further innovations in synthetic strategies are required to facilitate their efficient construction. These aspirational breakthroughs often go hand-in-hand with considerable redns. in cost and environmental impact. Enzyme-catalyzed reactions have become an impressive and necessary tool that offers benefits such as increased selectivity and waste limitation. These benefits are amplified when enzymic processes are conducted in a cascade in combination with novel bond-forming strategies. In this article, we report a highly diastereoselective synthesis of MK-1454, a potent agonist of the stimulator of interferon gene (STING) signaling pathway. The synthesis begins with the asym. construction of two fluoride-bearing deoxynucleotides. The routes were designed for max. convergency and selectivity, relying on the same benign electrophilic fluorinating reagent. From these complex subunits, four enzymes are used to construct the two bridging thiophosphates in a highly selective, high yielding cascade process. Crit. to the success of this reaction was a thorough understanding of the role transition metals play in bond formation.
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    23. 23
      McIntosh, J. A.; Liu, Z.; Andresen, B. M.; Marzijarani, N. S.; Moore, J. C.; Marshall, N. M.; Borra-Garske, M.; Obligacion, J. V.; Fier, P. S.; Peng, F.; Forstater, J. H.; Winston, M. S.; An, C.; Chang, W.; Lim, J.; Huffman, M. A.; Miller, S. P.; Tsay, F. R.; Altman, M. D.; Lesburg, C. A.; Steinhuebel, D.; Trotter, B. W.; Cumming, J. N.; Northrup, A.; Bu, X.; Mann, B. F.; Biba, M.; Hiraga, K.; Murphy, G. S.; Kolev, J. N.; Makarewicz, A.; Pan, W.; Farasat, I.; Bade, R. S.; Stone, K.; Duan, D.; Alvizo, O.; Adpressa, D.; Guetschow, E.; Hoyt, E.; Regalado, E. L.; Castro, S.; Rivera, N.; Smith, J. P.; Wang, F.; Crespo, A.; Verma, D.; Axnanda, S.; Dance, Z. E. X.; Devine, P. N.; Tschaen, D.; Canada, K. A.; Bulger, P. G.; Sherry, B. D.; Truppo, M. D.; Ruck, R. T.; Campeau, L. C.; Bennett, D. J.; Humphrey, G. R.; Campos, K. R.; Maddess, M. L. A Kinase-CGAS Cascade to Synthesize a Therapeutic STING Activator. Nat. 2022 6037901 2022, 603 (7901), 439– 444,  DOI: 10.1038/s41586-022-04422-9
      There is no corresponding record for this reference.
    24. 24
      Ertl, P.; Altmann, E.; Mckenna, J. M. The Most Common Functional Groups in Bioactive Molecules and How Their Popularity Has Evolved over Time. J. Med. Chem. 2020, 63 (15), 8408– 8418,  DOI: 10.1021/acs.jmedchem.0c00754
      24
      The Most Common Functional Groups in Bioactive Molecules and How Their Popularity Has Evolved over Time
      Ertl, Peter; Altmann, Eva; McKenna, Jeffrey M.
      Journal of Medicinal Chemistry (2020), 63 (15), 8408-8418CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      The concept of functional groups (FGs), sets of connected atoms that can det. the intrinsic reactivity of the parent mol. and in part are responsible for the overall properties of the mol., form a foundation within modern medicinal chem. In this Article, we analyze the occurrence of various FGs in mols. described in the medicinal chem. literature over the last 40 years and show how their development and utilization over time has varied. The popularity of various FGs has not evolved randomly, but instead, clear patterns of use are evident. Various factors influencing these patterns, including the introduction of new synthetic methods, novel techniques, and strategies applied in drug discovery and the better knowledge of mol. properties affecting the success of candidate development, are discussed.
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    25. 25
      Young, R. J.; Flitsch, S. L.; Grigalunas, M.; Leeson, P. D.; Quinn, R. J.; Turner, N. J.; Waldmann, H. The Time and Place for Nature in Drug Discovery. J. Am. Chem. Soc. 2022, 2 (11), 2400– 2416,  DOI: 10.1021/jacsau.2c00415
      25
      The Time and Place for Nature in Drug Discovery
      Young, Robert J.; Flitsch, Sabine L.; Grigalunas, Michael; Leeson, Paul D.; Quinn, Ronald J.; Turner, Nicholas J.; Waldmann, Herbert
      JACS Au (2022), 2 (11), 2400-2416CODEN: JAAUCR; ISSN:2691-3704. (American Chemical Society)
      A review. The case for a renewed focus on Nature in drug discovery is reviewed; not in terms of natural product screening, but how and why biomimetic mols., esp. those produced by natural processes, should deliver in the age of artificial intelligence and screening of vast collections both in vitro and in silico. The declining natural product-likeness of licensed drugs and the consequent physicochem. implications of this trend in the context of current practices are noted. To arrest these trends, the logic of seeking new bioactive agents with enhanced natural mimicry is considered; notably that mols. constructed by proteins (enzymes) are more likely to interact with other proteins (e.g., targets and transporters), a notion validated by natural products. Nature's finite no. of building blocks and their interactions necessarily reduce potential nos. of structures, yet these enable expansion of chem. space with their inherent diversity of phys. characteristics, pertinent to property-based design. The feasible variations on natural motifs are considered and expanded to encompass pseudo-natural products, leading to the further logical step of harnessing bioprocessing routes to access them. Together, these offer opportunities for enhancing natural mimicry, thereby bringing innovation to drug synthesis exploiting the characteristics of natural recognition processes. The potential for computational guidance to help identifying binding commonalities in the route map is a logical opportunity to enable the design of tailored mols., with a focus on "org./biol." rather than purely "synthetic" structures. The design and synthesis of prototype structures should pay dividends in the disposition and efficacy of the mols., while inherently enabling greener and more sustainable manufg. techniques.
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    26. 26
      Bauer, R. A.; Wurst, J. M.; Tan, D. S. Expanding the Range of ‘Druggable’ Targets with Natural Product-Based Libraries: An Academic Perspective. Curr. Opin. Chem. Biol. 2010, 14 (3), 308– 314,  DOI: 10.1016/j.cbpa.2010.02.001
      26
      Expanding the range of druggable' targets with natural product-based libraries: an academic perspective
      Bauer, Renato A.; Wurst, Jacqueline M.; Tan, Derek S.
      Current Opinion in Chemical Biology (2010), 14 (3), 308-314CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)
      A review. Existing drugs address a relatively narrow range of biol. targets. As a result, libraries of drug-like mols. have proven ineffective against a variety of challenging targets, such as protein-protein interactions, nucleic acid complexes, and antibacterial modalities. In contrast, natural products are known to be effective at modulating such targets, and new libraries are being developed based on underrepresented scaffolds and regions of chem. space assocd. with natural products. This has led to several recent successes in identifying new chem. probes that address these challenging targets.
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    27. 27
      Newman, D. J.; Cragg, G. M. Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019. J. Nat. Prod. 2020, 83 (3), 770– 803,  DOI: 10.1021/acs.jnatprod.9b01285
      27
      Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019
      Newman, David J.; Cragg, Gordon M.
      Journal of Natural Products (2020), 83 (3), 770-803CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)
      This review is an updated and expanded version of the five prior reviews that were published in this journal in 1997, 2003, 2007, 2012, and 2016. For all approved therapeutic agents, the time frame has been extended to cover the almost 39 years from the first of Jan. 1981 to the 30th of Sept. 2019 for all diseases worldwide and from ∼1946 (earliest so far identified) to the 30th of Sept. 2019 for all approved antitumor drugs worldwide. As in earlier reviews, only the first approval of any drug is counted, irresp. of how many "biosimilars" or added approvals were subsequently identified. As in the 2012 and 2016 reviews, we have continued to utilize our secondary subdivision of a "natural product mimic", or "NM", to join the original primary divisions, and the designation "natural product botanical", or "NB", to cover those botanical "defined mixts." now recognized as drug entities by the FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or synthetic variations using their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over the time frame from 1946 to 1980, of the 75 small mols., 40, or 53.3%, are N or ND. In the 1981 to date time frame the equiv. figures for the N* compds. of the 185 small mols. are 62, or 33.5%, though to these can be added the 58 S* and S*/NMs, bringing the figure to 64.9%. In other areas, the influence of natural product structures is quite marked with, as expected from prior information, the anti-infective area being dependent on natural products and their structures, though as can be seen in the review there are still disease areas (shown in Table 2) for which there are no drugs derived from natural products. Although combinatorial chem. techniques have succeeded as methods of optimizing structures and have been used very successfully in the optimization of many recently approved agents, we are still able to identify only two de novo combinatorial compds. (one of which is a little speculative) approved as drugs in this 39-yr time frame, though there is also one drug that was developed using the "fragment-binding methodol." and approved in 2012. We have also added a discussion of candidate drug entities currently in clin. trials as "warheads" and some very interesting preliminary reports on sources of novel antibiotics from Nature due to the abs. requirement for new agents to combat plasmid-borne resistance genes now in the general populace. We continue to draw the attention of readers to the recognition that a significant no. of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated"; thus we consider that this area of natural product research should be expanded significantly.
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    28. 28
      Yao, P.; Xu, Z.; Yu, S.; Wu, Q.; Zhu, D. Imine Reductase-Catalyzed Enantioselective Reduction of Bulky α,B-Unsaturated Imines En Route to a Pharmaceutically Important Morphinan Skeleton. Adv. Synth. Catal. 2019, 361 (3), 556– 561,  DOI: 10.1002/adsc.201801326
      28
      Imine Reductase-Catalyzed Enantioselective Reduction of Bulky α,β-Unsaturated Imines en Route to a Pharmaceutically Important Morphinan Skeleton
      Yao, Peiyuan; Xu, Zefei; Yu, Shanshan; Wu, Qiaqing; Zhu, Dunming
      Advanced Synthesis & Catalysis (2019), 361 (3), 556-561CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The morphinan skeleton is an important sub-structure in many medicines such as dextromethorphan, and can be constructed from 1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (1-benzyl-OHIQ) derivs. 1-Benzyl-3,4,5,6,7,8-hexahydroisoquinolines (1-benzyl-HHIQs), the precursors of 1-benzyl-OHIQs, constitute a type of bulky α, β-unsatd. imines. Until now, the application of imine reductases (IREDs) to α, β-unsatd. imines has only rarely been reported. In this study, through evaluation of 48 IREDs, both enantiomers of 1-(4-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (1-(4-methoxybenzyl)-OHIQ) were obtained in high yield and excellent optical purity. Among the enzymes, the most steric hindrance-tolerant IRED from Sandarearacinus amylolyticus (IR40) was able to convert various Ph substituted 1-benzyl-HHIQ to the corresponding 1-benzyl-OHIQ derivs. with excellent enantiomeric excess. These results provide an effective route to synthesize these important compds. via enantioselective redn. of bulky α, β-unsatd. imine precursors, which can be readily prepd. from 2-(1-cyclohexenyl)ethylamine and corresponding aryl acetic acids.
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    29. 29
      Arnold, F. H. Directed Evolution: Bringing New Chemistry to Life. Angew. Chemie - Int. Ed. 2018, 57 (16), 4143– 4148,  DOI: 10.1002/anie.201708408
      29
      Directed evolution: Bringing new chemistry to life
      Arnold, Frances H.
      Angewandte Chemie, International Edition (2018), 57 (16), 4143-4148CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Directed evolution mimics evolution by artificial selection, and is accelerated in the lab. setting by focusing on individual genes expressed in fast-growing microorganisms. We start with existing proteins (sourced from Nature or engineered), introduce mutations, and then screen for the progeny proteins with enhanced activity (or other desirable traits). We use the improved enzymes as parents for the next round of mutation and screening, recombining beneficial mutations as needed, and continuing until we reach the target level of performance. Thus, the evolution of Nature's enzymes can lead to the discovery of new reactivity, transformations not known in biol., and reactivity inaccessible by small-mol. catalysis.
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    30. 30
      Aleku, G. A.; Man, H.; France, S. P.; Leipold, F.; Hussain, S.; Toca-Gonzalez, L.; Marchington, R.; Hart, S.; Turkenburg, J. P.; Grogan, G.; Turner, N. J. Stereoselectivity and Structural Characterization of an Imine Reductase (IRED) from Amycolatopsis Orientalis. ACS Catal. 2016, 6 (6), 3880– 3889,  DOI: 10.1021/acscatal.6b00782
      30
      Stereoselectivity and structural characterization of an imine reductase (IRED) from Amycolatopsis orientalis
      Aleku, Godwin A.; Man, Henry; France, Scott P.; Leipold, Friedemann; Hussain, Shahed; Toca-Gonzalez, Laura; Marchington, Rebecca; Hart, Sam; Turkenburg, Johan P.; Grogan, Gideon; Turner, Nicholas J.
      ACS Catalysis (2016), 6 (6), 3880-3889CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      Imine reductase AoIRED from A. orientalis (Uniprot R4SNK4) catalyzes the NADPH-dependent redn. of a wide range of prochiral imines and iminium ions, predominantly with (S)-selectivity and with ee's of up to >99%. AoIRED displays up to 100-fold greater catalytic efficiency for 2-methyl-1-pyrroline (2MPN) compared to other IREDs, such as the enzyme from Streptomyces sp. GF3546, which also exhibits (S)-selectivity, and thus, AoIRED is an interesting candidate for preparative synthesis. AoIRED exhibits unusual catalytic properties, with inversion of stereoselectivity obsd. between structurally similar substrates, and also, in the case of 1-methyl-3,4-dihydroisoquinoline, for the same substrate, dependent on the age of the enzyme after purifn. The structure of AoIRED was detd. in an "open" apo-form, revealing a canonical dimeric IRED fold in which the active site is formed between the N- and C-terminal domains of participating monomers. Co-crystn. with NADPH gave a "closed" form in complex with the cofactor, in which a relative closure of domains, and assocd. loop movements, resulted in a much smaller active site. A ternary complex was also obtained by cocrystn. with NADPH and 1-methyl-1,2,3,4-tetrahydroisoquinoline, and it revealed a binding site for the (R)-amine product, which placed the chiral carbon within 4 Å of the putative location of the C4 atom of NADPH that delivers hydride to the C:N bond of the substrate. The ternary complex permitted structure-informed mutation of the active site, resulting in mutants including Y179A, Y179F, and N241A, of altered activity and stereoselectivity.
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    31. 31
      Gilio, A. K.; Thorpe, T. W.; Heyam, A.; Petchey, M. R.; Pogrányi, B.; France, S. P.; Howard, R. M.; Karmilowicz, M. J.; Lewis, R.; Turner, N.; Grogan, G. A Reductive Aminase Switches to Imine Reductase Mode for a Bulky Amine Substrate. ACS Catal. 2023, 13 (3), 1669– 1677,  DOI: 10.1021/acscatal.2c06066
      31
      A Reductive Aminase Switches to Imine Reductase Mode for a Bulky Amine Substrate
      Gilio, Amelia K.; Thorpe, Thomas W.; Heyam, Alex; Petchey, Mark R.; Pogranyi, Balazs; France, Scott P.; Howard, Roger M.; Karmilowicz, Michael J.; Lewis, Russell; Turner, Nicholas; Grogan, Gideon
      ACS Catalysis (2023), 13 (3), 1669-1677CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      Imine reductases (IREDs) catalyze the asym. redn. of cyclic imines, but also in some cases the coupling of ketones and amines to form secondary amine products in an enzyme-catalyzed reductive amination (RedAm) reaction. Enzymic RedAm reactions have typically used small hydrophobic amines, but many interesting pharmaceutical targets require that larger amines be used in these coupling reactions. Following the identification of IR77 from Ensifer adhaerens as a promising biocatalyst for the reductive amination of cyclohexanone with pyrrolidine, we have characterized the ability of this enzyme to catalyze couplings with larger bicyclic amines such as isoindoline and octahydrocyclopenta(c)pyrrole. By comparing the activity of IR77 with redns. using sodium cyanoborohydride in water, it was shown that, while the coupling of cyclohexanone and pyrrolidine involved at least some element of reductive amination, the amination with the larger amines likely occurred ex situ, with the imine recruited from soln. for enzyme redn. The structure of IR77 was detd., and using this as a basis, structure-guided mutagenesis, coupled with point mutations selecting improving amino acid sites suggested by other groups, permitted the identification of a mutant A208N with improved activity for amine product formation. Improvements in conversion were attributed to greater enzyme stability as revealed by X-ray crystallog. and nano differential scanning fluorimetry. The mutant IR77-A208N was applied to the preparative scale amination of cyclohexanone at 50 mM concn., with 1.2 equiv of three larger amines, in isolated yields of up to 93%.
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    32. 32
      Montgomery, S. L.; Pushpanath, A.; Heath, R. S.; Marshall, J. R.; Klemstein, U.; Galman, J. L.; Woodlock, D.; Bisagni, S.; Taylor, C. J.; Mangas-Sanchez, J.; Ramsden, J. I.; Dominguez, B.; Turner, N. J. Characterization of Imine Reductases in Reductive Amination for the Exploration of Structure-Activity Relationships. Sci. Adv. 2020, 6 (21), eaay9320  DOI: 10.1126/sciadv.aay9320
      There is no corresponding record for this reference.
    33. 33
      Grogan, G. Synthesis of Chiral Amines Using Redox Biocatalysis. Curr. Opin. Chem. Biol. 2018, 43, 15– 22,  DOI: 10.1016/j.cbpa.2017.09.008
      33
      Synthesis of chiral amines using redox biocatalysis
      Grogan, Gideon
      Current Opinion in Chemical Biology (2018), 43 (), 15-22CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)
      Chiral amines feature in a large no. of small mol. pharmaceuticals, and thus methods for their asym. synthesis are of considerable interest. Biocatalytic approaches have come to the fore in recent years as these offer advantages of superior atom economy, mild reaction conditions and excellent stereoselectivity. Advances in redox cofactor process technol. have meant that oxidoreductase enzymes in particular now have growing potential as industrial catalysts for amine formation. In this review we survey recent developments in the discovery and application of oxidoreductase enzymes for amine prodn., including Monoamine Oxidases (MAOs), engineered and natural Amine Dehydrogenases (AmDHs), Imine Reductases (IREDs) and Reductive Aminases (RedAms), in addn. to their application in enzyme cascades.
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    34. 34
      Sharma, M.; Mangas-Sanchez, J.; France, S. P.; Aleku, G. A.; Montgomery, S. L.; Ramsden, J. I.; Turner, N. J.; Grogan, G. A Mechanism for Reductive Amination Catalyzed by Fungal Reductive Aminases. ACS Catal. 2018, 8 (12), 11534– 11541,  DOI: 10.1021/acscatal.8b03491
      34
      A mechanism for reductive amination catalyzed by fungal reductive aminases
      Sharma, Mahima; Mangas-Sanchez, Juan; France, Scott P.; Aleku, Godwin A.; Montgomery, Sarah L.; Ramsden, Jeremy I.; Turner, Nicholas J.; Grogan, Gideon
      ACS Catalysis (2018), 8 (12), 11534-11541CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)
      Reductive aminases (RedAms) catalyze the asym. reductive amination of ketones with primary amines to give secondary amine products. RedAms have great potential for the synthesis of bioactive chiral amines; however, insights into their mechanism are currently limited. Comparative studies on reductive amination of cyclohexanone with allylamine in the presence of RedAms, imine reductases (IREDs), or NaBH3CN support the distinctive activity of RedAms in catalyzing both imine formation and redn. in the reaction. Structures of AtRedAm from Aspergillus terreus, in complex with NADPH and ketone and amine substrates, along with kinetic anal. of active-site mutants, reveal modes of substrate binding, the basis for the specificity of RedAms for redn. of imines over ketones, and the importance of domain flexibility in bringing the reactive participants together for the reaction. This information is used to propose a mechanism for their action and also to expand the substrate specificity of RedAms using protein engineering.
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    35. 35
      Zumbrägel, N.; Machui, P.; Nonnhoff, J.; Gröger, H. Enantioselective Biocatalytic Reduction of 2 H-1,4-Benzoxazines Using Imine Reductases. J. Org. Chem. 2019, 84 (3), 1440– 1447,  DOI: 10.1021/acs.joc.8b02867
      35
      Enantioselective Biocatalytic Reduction of 2 H-1,4-Benzoxazines Using Imine Reductases
      Zumbragel Nadine; Machui Paul; Nonnhoff Jannis; Groger Harald
      The Journal of organic chemistry (2019), 84 (3), 1440-1447 ISSN:.
      A biocatalytic reduction of 2 H-1,4-benzoxazines using imine reductases is reported. This process enables a smooth and enantioselective synthesis of the resulting cyclic amines under mild conditions in aqueous media by means of a catalytic amount of the cofactor NADPH as hydride source as well as glucose as the reducing agent used in stoichiometric amounts for in situ cofactor recycling. Several substrates were studied, and the 3,4-dihydro-2 H-1,4-benzoxazines were obtained with up to 99% ee. In addition, the efficiency of this reduction process based on imine reductases as catalysts has been demonstrated for one 2 H-1,4-benzoxazine on an elevated laboratory scale running at a substrate loading of 10 g L(-1) in the presence of a tailor-made whole-cell catalyst.
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    36. 36
      Marshall, J. R.; Yao, P.; Montgomery, S. L.; Finnigan, J. D.; Thorpe, T. W.; Palmer, R. B.; Mangas-Sanchez, J.; Duncan, R. A. M.; Heath, R. S.; Graham, K. M.; Cook, D. J.; Charnock, S. J.; Turner, N. J. Screening and Characterization of a Diverse Panel of Metagenomic Imine Reductases for Biocatalytic Reductive Amination. Nat. Chem. 2021, 13 (2), 140– 148,  DOI: 10.1038/s41557-020-00606-w
      36
      Screening and characterization of a diverse panel of metagenomic imine reductases for biocatalytic reductive amination
      Marshall, James R.; Yao, Peiyuan; Montgomery, Sarah L.; Finnigan, James D.; Thorpe, Thomas W.; Palmer, Ryan B.; Mangas-Sanchez, Juan; Duncan, Richard A. M.; Heath, Rachel S.; Graham, Kirsty M.; Cook, Darren J.; Charnock, Simon J.; Turner, Nicholas J.
      Nature Chemistry (2021), 13 (2), 140-148CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)
      Finding faster and simpler ways to screen protein sequence space to enable the identification of new biocatalysts for asym. synthesis remains both a challenge and a rate-limiting step in enzyme discovery. Biocatalytic strategies for the synthesis of chiral amines are increasingly attractive and include enzymic asym. reductive amination, which offers an efficient route to many of these high-value compds. Here we report the discovery of over 300 new imine reductases and the prodn. of a large (384 enzymes) and sequence-diverse panel of imine reductases available for screening. We also report the development of a facile high-throughput screen to interrogate their activity. Through this approach we identified imine reductase biocatalysts capable of accepting structurally demanding ketones and amines, which include the preparative synthesis of N-substituted β-amino ester derivs. via a dynamic kinetic resoln. process, with excellent yields and stereochem. purities.
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    37. 37
      Aleku, G. A.; France, S. P.; Man, H.; Mangas-Sanchez, J.; Montgomery, S. L.; Sharma, M.; Leipold, F.; Hussain, S.; Grogan, G.; Turner, N. J. A Reductive Aminase from Aspergillus Oryzae. Nat. Chem. 2017, 9 (10), 961– 969,  DOI: 10.1038/nchem.2782
      37
      A reductive aminase from Aspergillus oryzae
      Aleku, Godwin A.; France, Scott P.; Man, Henry; Mangas-Sanchez, Juan; Montgomery, Sarah L.; Sharma, Mahima; Leipold, Friedemann; Hussain, Shahed; Grogan, Gideon; Turner, Nicholas J.
      Nature Chemistry (2017), 9 (10), 961-969CODEN: NCAHBB; ISSN:1755-4330. (Nature Research)
      Reductive amination is one of the most important methods for the synthesis of chiral amines. Here we report the discovery of an NADP(H)-dependent reductive aminase from Aspergillus oryzae (AspRedAm, Uniprot code Q2TW47) that can catalyze the reductive coupling of a broad set of carbonyl compds. with a variety of primary and secondary amines with up to >98% conversion and with up to >98% enantiomeric excess. In cases where both carbonyl and amine show high reactivity, it is possible to employ a 1:1 ratio of the substrates, forming amine products with up to 94% conversion. Steady-state kinetic studies establish that the enzyme is capable of catalyzing imine formation as well as redn. Crystal structures of AspRedAm in complex with NADP(H) and also with both NADP(H) and the pharmaceutical ingredient (R)-rasagiline are reported. We also demonstrate preparative scale reductive aminations with wild-type and Q240A variant biocatalysts displaying total turnover nos. of up to 32,000 and space time yields up to 3.73 g l-1 d-1.
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    38. 38
      France, S. P.; Howard, R. M.; Steflik, J.; Weise, N. J.; Mangas-Sanchez, J.; Montgomery, S. L.; Crook, R.; Kumar, R.; Turner, N. J. Identification of Novel Bacterial Members of the Imine Reductase Enzyme Family That Perform Reductive Amination. ChemCatChem. 2018, 10 (3), 510– 514,  DOI: 10.1002/cctc.201701408
      38
      Identification of Novel Bacterial Members of the Imine Reductase Enzyme Family that Perform Reductive Amination
      France, Scott P.; Howard, Roger M.; Steflik, Jeremy; Weise, Nicholas J.; Mangas-Sanchez, Juan; Montgomery, Sarah L.; Crook, Robert; Kumar, Rajesh; Turner, Nicholas J.
      ChemCatChem (2018), 10 (3), 510-514CODEN: CHEMK3; ISSN:1867-3880. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Reductive amination of carbonyl compds. constitutes one of the most efficient ways to rapidly construct chiral and achiral amine frameworks. Imine reductase (IRED) biocatalysts represent a versatile family of enzymes for amine synthesis through NADPH-mediated imine redn. The reductive aminases (RedAms) are a subfamily of IREDs that were recently shown to catalyze imine formation as well as imine redn. Herein, a diverse library of novel enzymes were expressed and screened as cell-free lysates for their ability to facilitate reductive amination to expand the known suite of biocatalysts for this transformation and to identify more enzymes with potential industrial applications. A range of ketones and amines were examd., and enzymes were identified that were capable of accepting benzylamine, pyrrolidine, ammonia, and aniline. Amine equiv. as low as 2.5 were employed to afford up to >99 % conversion, and for chiral products, up to >98 % ee could be achieved. Preparative-scale reactions were conducted with low amine equiv. (1.5 or 2.0) of methylamine, allylamine, and pyrrolidine, achieving up to >99 % conversion and 76 % yield.
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    39. 39
      Harawa, V.; W. Thorpe, T.; R. Marshall, J.; J. Sangster, J.; K. Gilio, A.; Pirvu, L.; S. Heath, R.; Angelastro, A.; D. Finnigan, J.; J. Charnock, S.; W. Nafie, J.; Grogan, G.; C. Whitehead, R.; J. Turner, N. Synthesis of Stereoenriched Piperidines via Chemo-Enzymatic Dearomatization of Activated Pyridines. J. Am. Chem. Soc. 2022, 144 (46), 21088– 21095,  DOI: 10.1021/jacs.2c07143
      39
      Synthesis of Stereoenriched Piperidines via Chemo-Enzymatic Dearomatization of Activated Pyridines
      Harawa, Vanessa; Thorpe, Thomas W.; Marshall, James R.; Sangster, Jack J.; Gilio, Amelia K.; Pirvu, Lucian; Heath, Rachel S.; Angelastro, Antonio; Finnigan, James D.; Charnock, Simon J.; Nafie, Jordan W.; Grogan, Gideon; Whitehead, Roger C.; Turner, Nicholas J.
      Journal of the American Chemical Society (2022), 144 (46), 21088-21095CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      By combining chem. synthesis and biocatalysis, a general chemo-enzymic approach for the asym. dearomatization of activated pyridines for the prepn. of substituted piperidines with precise stereochem. was presented. The key step involved a stereoselective one-pot amine oxidase/ene imine reductase cascade to convert N-substituted tetrahydropyridines to stereo-defined 3- and 3,4-substituted piperidines. This chemo-enzymic approach has proved useful for key transformations in the syntheses of antipsychotic drugs Preclamol and OSU-6162, as well as for the prepn. of two important intermediates in synthetic routes of the ovarian cancer monotherapeutic Niraparib.
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    40. 40
      Mangas-Sanchez, J.; Sharma, M.; Cosgrove, S. C.; Ramsden, J. I.; Marshall, J. R.; Thorpe, T. W.; Palmer, R. B.; Grogan, G.; Turner, N. J. Asymmetric Synthesis of Primary Amines Catalyzed by Thermotolerant Fungal Reductive Aminases. Chem. Sci. 2020, 11 (19), 22– 25,  DOI: 10.1039/d0sc02253e
      There is no corresponding record for this reference.
    41. 41
      Husain, S. M.; Schätzle, M. A.; Lüdeke, S.; Müller, M. Unprecedented Role of Hydronaphthoquinone Tautomers in Biosynthesis. Angew. Chemie - Int. Ed. 2014, 53 (37), 9806– 9811,  DOI: 10.1002/anie.201404560
      41
      Unprecedented Role of Hydronaphthoquinone Tautomers in Biosynthesis
      Husain, Syed Masood; Schaetzle, Michael A.; Luedeke, Steffen; Mueller, Michael
      Angewandte Chemie, International Edition (2014), 53 (37), 9806-9811CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Quinones and hydroquinones are among the most common cellular cofactors, redox mediators, and natural products. Here, we report on the redn. of 2-hydroxynaphthoquinones to the stable 1,4-diketo tautomeric form of hydronaphthoquinones and their further redn. by fungal tetrahydroxynaphthalene reductase (T4HNR). The very high diastereomeric and enantiomeric excess, together with the high yield of cis-3,4-dihydroxy-1-tetralone, exclude an intermediary hydronaphthoquinone. Labeling expts. with NADPH and NADPD corroborated the formation of an unexpected 1,4-diketo tautomeric form of 2-hydroxyhydronaphthoquinone as a stable intermediate. Similar 1,4-diketo tautomers of hydronaphthoquinones were established as products of the NADPH-dependent enzymic redn. of other 1,4-naphthoquinones, and as substrates for different members of the superfamily of short-chain dehydrogenases. We propose an essential role of hydroquinone diketo tautomers in biosynthesis and detoxification processes.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtFyqurzJ&md5=70b8dae134a8e2f52ba2d440d87b394c
    42. 42
      Conradt, D.; Schätzle, M. A.; Husain, S. M.; Müller, M. Diversity in Reduction with Short-Chain Dehydrogenases: Tetrahydroxynaphthalene Reductase, Trihydroxynaphthalene Reductase, and Glucose Dehydrogenase. ChemCatChem. 2015, 7 (19), 3116– 3120,  DOI: 10.1002/cctc.201500605
      42
      Diversity in Reduction with Short-Chain Dehydrogenases: Tetrahydroxynaphthalene Reductase, Trihydroxynaphthalene Reductase, and Glucose Dehydrogenase
      Conradt, David; Schaetzle, Michael A.; Husain, Syed Masood; Mueller, Michael
      ChemCatChem (2015), 7 (19), 3116-3120CODEN: CHEMK3; ISSN:1867-3880. (Wiley-VCH Verlag GmbH & Co. KGaA)
      NAD(P)H-dependent oxidoreductases from the short-chain dehydrogenases/reductases (SDRs) family possess high functional diversity. Three SDRs, namely, tetrahydroxy- and trihydroxynaphthalene reductases (T4HNR, T3HNR) involved in the dihydroxynaphthalene-melanin biosynthesis of the phytopathogenic fungus Magnaporthe grisea, and glucose dehydrogenase (GDH) from Bacillus subtilis, were characterized regarding their substrate range and functional behavior. T4HNR and T3HNR share activities towards the stereoselective redn. of 2-tetralone derivs. and 2,3-dihydro-1,4-naphthoquinones and show distinct but different stereochem. outcome in the case of epoxy-1,4-naphthoquinones as substrates. GDH shares the activity towards 2,3-dihydro-1,4-naphthoquinones, however, with low stereocontrol. Moreover, GDH reduces 2-hydroxy-2,3-dihydro-1,4-naphthoquinone into trans-4-hydroxyscytalone with a high diastereomeric excess (96 %), whereas T4HNR gave the cis diastereomer (diastereomeric excess>99 %). Thus, SDRs provide a much higher functional and stereochem. diversity than previously thought, already exemplified by many transformations of three members of this enzyme family.
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    43. 43
      Huber, T.; Schneider, L.; Präg, A.; Gerhardt, S.; Einsle, O.; Müller, M. Direct Reductive Amination of Ketones: Structure and Activity of S-Selective Imine Reductases from Streptomyces. ChemCatChem. 2014, 6 (8), 2248– 2252,  DOI: 10.1002/cctc.201402218
      43
      Direct Reductive Amination of Ketones: Structure and Activity of S-Selective Imine Reductases from Streptomyces
      Huber, Tobias; Schneider, Lisa; Praeg, Andreas; Gerhardt, Stefan; Einsle, Oliver; Mueller, Michael
      ChemCatChem (2014), 6 (8), 2248-2252CODEN: CHEMK3; ISSN:1867-3880. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The importance and structural diversity of chiral amines is well-demonstrated by the myriad nonenzymic methods for their chem. prodn. In nature, the prodn. of amines is performed by transamination rather than by redn. of an imine precursor derived from the corresponding ketone. Imine reductases, however, show great potential in the redn. of cyclic imines that are stable towards hydrolysis in aq. reaction media. Here, we report the catalytic activity of two S-selective imine reductases towards 3,4-dihydroisoquinolines and 3,4-dihydro-β-carbolines and their activity in the direct reductive amination of ketone substrates. The crystal structures of the enzyme from Streptomyces sp. GF3546 in complex with the cofactor NADPH and from Streptomyces aurantiacus in native form have been solved and refined to a resoln. of 1.9 Å.
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    44. 44
      Scheller, P. N.; Lenz, M.; Hammer, S. C.; Hauer, B.; Nestl, B. M. Imine Reductase-Catalyzed Intermolecular Reductive Amination of Aldehydes and Ketones. ChemCatChem. 2015, 7 (20), 3239– 3242,  DOI: 10.1002/cctc.201500764
      44
      Imine Reductase-Catalyzed Intermolecular Reductive Amination of Aldehydes and Ketones
      Scheller, Philipp N.; Lenz, Maike; Hammer, Stephan C.; Hauer, Bernhard; Nestl, Bettina M.
      ChemCatChem (2015), 7 (20), 3239-3242CODEN: CHEMK3; ISSN:1867-3880. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Imine reductases (IREDs) have emerged as promising biocatalysts for the synthesis of chiral amines. In this study, the asym. imine reductase-catalyzed intermol. reductive amination with NADPH as the hydrogen source was investigated. A highly chemo- and stereoselective imine reductase was applied for the reductive amination by using a panel of carbonyls with different amine nucleophiles. Primary and secondary amine products were generated in moderate to high yields with high enantiomeric excess values. The formation of the imine intermediate was studied between carbonyl substrates and methylamine in aq. soln. in the pH range of 4.0 to 9.0 by 1H NMR spectroscopy. We further measured the kinetics of the reductive amination of benzaldehyde with methylamine. This imine reductase-catalyzed approach constitutes a powerful and direct method for the synthesis of valuable amines under mild reaction conditions.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVCntLrN&md5=72cce3adc9ff95c460cea2773c2b0a52
    45. 45
      AutoDock Vina Documentation Release 1.2.0; Center of Computational Structural Biology (CCSB)-Scripps Research, 2022.
      There is no corresponding record for this reference.

  • Supporting Information

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