Dual-Bioorthogonal Catalysis by a Palladium Peptide Complex

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1. 1

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   Metalloproteomics, metalloproteomes, and the annotation of metalloproteins

   Maret, Wolfgang

   Metallomics (2010), 2 (2), 117-125CODEN: METAJS; ISSN:1756-591X. (Royal Society of Chemistry)

   A review. Metalloproteomics includes approaches that address the expression of metalloproteins and their changes in biol. time and space. Metalloproteomes are investigated by a combination of approaches. Exptl. approaches include structural genomics, which provides insights into the architecture of metal-binding sites in metalloproteins and establishes ligand signatures from the types and spacings of the metal ligands in the protein sequence. Theor. approaches employ these ligand signatures as templates for homol. searches in sequence databases. In this way, the no. of metalloproteins in the iron, copper, and zinc metalloproteomes in various phyla of life has been estd. Yet, manganese metalloproteomes remain poorly defined. Metals have catalytic and structural functions in proteins. However, addnl. functions have evolved. Proteins that control metal homeostasis and proteins that are metal-regulated bind metal ions transiently and are generally not accounted for in ests. from bioinformatics. Thus, metalloproteomes are dynamic and likely to be larger than present ests. suggest. This account discusses the assignment of transition metals in metalloproteins and the ensuing issues facing anal. chemists and structural and computational biologists. Biol. and chem. selectivities render metal selection by metalloproteins either more stringent or less stringent depending on the metal homeostatic system of the organism, the subcellular location of the protein, and environmental factors. Failure to recognize the principles of metal utilization has led to assigning the wrong metal in metalloproteins and has missed some of the regulatory functions of transition metal ions.
2. 2

   Li, J.; Yu, J.; Zhao, J.; Wang, J.; Zheng, S.; Lin, S.; Chen, L.; Yang, M.; Jia, S.; Zhang, X.; Chen, P. R. Palladium-triggered deprotection chemistry for protein activation in living cells. Nat. Chem. 2014, 6, 352– 361,  DOI: 10.1038/nchem.1887

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   Palladium-triggered deprotection chemistry for protein activation in living cells

   Li, Jie; Yu, Juntao; Zhao, Jingyi; Wang, Jie; Zheng, Siqi; Lin, Shixian; Chen, Long; Yang, Maiyun; Jia, Shang; Zhang, Xiaoyu; Chen, Peng R.

   Nature Chemistry (2014), 6 (4), 352-361CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)

   Employing small mols. or chem. reagents to modulate the function of an intracellular protein, particularly in a gain-of-function fashion, remains a challenge. In contrast to inhibitor-based loss-of-function approaches, methods based on a gain of function enable specific signalling pathways to be activated inside a cell. Here we report a chem. rescue strategy that uses a palladium-mediated deprotection reaction to activate a protein within living cells. We identify biocompatible and efficient palladium catalysts that cleave the propargyl carbamate group of a protected lysine analog to generate a free lysine. The lysine analog can be genetically and site-specifically incorporated into a protein, which enables control over the reaction site. This deprotection strategy is shown to work with a range of different cell lines and proteins. We further applied this biocompatible protection group/catalyst pair for caging and subsequent release of a crucial lysine residue in a bacterial Type III effector protein within host cells, which reveals details of its virulence mechanism.
3. 3

   Li, J.; Chen, P. R. Development and application of bond cleavage reactions in bioorthogonal chemistry. Nat. Chem. Biol. 2016, 12, 129– 137,  DOI: 10.1038/nchembio.2024

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   Development and application of bond cleavage reactions in bioorthogonal chemistry

   Li, Jie; Chen, Peng R.

   Nature Chemical Biology (2016), 12 (3), 129-137CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)

   A review. Bioorthogonal chem. reactions are a thriving area of chem. research in recent years as an unprecedented technique to dissect native biol. processes through chem.-enabled strategies. However, current concepts of bioorthogonal chem. have largely centered on bond formation reactions between two mutually reactive bioorthogonal handles. Recently, in a reverse strategy, a collection of bond cleavage reactions has emerged with excellent biocompatibility. These reactions have expanded the bioorthogonal chem. repertoire, enabling an array of exciting new biol. applications that range from the chem. controlled spatial and temporal activation of intracellular proteins and small-mol. drugs to the direct manipulation of intact cells under physiol. conditions. Here the authors highlight the development and applications of these bioorthogonal cleavage reactions. Furthermore, the authors lay out challenges and propose future directions along this appealing avenue of research.
4. 4

   Weiss, J. T.; Dawson, J. C.; Macleod, K. G.; Rybski, W.; Fraser, C.; Torres-Sánchez, C.; Patton, E. E.; Bradley, M.; Carragher, N. O.; Unciti-Broceta, A. Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach. Nat. Commun. 2014, 5, 3277,  DOI: 10.1038/ncomms4277

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   Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach

   Weiss Jason T; Dawson John C; Macleod Kenneth G; Fraser Craig; Carragher Neil O; Unciti-Broceta Asier; Rybski Witold; Patton E Elizabeth; Torres-Sanchez Carmen; Bradley Mark

   Nature communications (2014), 5 (), 3277 ISSN:.

   A bioorthogonal organometallic reaction is a biocompatible transformation undergone by a synthetic material exclusively through the mediation of a non-biotic metal source; a selective process used to label biomolecules and activate probes in biological environs. Here we report the in vitro bioorthogonal generation of 5-fluorouracil from a biologically inert precursor by heterogeneous Pd(0) catalysis. Although independently harmless, combined treatment of 5-fluoro-1-propargyl-uracil and Pd(0)-functionalized resins exhibits comparable antiproliferative properties to the unmodified drug in colorectal and pancreatic cancer cells. Live-cell imaging and immunoassay studies demonstrate that the cytotoxic activity of the prodrug/Pd(0)-resin combination is due to the in situ generation of 5-fluorouracil. Pd(0)-resins can be carefully implanted in the yolk sac of zebrafish embryos and display excellent biocompatibility and local catalytic activity. The in vitro efficacy shown by this masking/activation strategy underlines its potential to develop a bioorthogonally activated prodrug approach and supports further in vivo investigations.
5. 5

   van de L’Isle, M. O. N.; Ortega-Liebana, M. C.; Unciti-Broceta, A. Transition metal catalysts for the bioorthogonal synthesis of bioactive agents. Curr. Opin. Chem. Biol. 2021, 61, 32– 42,  DOI: 10.1016/j.cbpa.2020.10.001

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   Transition metal catalysts for the bioorthogonal synthesis of bioactive agents

   van de L'Isle, Melissa O. N.; Ortega-Liebana, Mari Carmen; Unciti-Broceta, Asier

   Current Opinion in Chemical Biology (2021), 61 (), 32-42CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)

   A review. The incorporation of abiotic transition metal catalysis into the chem. biol. space has significantly expanded the tool kit of bioorthogonal chemistries accessible for cell culture and in vivo applications. A rich variety of homogeneous and heterogeneous catalysts has shown functional compatibility with physiol. conditions and biostability in complex environs, enabling their exploitation as extracellular or intracellular factories of bioactive agents. Current trends in the field are focusing on investigating new metals and sophisticated catalytic devices and toward more applied activities, such as the integration of subcellular, cell- and site-targeting capabilities or the exploration of novel biomedical applications. We present herein an overview of the latest advances in the field, highlighting the increasing role of transition metals for the controlled release of therapeutics.
6. 6

   Li, Z.; Shen, D.; Hu, S.; Su, T.; Huang, K.; Liu, F.; Hou, L.; Cheng, K. Pretargeting and Bioorthogonal Click Chemistry-Mediated Endogenous Stem Cell Homing for Heart Repair. ACS Nano 2018, 12, 12193– 12200,  DOI: 10.1021/acsnano.8b05892

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   Pretargeting and Bioorthogonal Click Chemistry-Mediated Endogenous Stem Cell Homing for Heart Repair

   Li, Zhenhua; Shen, Deliang; Hu, Shiqi; Su, Teng; Huang, Ke; Liu, Feiran; Hou, Lei; Cheng, Ke

   ACS Nano (2018), 12 (12), 12193-12200CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)

   Stem cell therapy is one of the promising strategies for the treatment of ischemic heart disease. However, the clin. application of stem cells transplantation is limited by low cell engraftment in the infarcted myocardium. Taking advantage of pretargeting and bioorthogonal chem., we engineered a pretargeting and bioorthogonal chem. (PTBC) system to capture endogenous circulating stem cells and target them to the injured heart for effective repair. Two bioorthogonal antibodies were i.v. administered with a pretargeting interval (48 h). Through bioorthogonal click reaction, the two antibodies are linked in vivo, engaging endogenous stem cells with circulating platelets. As a result, the platelets redirect the stem cells to the injured heart. In vitro and in vivo studies demonstrated that bioorthogonal click reaction was able to induce the conjugation of platelets and endothelial progenitor cells (EPCs) and enhance the binding of EPCs to collagen and injured blood vessels. More importantly, in a mouse model of acute myocardial infarction, the in vivo results of cardiac function, heart morphometry, and immunohistochem. assessment all confirmed effective heart repair by the PTBC system.
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   Selective fluorescence labeling of lipids in living cells

   Neef Anne B; Schultz Carsten

   Angewandte Chemie (International ed. in English) (2009), 48 (8), 1498-500 ISSN:.

   Click chemistry in vivo: Three phosphatidic acid derivatives with alkyne groups in their fatty acid chains were synthesized and incorporated into mammalian cell membranes. Copper(I)-catalyzed and strain-promoted azide-alkyne cycloaddition reactions were used for their visualization (see schematic representation and fluorescence microscopic image).
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   Plass, T.; Milles, S.; Koehler, C.; Schultz, C.; Lemke, E. A. Genetically encoded copper-free click chemistry. Angew. Chem., Int. Ed. Engl. 2011, 50, 3878– 3881,  DOI: 10.1002/anie.201008178

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   Genetically encoded copper-free click chemistry

   Plass Tilman; Milles Sigrid; Koehler Christine; Schultz Carsten; Lemke Edward A

   Angewandte Chemie (International ed. in English) (2011), 50 (17), 3878-81 ISSN:.

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   Saxon, E.; Bertozzi, C. R. Cell surface engineering by a modified Staudinger reaction. Science 2000, 287, 2007– 2010,  DOI: 10.1126/science.287.5460.2007

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   Cell surface engineering by a modified Staudinger reaction

   Saxon, Eliana; Bertozzi, Carolyn R.

   Science (Washington, D. C.) (2000), 287 (5460), 2007-2010CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

   Selective chem. reactions enacted within a cellular environment can be powerful tools for elucidating biol. processes or engineering novel interactions. A chem. transformation that permits the selective formation of covalent adducts among richly functionalized biopolymers within a cellular context is presented. A ligation modeled after the Staudinger reaction forms an amide bond by coupling of an azide and a specifically engineered triarylphosphine. Both reactive partners are abiotic and chem. orthogonal to native cellular components. Azides installed within cell surface glycoconjugates by metab. of a synthetic azidosugar were reacted with a biotinylated triarylphosphine to produce stable cell-surface adducts. The tremendous selectivity of the transformation should permit its execution within a cell's interior, offering new possibilities for probing intracellular interactions.
10. 10

    Agard, N. J.; Prescher, J. A.; Bertozzi, C. R. A strain-promoted [3 + 2] azide-alkyne cycloaddition for covalent modification of biomolecules in living systems. J. Am. Chem. Soc. 2004, 126, 15046– 15047,  DOI: 10.1021/ja044996f

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    A strain-promoted [3+2] azide-alkyne cycloaddition for covalent modification of biomolecules in living systems

    Agard, Nicholas J.; Prescher, Jennifer A.; Bertozzi, Carolyn R.

    Journal of the American Chemical Society (2004), 126 (46), 15046-15047CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    Selective chem. reactions that are orthogonal to the diverse functionality of biol. systems have become important tools in the field of chem. biol. Two notable examples are the Staudinger ligation of azides and phosphines and the Cu(I)-catalyzed [3+2] cycloaddn. of azides and alkynes ("click chem."). The Staudinger ligation has sufficient biocompatibility for performance in living animals but suffers from phosphine oxidn. and synthetic challenges. Click chem. obviates the requirement of phosphines, but the Cu(I) catalyst is toxic to cells, thereby precluding in vivo applications. Here we present a strain-promoted [3+2] cycloaddn. between cyclooctynes and azides that proceeds under physiol. conditions without the need for a catalyst. The utility of the reaction was demonstrated by selective modification of biomols. in vitro and on living cells, with no apparent toxicity.
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    Prescher, J. A.; Bertozzi, C. R. Chemistry in living systems. Nat. Chem. Biol. 2005, 1, 13– 21,  DOI: 10.1038/nchembio0605-13

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    Chemistry in living systems

    Prescher, Jennifer A.; Bertozzi, Carolyn R.

    Nature Chemical Biology (2005), 1 (1), 13-21CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)

    A review. Dissecting complex cellular processes requires the ability to track biomols. as they function within their native habitat. Although genetically encoded tags such as GFP are widely used to monitor discrete proteins, they can cause significant perturbations to a protein's structure and have no direct extension to other classes of biomols. such as glycans, lipids, nucleic acids and secondary metabolites. In recent years, an alternative tool for tagging biomols. has emerged from the chem. biol. community-the bioorthogonal chem. reporter. In a prototypical expt., a unique chem. motif, often as small as a single functional group, is incorporated into the target biomol. using the cell's own biosynthetic machinery. The chem. reporter is then covalently modified in a highly selective fashion with an exogenously delivered probe. This review highlights the development of bioorthogonal chem. reporters and reactions and their application in living systems.
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    Tomás-Gamasa, M.; Martínez-Calvo, M.; Couceiro, J. R.; Mascareñas, J. L. Transition metal catalysis in the mitochondria of living cells. Nat. Commun. 2016, 7, 12538,  DOI: 10.1038/ncomms12538

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    Transition metal catalysis in the mitochondria of living cells

    Tomas-Gamasa Maria; Martinez-Calvo Miguel; Couceiro Jose R; Mascarenas Jose L

    Nature communications (2016), 7 (), 12538 ISSN:.

    The development of transition metal catalysts capable of promoting non-natural transformations within living cells can open significant new avenues in chemical and cell biology. Unfortunately, the complexity of the cell makes it extremely difficult to translate standard organometallic chemistry to living environments. Therefore, progress in this field has been very slow, and many challenges, including the possibility of localizing active metal catalysts into specific subcellular sites or organelles, remain to be addressed. Herein, we report a designed ruthenium complex that accumulates preferentially inside the mitochondria of mammalian cells, while keeping its ability to react with exogenous substrates in a bioorthogonal way. Importantly, we show that the subcellular catalytic activity can be used for the confined release of fluorophores, and even allows selective functional alterations in the mitochondria by the localized transformation of inert precursors into uncouplers of the membrane potential.
13. 13

    Plunk, M. A.; Alaniz, A.; Olademehin, O. P.; Ellington, T. L.; Shuford, K. L.; Kane, R. R. Design and Catalyzed Activation of Tak-242 Prodrugs for Localized Inhibition of TLR4-Induced Inflammation. ACS Med. Chem. Lett. 2020, 11, 141– 146,  DOI: 10.1021/acsmedchemlett.9b00518

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    Design and catalyzed activation of Tak-242 prodrugs for localized inhibition of TLR4-induced inflammation

    Plunk, Michael A.; Alaniz, Alyssa; Olademehin, Olatunde P.; Ellington, Thomas L.; Shuford, Kevin L.; Kane, Robert R.

    ACS Medicinal Chemistry Letters (2020), 11 (2), 141-146CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)

    Tak-242 (resatorvid), a Toll-like Receptor 4 (TLR4) inhibitor, has been identified as a potent suppressor of innate inflammation. As a strategy to target Tak-242 to select tissue, four TLR4-inactive prodrugs were synthesized for activation via two different release mechanisms. Two nitrobenzyl Tak-242 prodrugs released the parent drug upon exposure to the exogenous enzyme nitroreductase, while the two propargyl prodrugs were converted to Tak-242 in the presence of Pd0.
14. 14

    Okamoto, Y.; Kojima, R.; Schwizer, F.; Bartolami, E.; Heinisch, T.; Matile, S.; Fussenegger, M.; Ward, T. R. A cell-penetrating artificial metalloenzyme regulates a gene switch in a designer mammalian cell. Nat. Commun. 2018, 9, 1943,  DOI: 10.1038/s41467-018-04440-0

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    A cell-penetrating artificial metalloenzyme regulates a gene switch in a designer mammalian cell

    Okamoto Yasunori; Schwizer Fabian; Heinisch Tillmann; Ward Thomas R; Kojima Ryosuke; Fussenegger Martin; Kojima Ryosuke; Bartolami Eline; Matile Stefan

    Nature communications (2018), 9 (1), 1943 ISSN:.

    Complementing enzymes in their native environment with either homogeneous or heterogeneous catalysts is challenging due to the sea of functionalities present within a cell. To supplement these efforts, artificial metalloenzymes are drawing attention as they combine attractive features of both homogeneous catalysts and enzymes. Herein we show that such hybrid catalysts consisting of a metal cofactor, a cell-penetrating module, and a protein scaffold are taken up into HEK-293T cells where they catalyze the uncaging of a hormone. This bioorthogonal reaction causes the upregulation of a gene circuit, which in turn leads to the expression of a nanoluc-luciferase. Relying on the biotin-streptavidin technology, variation of the biotinylated ruthenium complex: the biotinylated cell-penetrating poly(disulfide) ratio can be combined with point mutations on streptavidin to optimize the catalytic uncaging of an allyl-carbamate-protected thyroid hormone triiodothyronine. These results demonstrate that artificial metalloenzymes offer highly modular tools to perform bioorthogonal catalysis in live HEK cells.
15. 15

    Pérez-López, A. M.; Rubio-Ruiz, B.; Sebastián, V.; Hamilton, L.; Adam, C.; Bray, T. L.; Irusta, S.; Brennan, P. M.; Lloyd-Jones, G.; Sieger, D.; Santamaría, J.; Unciti-Broceta, A. Gold-Triggered Uncaging Chemistry in Living Systems. Angew. Chem., Int. Ed. Engl. 2017, 56, 12548– 12552,  DOI: 10.1002/anie.201705609

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    Gold-Triggered Uncaging Chemistry in Living Systems

    Perez-Lopez Ana M; Rubio-Ruiz Belen; Adam Catherine; Bray Thomas L; Brennan Paul M; Unciti-Broceta Asier; Sebastian Victor; Irusta Silvia; Santamaria Jesus; Sebastian Victor; Irusta Silvia; Santamaria Jesus; Hamilton Lloyd; Sieger Dirk; Brennan Paul M; Lloyd-Jones Guy C

    Angewandte Chemie (International ed. in English) (2017), 56 (41), 12548-12552 ISSN:.

    Recent advances in bioorthogonal catalysis are increasing the capacity of researchers to manipulate the fate of molecules in complex biological systems. A bioorthogonal uncaging strategy is presented, which is triggered by heterogeneous gold catalysis and facilitates the activation of a structurally diverse range of therapeutics in cancer cell culture. Furthermore, this solid-supported catalytic system enabled locally controlled release of a fluorescent dye into the brain of a zebrafish for the first time, offering a novel way to modulate the activity of bioorthogonal reagents in the most fragile and complex organs.
16. 16

    Bray, T. L.; Salji, M.; Brombin, A.; Pérez-López, A. M.; Rubio-Ruiz, B.; Galbraith, L. C. A.; Patton, E. E.; Leung, H.; Unciti-Broceta, A. Bright insights into palladium-triggered local chemotherapy. Chem. Sci. 2018, 9, 7354– 7361,  DOI: 10.1039/C8SC02291G

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    Bright insights into palladium-triggered local chemotherapy

    Bray, Thomas L.; Salji, Mark; Brombin, Alessandro; Perez-Lopez, Ana M.; Rubio-Ruiz, Belen; Galbraith, Laura C. A.; Patton, E. Elizabeth; Leung, Hing Y.; Unciti-Broceta, Asier

    Chemical Science (2018), 9 (37), 7354-7361CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)

    The incorporation of transition metal catalysts to the bioorthogonal toolbox has opened the possibility of producing supra-stoichiometric amts. of xenobiotics in living systems in a non-enzymic fashion. For medical use, such metals could be embedded in implantable devices (i.e. heterogeneous catalyst) to "synthesize" drugs in desired locations (e.g. in a tumor) with high specificity and for extended periods of time, overcoming the useful life limitations of current local therapy modalities directed to specific organ sites (e.g. brachytherapy, controlled release systems). To translate this approach into a bona fide therapeutic option, it is essential to develop clin.-accessible implantation procedures and to understand and validate the activation process in relevant preclin. models. Herein we report the development of a novel Pd-activatable precursor of the red-fluorescent drug doxorubicin and Pd devices of optimized size and activity. Screening in state-of-the-art cancer models provided fundamental insights into the insertion protocols, safety and stability of the devices and into the prodrug distribution profile before and after activation.
17. 17

    Sancho-Albero, M.; Rubio-Ruiz, B.; Pérez-López, A. M.; Sebastián, V.; Martín-Duque, P.; Arruebo, M.; Santamaría, J.; Unciti-Broceta, A. Cancer-derived exosomes loaded with ultrathin palladium nanosheets for targeted bioorthogonal catalysis. Nat. Catal. 2019, 2, 864– 872,  DOI: 10.1038/s41929-019-0333-4

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    Cancer-derived exosomes loaded with ultrathin palladium nanosheets for targeted bioorthogonal catalysis

    Sancho-Albero, Maria; Rubio-Ruiz, Belen; Perez-Lopez, Ana M.; Sebastian, Victor; Martin-Duque, Pilar; Arruebo, Manuel; Santamaria, Jesus; Unciti-Broceta, Asier

    Nature Catalysis (2019), 2 (10), 864-872CODEN: NCAACP; ISSN:2520-1158. (Nature Research)

    The transformational impact of bioorthogonal chemistries has inspired new strategies for the in vivo synthesis of bioactive agents through non-natural means. Among these, Pd catalysts have played a prominent role in the growing subfield of bioorthogonal catalysis by producing xenobiotics and uncaging biomols. in living systems. However, delivering catalysts selectively to specific cell types still lags behind catalyst development. Here, we have developed a bioartificial device comprising cancer-derived exosomes that are loaded with Pd catalysts by a method that enables the controlled assembly of Pd nanosheets directly inside the vesicles. This hybrid system mediates Pd-triggered dealkylation reactions in vitro and inside cells, and displays preferential tropism for their progenitor cells. The use of Trojan exosomes to deliver abiotic catalysts into designated cancer cells creates the opportunity for a new targeted therapy modality; i.e., exosome-directed catalyst prodrug therapy, whose first steps are presented herein with the cell-specific release of the anticancer drug panobinostat.
18. 18

    Wang, J.; Wang, X.; Fan, X.; Chen, P. R. Unleashing the Power of Bond Cleavage Chemistry in Living Systems. ACS Cent. Sci. 2021, 7, 929– 943,  DOI: 10.1021/acscentsci.1c00124

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    Unleashing the Power of Bond Cleavage Chemistry in Living Systems

    Wang, Jie; Wang, Xin; Fan, Xinyuan; Chen, Peng R.

    ACS Central Science (2021), 7 (6), 929-943CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)

    A review. Bioorthogonal cleavage chem. has been rapidly emerging as a powerful tool for manipulation and gain-of-function studies of biomols. in living systems. While the initial bond formation-centered bioorthogonal reactions have been widely adopted for labeling, tracing, and capturing biomols., the newly developed bond cleavage-enabled bioorthogonal reactions have opened new possibilities for rescuing small mols. as well as biomacromols. in living systems, allowing multidimensional controls over biol. processes in vitro and in vivo. In this Outlook, we first summarized the development and applications of bioorthogonal cleavage reactions (BCRs) that restore the functions of chem. structures as well as more complex networks, including the liberation of prodrugs, release of bioconjugates, and in situ reactivation of intracellular proteins. As we embarked on this fruitful progress, we outlined the unmet scientific needs and future directions along this exciting avenue. We believe that the potential of BCRs will be further unleashed when combined with other frontier technologies, such as genetic code expansion and proximity-enabled chem. labeling.
19. 19

    Miller, M. A.; Askevold, B.; Mikula, H.; Kohler, R. H.; Pirovich, D.; Weissleder, R. Nano-palladium is a cellular catalyst for in vivo chemistry. Nat. Commun. 2017, 8, 15906,  DOI: 10.1038/ncomms15906

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    Nano-palladium is a cellular catalyst for in vivo chemistry

    Miller, Miles A.; Askevold, Bjorn; Mikula, Hannes; Kohler, Rainer H.; Pirovich, David; Weissleder, Ralph

    Nature Communications (2017), 8 (), 15906CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)

    Palladium catalysts have been widely adopted for org. synthesis and diverse industrial applications given their efficacy and safety, yet their biol. in vivo use has been limited to date. Here we show that nanoencapsulated palladium is an effective means to target and treat disease through in vivo catalysis. Palladium nanoparticles (Pd-NPs) were created by screening different Pd compds. and then encapsulating bis[tri(2-furyl)phosphine]palladium(II) dichloride in a biocompatible poly(lactic-co-glycolic acid)-b-polyethyleneglycol platform. Using mouse models of cancer, the NPs efficiently accumulated in tumors, where the Pd-NP activated different model prodrugs. Longitudinal studies confirmed that prodrug activation by Pd-NP inhibits tumor growth, extends survival in tumor-bearing mice and mitigates toxicity compared to std. doxorubicin formulations. Thus, here we demonstrate safe and efficacious in vivo catalytic activity of a Pd compd. in mammals.
20. 20

    Pérez-López, A. M.; Rubio-Ruiz, B.; Valero, T.; Contreras-Montoya, R.; Alvarez de Cienfuegos, L.; Sebastián, V.; Santamaría, J.; Unciti-Broceta, A. Bioorthogonal Uncaging of Cytotoxic Paclitaxel through Pd Nanosheet-Hydrogel Frameworks. J. Med. Chem. 2020, 63, 9650– 9659,  DOI: 10.1021/acs.jmedchem.0c00781

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    20

    Bioorthogonal Uncaging of Cytotoxic Paclitaxel through Pd Nanosheet-Hydrogel Frameworks

    Perez-Lopez, Ana M.; Rubio-Ruiz, Belen; Valero, Teresa; Contreras-Montoya, Rafael; Alvarez de Cienfuegos, Luis; Sebastian, Victor; Santamaria, Jesus; Unciti-Broceta, Asier

    Journal of Medicinal Chemistry (2020), 63 (17), 9650-9659CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    The promising potential of bioorthogonal catalysis in biomedicine is inspiring incremental efforts to design strategies that regulate drug activity in living systems. To achieve this, it is not only essential to develop customized inactive prodrugs and biocompatible metal catalysts but also the right phys. environment for them to interact and enable drug prodn. under spatial and/or temporal control. Toward this goal, here, we report the first inactive precursor of the potent broad-spectrum anticancer drug paclitaxel (a.k.a. Taxol) that is stable in cell culture and labile to Pd catalysts. This new prodrug is effectively uncaged in cancer cell culture by Pd nanosheets captured within agarose and alginate hydrogels, providing a biodegradable catalytic framework to achieve controlled release of one of the most important chemotherapy drugs in medical practice. The compatibility of bioorthogonal catalysis and phys. hydrogels opens up new opportunities to administer and modulate the mobility of transition metal catalysts in living environs.
21. 21

    Destito, P.; Sousa-Castillo, A.; Couceiro, J. R.; López, F.; Correa-Duarte, M. A.; Mascareñas, J. L. Hollow nanoreactors for Pd-catalyzed Suzuki-Miyaura coupling and O-propargyl cleavage reactions in bio-relevant aqueous media. Chem. Sci. 2019, 10, 2598– 2603,  DOI: 10.1039/C8SC04390F

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    21

    Hollow nanoreactors for Pd-catalyzed Suzuki-Miyaura coupling and O-propargyl cleavage reactions in bio-relevant aqueous media

    Destito, Paolo; Sousa-Castillo, Ana; Couceiro, Jose R.; Lopez, Fernando; Correa-Duarte, Miguel A.; Mascarenas, Jose L.

    Chemical Science (2019), 10 (9), 2598-2603CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)

    Fabrication of hollow microspheres consisting of mesoporous silica nanoshells decorated with an inner layer of palladium nanoparticles and their use as Pd-nanoreactors in aq. media was described. These palladium-equipped capsules can be used to promote the uncaging of propargyl-protected phenols, as well as Suzuki-Miyaura cross-coupling, in water and at physiol. compatible temps. Importantly, the depropargylation reaction can be accomplished in a bioorthogonal manner in the presence of relatively high concns. of biomol. components and even in the presence of mammalian cells.
22. 22

    Kumar, A.; Kumar, S.; Kumari, N.; Lee, S. H.; Han, J.; Michael, I. J.; Cho, Y.-K.; Lee, I. S. Plasmonically Coupled Nanoreactors for NIR-Light-Mediated Remote Stimulation of Catalysis in Living Cells. ACS Catal. 2019, 9, 977– 990,  DOI: 10.1021/acscatal.8b04005

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    Plasmonically Coupled Nanoreactors for NIR-Light-Mediated Remote Stimulation of Catalysis in Living Cells

    Kumar, Amit; Kumar, Sumit; Kumari, Nitee; Lee, Seon Hee; Han, Jay; Michael, Issac J.; Cho, Yoon-Kyoung; Lee, In Su

    ACS Catalysis (2019), 9 (2), 977-990CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)

    Artificial nanoreactors that can facilitate catalysis in living systems on-demand with the aid of a remotely operable and biocompatible energy source are needed to leverage the chem. diversity and expediency of advanced chem. synthesis in biol. and medicine. Here, we designed and synthesized plasmonically integrated nanoreactors (PINERs) with highly tunable structure and NIR-light-induced synergistic function for efficiently promoting unnatural catalytic reactions inside living cells. We devised a synthetic approach toward PINERs by investigating the crucial role of metal-tannin coordination polymer nanofilm-the pH-induced decomplexation-mediated phase-transition process-for growing arrays of Au-nanospheroid-units, constructing a plasmonic corona around the proximal and reactant-accessible silica-compartmentalized catalytic nanospace. Owing to the extensive plasmonic coupling effect, PINERs show strong and tunable optical absorption in the visible to NIR range, ultrabright plasmonic light scattering, controllable thermoplasmonic effect, and remarkable catalysis; and, upon internalization by living cells, PINERs are highly biocompatible and demonstrate dark-field microscopy-based bioimaging features. Empowered with the synergy between plasmonic and catalytic effects and reactant/product transport, facilitated by the NIR-irradn., PINERs can perform intracellular catalytic reactions with dramatically accelerated rates and efficiently synthesize chem. activated fluorescence-probes inside living cells.
23. 23

    Cao-Milán, R.; Gopalakrishnan, S.; He, L. D.; Huang, R.; Wang, L.-S.; Castellanos, L.; Luther, D. C.; Landis, R. F.; Makabenta, J. M. V.; Li, C.-H.; Zhang, X.; Scaletti, F.; Vachet, R. W.; Rotello, V. M. Thermally Gated Bio-orthogonal Nanozymes with Supramolecularly Confined Porphyrin Catalysts for Antimicrobial Uses. Chem 2020, 6, 1113– 1124,  DOI: 10.1016/j.chempr.2020.01.015

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    Thermally Gated Bio-orthogonal Nanozymes with Supramolecularly Confined Porphyrin Catalysts for Antimicrobial Uses

    Cao-Milan, Roberto; Gopalakrishnan, Sanjana; He, Luke D.; Huang, Rui; Wang, Li-Sheng; Castellanos, Laura; Luther, David C.; Landis, Ryan F.; Makabenta, Jessa Marie V.; Li, Cheng-Hsuan; Zhang, Xianzhi; Scaletti, Federica; Vachet, Richard W.; Rotello, Vincent M.

    Chem (2020), 6 (5), 1113-1124CODEN: CHEMVE; ISSN:2451-9294. (Cell Press)

    Bio-orthogonal catalysis has the capability of localized generation of imaging and therapeutic mols. in vitro and in vivo. The integration of these catalysts into thermoresponsive nanoparticle platforms would generate bio-orthogonal "nanozymes" that could be controlled through endogenous or exogenous thermal control. We have fabricated thermoresponsive nanozymes by confining supramol. assemblies of porphyrins into the monolayer of gold nanoparticles. The resulting nanodevices feature an on-off gated thermal response occurring over a 3°C range with commensurate tunability of activation temp. from 25°C to 37°C. Reversible activation of catalysis was demonstrated in complex biol. environments, and the efficacy of bi-stable thermoresponsive nanozymes demonstrated through thermal activation of antibiotic-based prodrugs to effectively treat bacterial biofilms.
24. 24

    Tonga, G. Y.; Jeong, Y.; Duncan, B.; Mizuhara, T.; Mout, R.; Das, R.; Kim, S. T.; Yeh, Y.-C.; Yan, B.; Hou, S.; Rotello, V. M. Supramolecular regulation of bioorthogonal catalysis in cells using nanoparticle-embedded transition metal catalysts. Nat. Chem. 2015, 7, 597– 603,  DOI: 10.1038/nchem.2284

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    24

    Supramolecular regulation of bioorthogonal catalysis in cells using nanoparticle-embedded transition metal catalysts

    Tonga, Gulen Yesilbag; Jeong, Youngdo; Duncan, Bradley; Mizuhara, Tsukasa; Mout, Rubul; Das, Riddha; Kim, Sung Tae; Yeh, Yi-Cheun; Yan, Bo; Hou, Singyuk; Rotello, Vincent M.

    Nature Chemistry (2015), 7 (7), 597-603CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)

    Bioorthogonal catalysis broadens the functional possibilities of intracellular chem. Effective delivery and regulation of synthetic catalytic systems in cells are challenging due to the complex intracellular environment and catalyst instability. Here, we report the fabrication of protein-sized bioorthogonal nanozymes through the encapsulation of hydrophobic transition metal catalysts into the monolayer of water-sol. gold nanoparticles. The activity of these catalysts can be reversibly controlled by binding a supramol. cucurbit[7]uril 'gate-keeper' onto the monolayer surface, providing a biomimetic control mechanism that mimics the allosteric regulation of enzymes. The potential of this gated nanozyme for use in imaging and therapeutic applications was demonstrated through triggered cleavage of allylcarbamates for pro-fluorophore activation and propargyl groups for prodrug activation inside living cells.
25. 25

    Martínez, R.; Carrillo-Carrión, C.; Destito, P.; Alvarez, A.; Tomás-Gamasa, M.; Pelaz, B.; Lopez, F.; Mascareñas, J. L.; Del Pino, P. Core-Shell Palladium/MOF Platforms as Diffusion-Controlled Nanoreactors in Living Cells and Tissue Models. Cell Rep. Phys. Sci. 2020, 1, 100076,  DOI: 10.1016/j.xcrp.2020.100076

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    25

    Core-Shell Palladium/MOF Platforms as Diffusion-Controlled Nanoreactors in Living Cells and Tissue Models

    Martinez Raquel; Carrillo-Carrion Carolina; Alvarez Aitor; Del Pino Pablo; Destito Paolo; Tomas-Gamasa Maria; Lopez Fernando; Mascarenas Jose L; Pelaz Beatriz; Lopez Fernando

    Cell reports. Physical science (2020), 1 (6), 100076 ISSN:.

    Translating the potential of transition metal catalysis to biological and living environments promises to have a profound impact in chemical biology and biomedicine. A major challenge in the field is the creation of metal-based catalysts that remain active over time. Here, we demonstrate that embedding a reactive metallic core within a microporous metal-organic framework-based cloak preserves the catalytic site from passivation and deactivation, while allowing a suitable diffusion of the reactants. Specifically, we report the fabrication of nanoreactors composed of a palladium nanocube core and a nanometric imidazolate framework, which behave as robust, long-lasting nanoreactors capable of removing propargylic groups from phenol-derived pro-fluorophores in biological milieu and inside living cells. These heterogeneous catalysts can be reused within the same cells, promoting the chemical transformation of recurrent batches of reactants. We also report the assembly of tissue-like 3D spheroids containing the nanoreactors and demonstrate that they can perform the reactions in a repeated manner.
26. 26

    Wang, F.; Zhang, Y.; Liu, Z.; Du, Z.; Zhang, L.; Ren, J.; Qu, X. A Biocompatible Heterogeneous MOF-Cu Catalyst for In Vivo Drug Synthesis in Targeted Subcellular Organelles. Angew. Chem., Int. Ed. Engl. 2019, 58, 6987– 6992,  DOI: 10.1002/anie.201901760

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    A Biocompatible Heterogeneous MOF-Cu Catalyst for In Vivo Drug Synthesis in Targeted Subcellular Organelles

    Wang Faming; Zhang Yan; Liu Zhengwei; Du Zhi; Zhang Lu; Ren Jinsong; Qu Xiaogang; Wang Faming; Zhang Yan; Liu Zhengwei; Du Zhi; Zhang Lu

    Angewandte Chemie (International ed. in English) (2019), 58 (21), 6987-6992 ISSN:.

    As a typical bioorthogonal reaction, the copper-catalyzed azide-alkyne cycloaddition (CuAAC) has been used for drug design and synthesis. However, for localized drug synthesis, it is important to be able to determine where the CuAAC reaction occurs in living cells. In this study, we constructed a heterogeneous copper catalyst on a metal-organic framework that could preferentially accumulate in the mitochondria of living cells. Our system enabled the localized synthesis of drugs through a site-specific CuAAC reaction in mitochondria with good biocompatibility. Importantly, the subcellular catalytic process for localized drug synthesis avoided the problems of the delivery and distribution of toxic molecules. In vivo tumor therapy experiments indicated that the localized synthesis of resveratrol-derived drugs led to greater antitumor efficacy and minimized side effects usually associated with drug delivery and distribution.
27. 27

    Das, R.; Hardie, J.; Joshi, B. P.; Zhang, X.; Gupta, A.; Luther, D. C.; Fedeli, S.; Farkas, M. E.; Rotello, V. M. Macrophage-Encapsulated Bioorthogonal Nanozymes for Targeting Cancer Cells. JACS Au 2022, 2, 1679– 1685,  DOI: 10.1021/jacsau.2c00247

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    27

    Macrophage-Encapsulated Bioorthogonal Nanozymes for Targeting Cancer Cells

    Das, Riddha; Hardie, Joseph; Joshi, Bishnu P.; Zhang, Xianzhi; Gupta, Aarohi; Luther, David C.; Fedeli, Stefano; Farkas, Michelle E.; Rotello, Vincent M.

    JACS Au (2022), 2 (7), 1679-1685CODEN: JAAUCR; ISSN:2691-3704. (American Chemical Society)

    Macrophages migrate to tumor sites by following chemoattractant gradients secreted by tumor cells, providing a truly active targeting strategy for cancer therapy. However, macrophage-based delivery faces challenges of cargo loading, control of release, and effects of the payload on the macrophage vehicle. We present a strategy that employs bioorthogonal "nanozymes" featuring transition metal catalysts (TMCs) to provide intracellular "factories" for the conversion of prodyes and prodrugs into imaging agents and chemotherapeutics. These nanozymes solubilize and stabilize the TMCs by embedding them into self-assembled monolayer coating gold nanoparticles. Nanozymes delivered into macrophages were intracellularly localized and retained activity even after prolonged (72 h) incubation. Significantly, nanozyme-loaded macrophages maintained their inherent migratory ability toward tumor cell chemoattractants, efficiently killing cancer cells in cocultures. This work establishes the potential of nanozyme-loaded macrophages for tumor site activation of prodrugs, providing readily tunable dosages and delivery rates while minimizing off-target toxicity of chemotherapeutics.
28. 28

    Cui, X.; Li, W.; Ryabchuk, P.; Junge, K.; Beller, M. Bridging homogeneous and heterogeneous catalysis by heterogeneous single-metal-site catalysts. Nat. Catal. 2018, 1, 385– 397,  DOI: 10.1038/s41929-018-0090-9

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    Bridging homogeneous and heterogeneous catalysis by heterogeneous single-metal-site catalysts

    Cui, Xinjiang; Li, Wu; Ryabchuk, Pavel; Junge, Kathrin; Beller, Matthias

    Nature Catalysis (2018), 1 (6), 385-397CODEN: NCAACP; ISSN:2520-1158. (Nature Research)

    A review. In heterogeneous single-metal-site catalysts (HSMSCs) the active metal centers are located individually on a support and are stabilized by neighboring surface atoms such as nitrogen, oxygen or sulfur. Modern characterization techniques allow the identification of these individual metal atoms on a given support, and the resulting materials are often referred as single-atom catalysts. Their electronic properties and catalytic activity are tuned by the interaction between the central metal and the neighboring surface atoms, and their atomically dispersed nature allows for metal utilization of up to 100%. In this way, HSMSCs provide new opportunities for catalysis, and with respect to structure build a bridge between homogeneous and heterogeneous catalysis. Herein, selected publications from 2010 in this area are ed and their perspectives for the near future are highlighted. Where appropriate, comparisons between HSMSCs and homogeneous/heterogeneous counterparts are presented.
29. 29

    Streu, C.; Meggers, E. Ruthenium-induced allylcarbamate cleavage in living cells. Angew. Chem., Int. Ed. Engl. 2006, 45, 5645– 5648,  DOI: 10.1002/anie.200601752

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    29

    Ruthenium-induced allylcarbamate cleavage in living cells

    Streu Craig; Meggers Eric

    Angewandte Chemie (International ed. in English) (2006), 45 (34), 5645-8 ISSN:1433-7851.

    There is no expanded citation for this reference.
30. 30

    Vidal, C.; Tomás-Gamasa, M.; Destito, P.; López, F.; Mascareñas, J. L. Concurrent and orthogonal gold(I) and ruthenium(II) catalysis inside living cells. Nat. Commun. 2018, 9, 1913,  DOI: 10.1038/s41467-018-04314-5

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    Concurrent and orthogonal gold(I) and ruthenium(II) catalysis inside living cells

    Vidal Cristian; Tomas-Gamasa Maria; Destito Paolo; Lopez Fernando; Mascarenas Jose L; Lopez Fernando

    Nature communications (2018), 9 (1), 1913 ISSN:.

    The viability of building artificial metabolic pathways within a cell will depend on our ability to design biocompatible and orthogonal catalysts capable of achieving non-natural transformations. In this context, transition metal complexes offer unique possibilities to develop catalytic reactions that do not occur in nature. However, translating the potential of metal catalysts to living cells poses numerous challenges associated to their biocompatibility, and their stability and reactivity in crowded aqueous environments. Here we report a gold-mediated C-C bond formation that occurs in complex aqueous habitats, and demonstrate that the reaction can be translated to living mammalian cells. Key to the success of the process is the use of designed, water-activatable gold chloride complexes. Moreover, we demonstrate the viability of achieving the gold-promoted process in parallel with a ruthenium-mediated reaction, inside living cells, and in a bioorthogonal and mutually orthogonal manner.
31. 31

    Li, J.; Lin, S.; Wang, J.; Jia, S.; Yang, M.; Hao, Z.; Zhang, X.; Chen, P. R. Ligand-free palladium-mediated site-specific protein labeling inside gram-negative bacterial pathogens. J. Am. Chem. Soc. 2013, 135, 7330– 7338,  DOI: 10.1021/ja402424j

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    Ligand-Free Palladium-Mediated Site-Specific Protein Labeling Inside Gram-Negative Bacterial Pathogens

    Li, Jie; Lin, Shixian; Wang, Jie; Jia, Shang; Yang, Maiyun; Hao, Ziyang; Zhang, Xiaoyu; Chen, Peng R.

    Journal of the American Chemical Society (2013), 135 (19), 7330-7338CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    Palladium, a key transition metal in advancing modern org. synthesis, mediates diverse chem. conversions including many carbon-carbon bond formation reactions between org. compds. However, expanding palladium chem. for conjugation of biomols. such as proteins, particularly within their native cellular context, is still in its infancy. Here the authors report the site-specific protein labeling inside pathogenic Gram-neg. bacterial cells via a ligand-free palladium-mediated cross-coupling reaction. Two rationally designed pyrrolysine analogs bearing an aliph. alkyne or an iodophenyl handle were first encoded in different enteric bacteria, which offered two facial handles for palladium-mediated Sonogashira coupling reaction on proteins within these pathogens. A GFP-based bioorthogonal reaction screening system was then developed, allowing evaluation of both the efficiency and the biocompatibility of various palladium reagents in promoting protein-small mol. conjugation. The identified simple compd. Pd(NO3)2 exhibited high efficiency and biocompatibility for site-specific labeling of proteins in vitro and inside living E. coli cells. This Pd-mediated protein coupling method was further used to label and visualize a Type-III Secretion (T3S) toxin-OspF in Shigella cells. The authors' strategy may be generally applicable for imaging and tracking various virulence proteins within Gram-neg. bacterial pathogens.
32. 32

    Vidal, C.; Tomás-Gamasa, M.; Gutiérrez-González, A.; Mascareñas, J. L. Ruthenium-Catalyzed Redox Isomerizations inside Living Cells. J. Am. Chem. Soc. 2019, 141, 5125– 5129,  DOI: 10.1021/jacs.9b00837

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    32

    Ruthenium-Catalyzed Redox Isomerizations inside Living Cells

    Vidal, Cristian; Tomas-Gamasa, Maria; Gutierrez-Gonzalez, Alejandro; Mascarenas, Jose L.

    Journal of the American Chemical Society (2019), 141 (13), 5125-5129CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    Tailored ruthenium(IV) complexes can catalyze the isomerization of allylic alcs. into satd. carbonyl derivs. under physiol. relevant conditions, and even inside living mammalian cells. The reaction, which involves ruthenium-hydride intermediates, is bioorthogonal and biocompatible, and can be used for the "in cellulo" generation of fluorescent and bioactive probes. Overall, the research reveals a novel metal-based tool for cellular intervention, and comes to further demonstrate the compatibility of organometallic mechanisms with the complex environment of cells.
33. 33

    Sabatino, V.; Rebelein, J. G.; Ward, T. R. “Close-to-Release”: Spontaneous Bioorthogonal Uncaging Resulting from Ring-Closing Metathesis. J. Am. Chem. Soc. 2019, 141, 17048– 17052,  DOI: 10.1021/jacs.9b07193

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    33

    "Close-to-Release": Spontaneous Bioorthogonal Uncaging Resulting from Ring-Closing Metathesis

    Sabatino, Valerio; Rebelein, Johannes G.; Ward, Thomas R.

    Journal of the American Chemical Society (2019), 141 (43), 17048-17052CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    Bioorthogonal uncaging reactions offer versatile tools in chem. biol. In recent years, reactions have been developed to proceed efficiently under physiol. conditions. We present herein an uncaging reaction that results from ring-closing metathesis (RCM). A caged mol., tethered to a diolefinic substrate, is released via spontaneous 1,4-elimination following RCM. Using this strategy, which we term "close-to-release", we show that drugs and fluorescent probes are uncaged with fast rates, including in the presence of mammalian cells or in the periplasm of Escherichia coli. We envision that this tool may find applications in chem. biol., bioengineering and medicine.
34. 34

    Martínez-Calvo, M.; Couceiro, J. R.; Destito, P.; Rodríguez, J.; Mosquera, J.; Mascareñas, J. L. Intracellular Deprotection Reactions Mediated by Palladium Complexes Equipped with Designed Phosphine Ligands. ACS Catal. 2018, 8, 6055– 6061,  DOI: 10.1021/acscatal.8b01606

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    Intracellular Deprotection Reactions Mediated by Palladium Complexes Equipped with Designed Phosphine Ligands

    Martinez-Calvo, Miguel; Couceiro, Jose R.; Destito, Paolo; Rodriguez, Jessica; Mosquera, Jesus; Mascarenas, Jose L.

    ACS Catalysis (2018), 8 (7), 6055-6061CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)

    Discrete palladium(II) complexes featuring purposely designed phosphine ligands can promote depropargylation and deallylation reactions in cell lysates. These complexes perform better than other palladium sources, which apparently are rapidly deactivated in such hostile complex media. This good balance between reactivity and stability allows the use of these discrete phosphine palladium complexes in living mammalian cells, whereby they can mediate similar transformations. The presence of a phosphine ligand in the coordination sphere of palladium also provides for the introduction of targeting groups, such as hydrophobic phosphonium moieties, which facilitate the accumulation of the complexes in mitochondria.
35. 35

    Cherukaraveedu, D.; Cowling, P. T.; Birch, G. P.; Bradley, M.; Lilienkampf, A. Solid-phase synthesis of biocompatible N-heterocyclic carbene-Pd catalysts using a sub-monomer approach. Org. Biomol. Chem. 2019, 17, 5533– 5537,  DOI: 10.1039/C9OB00716D

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    35

    Solid-phase synthesis of biocompatible N-heterocyclic carbene-Pd catalysts using a sub-monomer approach

    Cherukaraveedu, Durgadas; Cowling, Paul T.; Birch, Gavin P.; Bradley, Mark; Lilienkampf, Annamaria

    Organic & Biomolecular Chemistry (2019), 17 (22), 5533-5537CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)

    Taking inspiration from the assembly of so-called peptoids (N-alkylglycine oligomers) we present a new synthetic methodol. whereby N-heterocyclic carbene (NHC) based Pd ligands were assembled using a sub-monomer approach and loaded with Pd via solid-phase synthesis. This allowed the rapid generation a library of NHC-palladium catalysts that were readily functionalized to allow bioconjugation. These catalysts were able to rapidly activate a caged fluorophore and 'switch-on' an anticancer prodrug in 3D cell culture.
36. 36

    Li, N.; Lim, R. K. V.; Edwardraja, S.; Lin, Q. Copper-free Sonogashira cross-coupling for functionalization of alkyne-encoded proteins in aqueous medium and in bacterial cells. J. Am. Chem. Soc. 2011, 133, 15316– 15319,  DOI: 10.1021/ja2066913

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    36

    Copper-Free Sonogashira Cross-Coupling for Functionalization of Alkyne-Encoded Proteins in Aqueous Medium and in Bacterial Cells

    Li, Nan; Lim, Reyna K.-V.; Edwardraja, Selvakumar; Lin, Qing

    Journal of the American Chemical Society (2011), 133 (39), 15316-15319CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    Bioorthogonal reactions suitable for functionalization of genetically or metabolically encoded alkynes, for example, copper-catalyzed azide-alkyne cycloaddn. reaction ("click chem."), have provided chem. tools to study biomol. dynamics and function in living systems. Despite its prominence in org. synthesis, copper-free Sonogashira cross-coupling reaction suitable for biol. applications has not been reported. In this work, the authors report the discovery of a robust aminopyrimidine-palladium(II) complex for copper-free Sonogashira cross-coupling that enables selective functionalization of a homopropargylglycine (HPG)-encoded ubiquitin protein in aq. medium. A wide range of arom. groups including fluorophores and fluorinated arom. compds. can be readily introduced into the HPG-contg. ubiquitin under mild conditions with good to excellent yields. The suitability of this reaction for functionalization of HPG-encoded ubiquitin in Escherichia coli was also demonstrated. The high efficiency of this new catalytic system should greatly enhance the utility of Sonogashira cross-coupling in bioorthogonal chem.
37. 37

    Zhou, X.-Q.; Carbo-Bague, I.; Siegler, M. A.; Hilgendorf, J.; Basu, U.; Ott, I.; Liu, R.; Zhang, L.; Ramu, V.; IJzerman, A. P.; Bonnet, S. Rollover Cyclometalation vs Nitrogen Coordination in Tetrapyridyl Anticancer Gold(III) Complexes: Effect on Protein Interaction and Toxicity. JACS Au 2021, 1, 380– 395,  DOI: 10.1021/jacsau.0c00104

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    37

    Rollover Cyclometalation vs Nitrogen Coordination in Tetrapyridyl Anticancer Gold(III) Complexes: Effect on Protein Interaction and Toxicity

    Zhou, Xue-Quan; Carbo-Bague, Imma; Siegler, Maxime A.; Hilgendorf, Jonathan; Basu, Uttara; Ott, Ingo; Liu, Rongfang; Zhang, Liyan; Ramu, Vadde; IJzerman, Adriaan P.; Bonnet, Sylvestre

    JACS Au (2021), 1 (4), 380-395CODEN: JAAUCR; ISSN:2691-3704. (American Chemical Society)

    In this work, a pair of gold(III) complexes derived from the analogous tetrapyridyl ligands H2biqbpy1 and H2biqbpy2 was prepd.: the rollover, bis-cyclometalated [Au(biqbpy1)Cl ([1]Cl) and its isomer [Au-(biqbpy2)Cl ([2]Cl). In [1]+, two pyridyl rings coordinate to the metal via a Au-C bond (C N N C coordination) and the two noncoordinated amine bridges of the ligand remain protonated, while in [2]+ all four pyridyl rings of the ligand coordinate to the metal via a Au-N bond (N N N N coordination), but both amine bridges are deprotonated. As a result, both complexes are monocationic, which allowed comparing the sole effect of cyclometalation on the chem., protein interaction, and anticancer properties of gold(III) compds. Due to their identical monocationic charge and similar mol. shape, both complexes [1]Cl and [2]Cl displaced ref. radioligand [3H]dofetilide equally well from cell membranes expressing the Kv11.1 (hERG) potassium channel, and more so than the tetrapyridyl ligands H2biqbpy1 and H2biqbpy2. By contrast, cyclometalation rendered [1]Cl coordinatively stable in the presence of biol. thiols, while [2]Cl was reduced by millimolar concn. of glutathione into metastable Au(I) species releasing the free ligand H2biqbpy2 and TrxR-inhibiting Au+ ions. The redox stability of [1]Cl dramatically decreased its thioredoxin reductase (TrxR) inhibition properties, compared to [2]Cl. On the other hand, unlike [2]Cl, [1]Cl aggregated into nanoparticles in FCS-contg. medium, which resulted in much more efficient gold cellular uptake. [1]Cl had much more selective anticancer properties than [2]Cl and cisplatin, as it was almost 10 times more cytotoxic to human cancer cells (A549, A431, A375, MCF7) than to noncancerous cells (MRC5). Mechanistic studies highlight the strikingly different mode-of-action of the two compds.: while for [1]Cl high gold cellular uptake, nuclear DNA damage, and interaction with hERG may contribute to cell killing, for [2]Cl extracellular redn. released TrxR-inhibiting Au+ ions that were taken up in minute amts. in the cytosol, and a toxic tetrapyridyl ligand also capable of binding to hERG. These results demonstrate that bis-cyclometalation is an appealing method to improve the redox stability of Au(III) compds. and to develop gold-based cytotoxic compds. that do not rely on TrxR inhibition to kill cancer cells.
38. 38

    Liu, Y.; Pujals, S.; Stals, P. J. M.; Paulöhrl, T.; Presolski, S. I.; Meijer, E. W.; Albertazzi, L.; Palmans, A. R. A. Catalytically Active Single-Chain Polymeric Nanoparticles: Exploring Their Functions in Complex Biological Media. J. Am. Chem. Soc. 2018, 140, 3423– 3433,  DOI: 10.1021/jacs.8b00122

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    38

    Catalytically Active Single-Chain Polymeric Nanoparticles: Exploring Their Functions in Complex Biological Media

    Liu, Yiliu; Pujals, Silvia; Stals, Patrick J. M.; Pauloehrl, Thomas; Presolski, Stanislav I.; Meijer, E. W.; Albertazzi, Lorenzo; Palmans, Anja R. A.

    Journal of the American Chemical Society (2018), 140 (9), 3423-3433CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    Dynamic single-chain polymeric nanoparticles (SCPNs) are intriguing, bioinspired architectures that result from the collapse or folding of an individual polymer chain into a nanometer-sized particle. Here we present a detailed biophys. study on the behavior of dynamic SCPNs in living cells and an evaluation of their catalytic functionality in such a complex medium. We first developed a no. of delivery strategies that allowed the selective localization of SCPNs in different cellular compartments. Live/dead tests showed that the SCPNs were not toxic to cells while spectral imaging revealed that SCPNs provide a structural shielding and reduced the influence from the outer biol. media. The ability of SCPNs to act as catalysts in biol. media was first assessed by investigating their potential for reactive oxygen species generation. With porphyrins covalently attached to the SCPNs, singlet oxygen was generated upon irradn. with light, inducing spatially controlled cell death. In addn., Cu(I)- and Pd(II)-based SCPNs were prepd. and these catalysts were screened in vitro and studied in cellular environments for the carbamate cleavage reaction of rhodamine-based substrates. This is a model reaction for the uncaging of bioactive compds. such as cytotoxic drugs for catalysis-based cancer therapy. We obsd. that the rate of the deprotection depends on both the organometallic catalysts and the nature of the protective group. The rate reduces from in vitro to the biol. environment, indicating a strong influence of biomols. on catalyst performance. The Cu(I)-based SCPNs in combination with the dimethylpropargyloxycarbonyl protective group showed the best performances both in vitro and in biol. environment, making this group promising in biomedical applications.
39. 39

    Chen, J.; Wang, J.; Bai, Y.; Li, K.; Garcia, E. S.; Ferguson, A. L.; Zimmerman, S. C. Enzyme-like Click Catalysis by a Copper-Containing Single-Chain Nanoparticle. J. Am. Chem. Soc. 2018, 140, 13695– 13702,  DOI: 10.1021/jacs.8b06875

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    Enzyme-like Click Catalysis by a Copper-Containing Single-Chain Nanoparticle

    Chen, Junfeng; Wang, Jiang; Bai, Yugang; Li, Ke; Garcia, Edzna S.; Ferguson, Andrew L.; Zimmerman, Steven C.

    Journal of the American Chemical Society (2018), 140 (42), 13695-13702CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    A major challenge in performing reactions in biol. systems is the requirement for low substrate concns., often in the micromolar range. We report that copper cross-linked single-chain nanoparticles (SCNPs) are able to significantly increase the efficiency of copper(I)-catalyzed alkyne-azide cycloaddn. (CuAAC) reactions at low substrate concn. in aq. buffer by promoting substrate binding. Using a fluorogenic click reaction and dye uptake expts., a structure-activity study is performed with SCNPs of different size and copper content and substrates of varying charge and hydrophobicity. The high catalytic efficiency and selectivity are attributed to a mechanism that involves an enzyme-like substrate binding process. Satn.-transfer difference (STD) NMR spectroscopy, 2D-NOESY NMR, kinetic analyses with varying substrate concns., and computational simulations are consistent with a Michaelis-Menten, two-substrate, random-sequential enzyme-like kinetic profile. This general approach may prove useful for developing more-sustainable catalysts and agents for biomedicine and chem. biol.
40. 40

    Sathyan, A.; Croke, S.; Pérez-López, A. M.; de Waal, B. F. M.; Unciti-Broceta, A.; Palmans, A. R. A. Developing Pd(II) based amphiphilic polymeric nanoparticles for pro-drug activation in complex media. Mol. Syst. Des. Eng. 2022, 7, 1736– 1748,  DOI: 10.1039/D2ME00173J

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    40

    Developing Pd(II) based amphiphilic polymeric nanoparticles for pro-drug activation in complex media

    Sathyan, Anjana; Croke, Stephen; Perez-Lopez, Ana M.; de Waal, Bas F. M.; Unciti-Broceta, Asier; Palmans, Anja R. A.

    Molecular Systems Design & Engineering (2022), 7 (12), 1736-1748CODEN: MSDEBG; ISSN:2058-9689. (Royal Society of Chemistry)

    Novel approaches to targeted cancer therapy that combine improved efficacy of current chemotherapies while minimising side effects are highly sought after. The development of single-chain polymeric nanoparticles (SCPNs) as bio-orthogonal catalysts for targeted site-specific pro-drug activation is a promising avenue to achieve this. Currently, the application of SCPNs as bio-orthogonal catalysts is in its early stages due to reduced performance when increasing the medium's complexity. Herein, we present a systematic approach to identify the various aspects of SCPN-based catalytic systems, to improve their efficiency in future in vitro/in vivo studies. We developed amphiphilic polymers with a polyacrylamide backbone and functionalised with the Pd(II)-binding ligands triphenylphosphine and bipyridine. The resulting polymers collapse into small-sized nanoparticles (5-6 nm) with an inner hydrophobic domain that comprises the Pd(II) catalyst. We systematically evaluated the effect of polymer microstructure, ligand-metal complex, and substrate hydrophobicity on the catalytic activity of the nanoparticles for depropargylation reactions in water, PBS or DMEM. The results show that the catalytic activity of nanoparticles is primarily impacted by the ligand-metal complex while polymer microstructure has a minor influence. Moreover, the rate of reaction is increased for hydrophobic substrates. In addn., Pd(II) leaching studies confirmed little to no loss of Pd(II) from the hydrophobic interior which can reduce off-target toxicities in future applications. Careful deconstruction of the catalytic system revealed that covalent attachment of the ligand to the polymer backbone is necessary to retain its catalytic activity in cell culture medium while not in water. Finally, we activated anti-cancer pro-drugs based on 5-FU, paclitaxel, and doxorubicin using the best-performing catalytic SCPNs. We found that the rate of pro-drug activation in water was accelerated efficiently by catalytic SCPNs, whereas in cell culture medium the results depended on the type of protecting group and hydrophobicity of the prodrug. We believe our findings will aid in the development of suitable catalytic systems and pro-drugs for future in vivo applications.
41. 41

    Chen, J.; Wang, J.; Li, K.; Wang, Y.; Gruebele, M.; Ferguson, A. L.; Zimmerman, S. C. Polymeric ‘Clickase’ Accelerates the Copper Click Reaction of Small Molecules, Proteins, and Cells. J. Am. Chem. Soc. 2019, 141, 9693– 9700,  DOI: 10.1021/jacs.9b04181

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    Polymeric "Clickase" Accelerates the Copper Click Reaction of Small Molecules, Proteins, and Cells

    Chen, Junfeng; Wang, Jiang; Li, Ke; Wang, Yuhan; Gruebele, Martin; Ferguson, Andrew L.; Zimmerman, Steven C.

    Journal of the American Chemical Society (2019), 141 (24), 9693-9700CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    Recent work has shown that polymeric catalysts can mimic some of the remarkable features of metalloenzymes by binding substrates in proximity to a bound metal center. We report here an unexpected role for the polymer: multivalent, reversible, and adaptive binding to protein surfaces allowing for accelerated catalytic modification of proteins. The catalysts studied are a group of copper-contg. single-chain polymeric nanoparticles (CuI-SCNP) that exhibit enzyme-like catalysis of the copper-mediated azide-alkyne cycloaddn. reaction. The CuI-SCNP use a previously obsd. "uptake mode", binding small-mol. alkynes and azides inside a water-sol. amphiphilic polymer and proximal to copper catalytic sites, but with unprecedented rates. Remarkably, a combined exptl. and computational study shows that the same CuI-SCNP perform a more efficient click reaction on modified protein surfaces and cell surface glycans than do small-mol. catalysts. The catalysis occurs through an "attach mode" where the SCNPs reversibly bind protein surfaces through multiple hydrophobic and electrostatic contacts. The results more broadly point to a wider capability for polymeric catalysts as artificial metalloenzymes, esp. as it relates to bioapplications.
42. 42

    Chen, J.; Li, K.; Shon, J. S. L.; Zimmerman, S. C. Single-Chain Nanoparticle Delivers a Partner Enzyme for Concurrent and Tandem Catalysis in Cells. J. Am. Chem. Soc. 2020, 142, 4565– 4569,  DOI: 10.1021/jacs.9b13997

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    Single-chain nanoparticle delivers a partner enzyme for concurrent and tandem catalysis in cells

    Chen, Junfeng; Li, Ke; Shon, Ji Seon "Lucy"; Zimmerman, Steven C.

    Journal of the American Chemical Society (2020), 142 (10), 4565-4569CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    Combining synthetic chem. and biocatalysis is a promising but underexplored approach to intracellular catalysis. We report a strategy to codeliver a single-chain nanoparticle (SCNP) catalyst and an exogenous enzyme into cells for performing bioorthogonal reactions. The nanoparticle and enzyme reside in endosomes, creating engineered artificial organelles that manuf. org. compds. intracellularly. This system operates in both concurrent and tandem reaction modes to generate fluorophores or bioactive agents. The combination of SCNP and enzymic catalysts provides a versatile tool for intracellular org. synthesis with applications in chem. biol.
43. 43

    Bai, Y.; Feng, X.; Xing, H.; Xu, Y.; Kim, B. K.; Baig, N.; Zhou, T.; Gewirth, A. A.; Lu, Y.; Oldfield, E.; Zimmerman, S. C. A Highly Efficient Single-Chain Metal-Organic Nanoparticle Catalyst for Alkyne-Azide ‘Click’ Reactions in Water and in Cells.. J. Am. Chem. Soc. 2016, 138, 11077– 11080,  DOI: 10.1021/jacs.6b04477

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    A Highly Efficient Single-Chain Metal-Organic Nanoparticle Catalyst for Alkyne-Azide "Click" Reactions in Water and in Cells

    Bai, Yugang; Feng, Xinxin; Xing, Hang; Xu, Yanhua; Kim, Boo Kyung; Baig, Noman; Zhou, Tianhui; Gewirth, Andrew A.; Lu, Yi; Oldfield, Eric; Zimmerman, Steven C.

    Journal of the American Chemical Society (2016), 138 (35), 11077-11080CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    We show that copper-contg. metal-org. nanoparticles (MONPs) are readily synthesized via Cu(II)-mediated intramol. crosslinking of aspartate-contg. polyolefins in water. In situ redn. with sodium ascorbate yields Cu(I)-contg. MONPs that serve as highly efficient supramol. catalysts for alkyne-azide "click chem." reactions, yielding the desired 1,4-adducts at low ppm catalyst levels. The nanoparticles have low toxicity and low metal loadings, making them convenient, green catalysts for alkyne-azide "click" reactions in water. The Cu-MONPs enter cells and perform efficient, biocompatible click chem., thus acting as intracellular nanoscale mol. synthesizers.
44. 44

    Jeschek, M.; Reuter, R.; Heinisch, T.; Trindler, C.; Klehr, J.; Panke, S.; Ward, T. R. Directed evolution of artificial metalloenzymes for in vivo metathesis. Nature 2016, 537, 661– 665,  DOI: 10.1038/nature19114

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    Directed evolution of artificial metalloenzymes for in vivo metathesis

    Jeschek, Markus; Reuter, Raphael; Heinisch, Tillmann; Trindler, Christian; Klehr, Juliane; Panke, Sven; Ward, Thomas R.

    Nature (London, United Kingdom) (2016), 537 (7622), 661-665CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)

    The authors report the compartmentalization and in vivo evolution of an artificial metalloenzyme for olefin metathesis, which represents an archetypal organometallic reaction without an equiv. in Nature. Building on previous work on an artificial metallohydrolase, the authors exploited the periplasm of Escherichia coli as a reaction compartment for the 'metathase' because it offers an auspicious environment for artificial metalloenzymes, mainly owing to low concns. of inhibitors such as glutathione, which has recently been identified as a major inhibitor. This strategy facilitated the assembly of a functional metathase in vivo and its directed evolution with substantially increased throughput compared to conventional approaches that rely on purified protein variants. The evolved metathase compared favorably with com. catalysts, showed activity for different metathesis substrates, and could be further evolved in different directions by adjusting the workflow. The results represent the systematic implementation and evolution of an artificial metalloenzyme that catalyzes an abiotic reaction in vivo, with potential applications in, e.g., non-natural metab.
45. 45

    Chordia, S.; Narasimhan, S.; Lucini Paioni, A.; Baldus, M.; Roelfes, G. In Vivo Assembly of Artificial Metalloenzymes and Application in Whole-Cell Biocatalysis. Angew. Chem., Int. Ed. Engl. 2021, 60, 5913– 5920,  DOI: 10.1002/anie.202014771

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    In Vivo Assembly of Artificial Metalloenzymes and Application in Whole-Cell Biocatalysis*

    Chordia Shreyans; Roelfes Gerard; Narasimhan Siddarth; Lucini Paioni Alessandra; Baldus Marc; Narasimhan Siddarth

    Angewandte Chemie (International ed. in English) (2021), 60 (11), 5913-5920 ISSN:.

    We report the supramolecular assembly of artificial metalloenzymes (ArMs), based on the Lactococcal multidrug resistance regulator (LmrR) and an exogeneous copper(II)-phenanthroline complex, in the cytoplasm of E. coli cells. A combination of catalysis, cell-fractionation, and inhibitor experiments, supplemented with in-cell solid-state NMR spectroscopy, confirmed the in-cell assembly. The ArM-containing whole cells were active in the catalysis of the enantioselective Friedel-Crafts alkylation of indoles and the Diels-Alder reaction of azachalcone with cyclopentadiene. Directed evolution resulted in two different improved mutants for both reactions, LmrR_A92E_M8D and LmrR_A92E_V15A, respectively. The whole-cell ArM system required no engineering of the microbial host, the protein scaffold, or the cofactor to achieve ArM assembly and catalysis. We consider this a key step towards integrating abiological catalysis with biosynthesis to generate a hybrid metabolism.
46. 46

    Eda, S.; Nasibullin, I.; Vong, K.; Kudo, N.; Yoshida, M.; Kurbangalieva, A.; Tanaka, K. Biocompatibility and therapeutic potential of glycosylated albumin artificial metalloenzymes. Nat. Catal. 2019, 2, 780– 792,  DOI: 10.1038/s41929-019-0317-4

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    Biocompatibility and therapeutic potential of glycosylated albumin artificial metalloenzymes

    Eda, Shohei; Nasibullin, Igor; Vong, Kenward; Kudo, Norio; Yoshida, Minoru; Kurbangalieva, Almira; Tanaka, Katsunori

    Nature Catalysis (2019), 2 (9), 780-792CODEN: NCAACP; ISSN:2520-1158. (Nature Research)

    The ability of natural metalloproteins to prevent inactivation of their metal cofactors by biol. metabolites, such as glutathione, is an area that has been largely ignored in the field of artificial metalloenzyme (ArM) development. Yet, for ArM research to transition into future therapeutic applications, biocompatibility remains a crucial component. The work presented here shows the creation of a human serum albumin-based ArM that can robustly protect the catalytic activity of a bound ruthenium metal, even in the presence of 20 mM glutathione under in vitro conditions. To exploit this biocompatibility, the concept of glycosylated artificial metalloenzymes (GArM) was developed, which is based on functionalizing ArMs with N-glycan targeting moieties. As a potential drug therapy, this study shows that ruthenium-bound GArM complexes could preferentially accumulate to varying cancer cell lines via glycan-based targeting for prodrug activation of the anticancer agent umbelliprenin using ring-closing metathesis.
47. 47

    Tanaka, K.; Vong, K. Unlocking the therapeutic potential of artificial metalloenzymes.. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 2020, 96, 79– 94,  DOI: 10.2183/pjab.96.007

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    Unlocking the therapeutic potential of artificial metalloenzymes

    Tanaka, Katsunori; Vong, Kenward

    Proceedings of the Japan Academy, Series B: Physical and Biological Sciences (2020), 96 (3), 79-94CODEN: PJABDW; ISSN:1349-2896. (Japan Academy)

    A review. In order to harness the functionality of metals, nature has evolved over billions of years to utilize metalloproteins as key components in numerous cellular processes. Despite this, transition metals such as ruthenium, palladium, iridium, and gold are largely absent from naturally occurring metalloproteins, likely due to their scarcity as precious metals. To mimic the evolutionary process of nature, the field of artificial metalloenzymes (ArMs) was born as a way to benefit from the unique chemoselectivity and orthogonality of transition metals in a biol. setting. In its current state, numerous examples have successfully incorporated transition metals into a variety of protein scaffolds. Using these ArMs, many examples of new-to-nature reactions have been carried out, some of which have shown substantial biocompatibility. Given the rapid rate at which this field is growing, this review aims to highlight some important studies that have begun to take the next step within this field; namely the development of ArM-centered drug therapies or biotechnol. tools.
48. 48

    Davis, H. J.; Ward, T. R. Artificial Metalloenzymes: Challenges and Opportunities. ACS Cent. Sci. 2019, 5, 1120– 1136,  DOI: 10.1021/acscentsci.9b00397

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    Artificial Metalloenzymes: Challenges and Opportunities

    Davis, Holly J.; Ward, Thomas R.

    ACS Central Science (2019), 5 (7), 1120-1136CODEN: ACSCII; ISSN:2374-7951. (American Chemical Society)

    A review. Artificial metalloenzymes (ArMs) result from the incorporation of an abiotic metal cofactor within a protein scaffold. From the earliest techniques of transition metals adsorbed on silk fibers, the field of ArMs has expanded dramatically over the past 60 years to encompass a range of reaction classes and inspired approaches: Assembly of the ArMs has taken multiple forms with both covalent and supramol. anchoring strategies, while the scaffolds have been intuitively selected and evolved, repurposed, or designed in silico. Herein, we discuss some of the most prominent recent examples of ArMs to highlight the challenges and opportunities presented by the field.
49. 49

    Indrigo, E.; Clavadetscher, J.; Chankeshwara, S. V.; Megia-Fernandez, A.; Lilienkampf, A.; Bradley, M. Intracellular delivery of a catalytic organometallic complex. Chem. Commun. 2017, 53, 6712– 6715,  DOI: 10.1039/C7CC02988H

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    Intracellular delivery of a catalytic organometallic complex

    Indrigo, Eugenio; Clavadetscher, Jessica; Chankeshwara, Sunay V.; Megia-Fernandez, Alicia; Lilienkampf, Annamaria; Bradley, Mark

    Chemical Communications (Cambridge, United Kingdom) (2017), 53 (50), 6712-6715CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)

    A homogeneous carbene-based palladium catalyst was conjugated to a cell-penetrating peptide, allowing intracellular delivery of catalytically active Pd complexes that demonstrated bioorthogonal activation of a profluorophore within prostate cancer cells.
50. 50

    Learte-Aymamí, S.; Vidal, C.; Gutiérrez-González, A.; Mascareñas, J. L. Intracellular Reactions Promoted by Bis(histidine) Miniproteins Stapled Using Palladium(II) Complexes. Angew. Chem., Int. Ed. Engl. 2020, 59, 9149– 9154,  DOI: 10.1002/anie.202002032

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    Intracellular Reactions Promoted by Bis(histidine) Miniproteins Stapled Using Palladium(II) Complexes

    Learte-Aymami Soraya; Vidal Cristian; Gutierrez-Gonzalez Alejandro; Mascarenas Jose L

    Angewandte Chemie (International ed. in English) (2020), 59 (23), 9149-9154 ISSN:.

    The generation of catalytically active metalloproteins inside living mammalian cells is a major research challenge at the interface between catalysis and cell biology. Herein we demonstrate that basic domains of bZIP transcription factors, mutated to include two histidine residues at i and i+4 positions, react with palladium(II) sources to generate catalytically active, stapled pallado-miniproteins. The resulting constrained peptides are efficiently internalized into living mammalian cells, where they perform palladium-promoted depropargylation reactions without cellular fixation. Control experiments confirm the requirement of the peptide scaffolding and the palladium staple for attaining the intracellular reactivity.
51. 51

    Hasan, K. Methyl salicylate functionalized magnetic chitosan immobilized palladium nanoparticles: An efficient catalyst for the Suzuki and heck coupling reactions in water. ChemistrySelect 2020, 5, 7129– 7140,  DOI: 10.1002/slct.202001933

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    Methyl Salicylate Functionalized Magnetic Chitosan Immobilized Palladium Nanoparticles: An Efficient Catalyst for the Suzuki and Heck Coupling Reactions in Water

    Hasan, Kamrul

    ChemistrySelect (2020), 5 (23), 7129-7140CODEN: CHEMUD; ISSN:2365-6549. (Wiley-VCH Verlag GmbH & Co. KGaA)

    A heterogeneous catalyst was fabricated by immobilization of chitosan on magnetic Fe3O4 following the deposition of palladium nanoparticles on its modified surface. The prepd. catalyst was characterized using Fourier transform IR (FTIR) spectroscopy, thermogravimetric anal. (TGA), X-ray diffractometer (XRD), SEM and energy dispersive X-ray spectroscopy (EDX). The catalyst was investigated for the Suzuki-Miyaura and Heck-Mizoroki cross-coupling reactions and afforded arylated products with high turnover no. TON (980) and turnover frequency TOF (980 h-1). The optimized catalytic system was found practical and green as catalyst loading was low (0.10 mol%), water used as solvent and the catalyst was sepd. with external magnet. A wide variety of aryl halides including electro withdrawing and releasing groups were investigated and found excellent to good yield of Suzuki and Heck cross-coupled products. Furthermore, the catalyst was recovered and reused up to seven times for Suzuki coupling reactions with 97% efficiency.
52. 52

    Fan, T.; Shen, H.-C.; Han, Z.-Y.; Gong, L.-Z. Palladium-catalyzed asymmetric dihydroxylation of 1,3-dienes with catechols. Chin. J. Chem. 2019, 37, 226– 232,  DOI: 10.1002/cjoc.201800540

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    Palladium-Catalyzed Asymmetric Dihydroxylation of 1,3-Dienes with Catechols

    Fan, Tao; Shen, Hong-Cheng; Han, Zhi-Yong; Gong, Liu-Zhu

    Chinese Journal of Chemistry (2019), 37 (3), 226-232CODEN: CJOCEV; ISSN:1001-604X. (Wiley-VCH Verlag GmbH & Co. KGaA)

    A palladium-catalyzed asym. dihydroxylation of 1,3-dienes (E)-RC6H4CH=CHCH=CH2 (R = 2-OCH3, 4-Cl, 3-CF3, etc.) with catechols, e.g., 2,3-dihydro-1H-indene-5,6-diol is developed using chiral pyridinebis(oxazoline) ligands. Various chiral 2-substituted 1,4-benzodioxanes I [R1 = R2 = H, F; R1R2 = -(CH2)3-] could be synthesized with moderate to high yields and enantioselectivities from readily available starting materials. The reaction is proposed to proceed through a cascade Wacker-type hydroxypalladation/asym. allylation process.
53. 53

    Shibata, M.; Ito, H.; Itami, K. C-H Arylation of Phenanthrene with Trimethylphenylsilane by Pd/o-Chloranil Catalysis: Computational Studies on the Mechanism, Regioselectivity, and Role of o-Chloranil. J. Am. Chem. Soc. 2018, 140, 2196– 2205,  DOI: 10.1021/jacs.7b11260

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    C-H Arylation of Phenanthrene with Trimethylphenylsilane by Pd/o-Chloranil Catalysis: Computational Studies on the Mechanism, Regioselectivity, and Role of o-Chloranil

    Shibata, Mari; Ito, Hideto; Itami, Kenichiro

    Journal of the American Chemical Society (2018), 140 (6), 2196-2205CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    The transition-metal-catalyzed C-H arylation of arom. hydrocarbons represents a useful and ideal method for the prodn. of biaryls and multiarylated arom. compds. We have previously reported the palladium-catalyzed direct C-H arylation of polycyclic arom. hydrocarbons, such as phenanthrene, pyrene, and corannulene with various organosilicon, -borane, and -germanium compds. In these reactions, o-chloranil proved to be an essential and unique promoter (stoichiometrically as an oxidant) and arylation occurred exclusively at the K-region. Herein, we report our mechanistic investigation of Pd/o-chloranil catalysis in C-H arylation of phenanthrene with trimethylphenylsilane by computational calcns. The results revealed that C-H arylation occurs through a sequence of transmetalation, carbometalation, and trans-β-hydrogen elimination steps. In addn., the triple role of o-chloranil as a ligand, oxidant, and base is also elucidated.
54. 54

    Tahara, K.; Kadowaki, T.; Kikuchi, J.-I.; Ozawa, Y.; Yoshimoto, S.; Abe, M. Synthesis and Characterization of a New Series of Binuclear Pd(II) Biscatecholato Complexes: Non-Innocent Ligand-Based Approach to a Wide Range of Variation in Near-Infrared Absorptions of Mixed-Valence Complexes. BCSJ. 2018, 91, 1630– 1639,  DOI: 10.1246/bcsj.20180187

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    Synthesis and characterization of a new series of binuclear Pd(II) biscatecholato complexes: non-innocent ligand-based approach to a wide range of variation in near-infrared absorptions of mixed-valence complexes

    Tahara, Keishiro; Kadowaki, Tomoya; Kikuchi, Jun-Ichi; Ozawa, Yoshiki; Yoshimoto, Soichiro; Abe, Masaaki

    Bulletin of the Chemical Society of Japan (2018), 91 (11), 1630-1639CODEN: BCSJA8; ISSN:0009-2673. (Chemical Society of Japan)

    The authors report synthesis of mixed-valence (MV) complexes having intervalence charge transfer (IVCT) energies variable from the 1st to the 3rd telecommunication window. This wide-range modulation was achieved by variation of covalently-dimerized catecholato ligands, in combination with Pd(II) ions, which lowered the oxidn. potentials and enabled access to MV states. Importantly, regulation of the conjugation lengths enabled energy gap control and annulation of an addnl. benzene ring switched the nature of the IVCT transitions. These changes were accompanied by a cross-over from moderately delocalized Class II to delocalized Class III character according to the Robin-Day classification. Through accurate comparisons with known ferrocene counterparts and their heteroconjugate, the authors' noninnocent ligand-based approach is effective for controlling IVCT parameters. These findings offer a new approach to materials design for electrooptic switching.
55. 55

    Bauer, G.; Nieger, M.; Gudat, D. Heterobimetallic catechol-phosphine complexes with palladium and a group-13 element: structural flexibility and dynamics. Dalton Trans. 2014, 43, 8911– 8920,  DOI: 10.1039/C4DT00785A

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    Heterobimetallic catechol-phosphine complexes with palladium and a group-13 element: structural flexibility and dynamics

    Bauer, G.; Nieger, M.; Gudat, D.

    Dalton Transactions (2014), 43 (23), 8911-8920CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)

    Group-13 metal acetylacetonates [M(acac)3] (M = Al, Ga, In) or Al(OiPr)3 react with [Pd(catphosH)2] that may act as chelating ligand towards a second metal, or with a mixt. of catechol phosphine (catphosH2) and [PdCl2(cod)], to give heterometallic complexes featuring either dinuclear M(catphos)2Pd or trinuclear M{(catphos)2Pd}2 motifs. Characterization of the products by crystallog. and soln. NMR studies gives insight into the structural diversity and flexibility of the coordination environments of the group-13 elements and their impact on the stability of the multinuclear complexes. Gallium and indium are the most suitable elements for the stabilization of di- and trinuclear assemblies, resp. Dynamic NMR spectroscopy allowed to follow the dynamic averaging of the coordination environments of the four distinguishable catechol phosphines in the indium complex [M{(catphos)2Pd}2]H. The isomerization follows a complicated pathway involving several distinguishable proton transfer steps, and allowed to propose a mechanistic explanation for the obsd. isomerization.
56. 56

    Coe, J. S.; Mentasti, E. Mechanisms of complex formation in the reactions of 1,2-dihydroxybenzene and 1,2-dihydroxy-4-methylbenzene with palladium(II) chloride and with aquapalladium(II), equilibria and kinetics in acid media. J. Chem. Soc., Dalton Trans. 1981, 2331– 2334,  DOI: 10.1039/dt9810002331

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    Mechanisms of complex formation in the reactions of 1,2-dihydroxybenzene and 1,2-dihydroxy-4-methylbenzene with palladium(II) chloride and with aquapalladium(II), equilibriums and kinetics in acid media

    Coe, John S.; Mentasti, Edoardo

    Journal of the Chemical Society, Dalton Transactions: Inorganic Chemistry (1972-1999) (1981), (12), 2331-4CODEN: JCDTBI; ISSN:0300-9246.

    PdCl2 and Pd(H2O)2+ react rapidly with 1,2-(HO)2C6H3R (R = H, 4-Me) to form a green 1:1 complex. The reactions are reversed by addn. of excess acid. Equil. consts. for the overall reaction were detd. both from measurements on the equil. mixts. and from kinetic parameters. The green product is a chelate complex of Pd and o-quinone. Reaction mechanisms are discussed.
57. 57

    Law, K.-Y.; Shoham, J. Photoinduced Proton Transfers in Methyl Salicylate and Methyl 2-Hydroxy-3-Naphthoate. J. Phys. Chem. 1994, 98, 3114– 3120,  DOI: 10.1021/j100063a013

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    Photoinduced Proton Transfers in Methyl Salicylate and Methyl 2-Hydroxy-3-Naphthoate

    Law, Kock-Yee; Shoham, Jonatham

    Journal of Physical Chemistry (1994), 98 (12), 3114-20CODEN: JPCHAX; ISSN:0022-3654.

    The effects of solvent and temp. on the dual fluorescence emission of Me salicylate (MSA) have been reinvestigated, and new insight regarding the photoinduced proton-transfer reactions is reported. The steady-state spectral data obtained in this work are found to be consistent with the spectral assignments proposed by previous investigators. Specifically, the dual emission bands in alcs. are shown to occur from excited states derived from two ground-state rotamers, a and b. The emission band from excited a (the normal band) is in mirror-image relationship with the absorption band and the Stokes shift of this band is ∼5000 cm-1. The long wavelength emission band, which has a Stokes shift of ∼10,700 cm-1, was postulated to be an emission from an excited zwitterion resulted from an intramol. proton transfer in excited b. Both emission bands exhibit monoexponential decays. The fluorescence lifetimes for the normal and the long wavelength band are 1.2 and 0.29 ns, resp. The monoexponential decays indicate that the two emitting states are not in thermodn. equil. This model is supported by time-resolved emission spectra. New evidence for the occurrence of tautomerization assocd. with the intramol. proton-transfer process in excited MSA is provided by a structural effect study. The authors have extended the measurements to Me 2-hydroxy-3-naphthoate (MNA). Exptl., MNA is found to exhibit dual fluorescence emission bands. The Stokes shift of the long wavelength emission ranges from 6300 to 9900 cm-1 depending on the solvent and the temp. and is smaller than that of MSA by 800 cm-1. It is argued, based on the smaller Stokes shift and the thermochromic and solvatochromic shifts of the long-wavelength emission, that keto → enol tautomerization occurs in excited NMA. The similarity in spectral properties between MSA and MNA suggests that a similar tautomerization process also occurs in excited MSA. Temp. and D-isotope effects on the fluorescence decay of the long wavelength emission band enable the authors to conclude that regeneration of the ground-state keto tautomer of MSA is the major radiationless decay for the excited enol tautomer.
58. 58

    Holliday, G. L.; Mitchell, J. B. O.; Thornton, J. M. Understanding the functional roles of amino acid residues in enzyme catalysis. J. Mol. Biol. 2009, 390, 560– 577,  DOI: 10.1016/j.jmb.2009.05.015

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    Understanding the functional roles of amino acid residues in enzyme catalysis

    Holliday, Gemma L.; Mitchell, John B. O.; Thornton, Janet M.

    Journal of Molecular Biology (2009), 390 (3), 560-577CODEN: JMOBAK; ISSN:0022-2836. (Elsevier Ltd.)

    The MACiE database contains 223 distinct step-wise enzyme reaction mechanisms and holds representatives from each EC sub-subclass where there is a crystal structure and sufficient evidence in the literature to support a mechanism. Each catalytic step of every reaction sequence in MACiE is fully annotated so that it includes the function of the catalytic residues involved in the reaction and the mechanism by which substrates are transformed into products. Using MACiE as a knowledge base, the authors have seen that the top 10 most catalytic residues are His, Asp, Glu, Lys, Cys, Arg, Ser, Thr, Tyr, and Trp. Of these, only 7 (Cys, His, Asp, Lys, Ser, Thr, and Tyr) dominate catalysis and provide essentially 5 functional roles that are essential. Stabilization is the most common and essential role for all classes of enzyme, followed by general acid/base (proton acceptor and proton donor) functionality, with nucleophilic addn. following closely behind (nucleophile and nucleofuge). The authors investigated the occurrence of these residues in MACiE and the Catalytic Site Atlas and found that, as expected, certain residue types were assocd. with each functional role, with some residue types able to perform diverse roles. In addn., it was seen that different EC classes of enzyme had a tendency to employ different residues for catalysis. Further, the authors showed that while the differences between EC classes in catalytic residue compn. were not immediately obvious from the general classes of Ingold mechanisms, there was some weak correlation between the mechanisms involved in a given EC class and the functions that the catalytic amino acid residues were performing. The anal. presented here provides a valuable insight into the functional roles of catalytic amino acid residues, which may have applications in many aspects of enzymol., from the design of novel enzymes to the prediction and validation of enzyme reaction mechanisms.
59. 59

    Lim, T.; Ryoo, J. Y.; Jang, M.; Han, M. S. Ligand-free Suzuki-Miyaura cross-coupling with low Pd content: rapid development by a fluorescence-based high-throughput screening method. Org. Biomol. Chem. 2021, 19, 1009– 1016,  DOI: 10.1039/D0OB02359K

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    Ligand-free Suzuki-Miyaura cross-coupling with low Pd content: rapid development by a fluorescence-based high-throughput screening method

    Lim, Taeho; Ryoo, Jeong Yup; Jang, Mingyeong; Han, Min Su

    Organic & Biomolecular Chemistry (2021), 19 (5), 1009-1016CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)

    In this study, a highly efficient Suzuki-Miyaura (SM) cross-coupling was developed using metal oxide catalysts: 0.02 mol% Pd, aq. solvent, no ligand, and room temp. Metal oxides contg. low Pd content (ppm scale) were prepd. by a simple co-pptn. method and used as a catalyst for the SM reaction. A fluorescence-based high-throughput screening (HTS) method was developed for the rapid evaluation of catalytic activity and reaction conditions. Among the various metal oxides, Pd/Fe2O3 showed the highest activity for the SM reaction. After further optimization by HTS, various biaryl compds. RR1 (R = 2-formylphenyl, 4-fluorophenyl, 2-chloro-5-nitrophenyl, etc.; R1 = Ph, 6-methoxynaphthalen-2-yl, pyren-1-yl, 4-fluoro-2-methylphenyl) were obtained under optimal conditions: Pd/Fe2O3 (0.02 mol% Pd) in aq. ethanol at mild temp. without any ligands.
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    Fingerhut, A.; Grau, D.; Tsogoeva, S. B. Peptides as Asymmetric Organocatalysts. In Sustainable Catalysis; RSC, 2015; pp 309– 353; Chapter 13.

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    D’Alterio, M. C.; Casals-Cruañas, È.; Tzouras, N. V.; Talarico, G.; Nolan, S. P.; Poater, A. Mechanistic Aspects of the Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling Reaction. Chemistry 2021, 27, 13481– 13493,  DOI: 10.1002/chem.202101880

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    Mechanistic Aspects of the Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling Reaction

    D'Alterio, Massimo C.; Casals-Cruanas, Eric; Tzouras, Nikolaos V.; Talarico, Giovanni; Nolan, Steven P.; Poater, Albert

    Chemistry - A European Journal (2021), 27 (54), 13481-13493CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)

    A review. The story of C-C bond formation includes several reactions, and surely Suzuki-Miyaura is among the most outstanding ones. Herein, a brief historical overview of insights regarding the reaction mechanism is provided. In particular, the formation of the catalytically active species is probably the main concern, thus the preactivation is in competition with, or even assumes the role of the rate detg. step (rds) of the overall reaction. Computational chem. is key in identifying the rds and thus leading to milder conditions on an exptl. level by means of predictive catalysis.
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    Weaver, B. A. How Taxol/paclitaxel kills cancer cells. Mol. Biol. Cell 2014, 25, 2677– 2681,  DOI: 10.1091/mbc.e14-04-0916

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    How taxol/paclitaxel kills cancer cells

    Weaver, Beth A.

    Molecular Biology of the Cell (2014), 25 (18), 2677-2681, 5 pp.CODEN: MBCEEV; ISSN:1939-4586. (American Society for Cell Biology)

    A review. Taxol (generic name paclitaxel) is a microtubule-stabilizing drug that is approved by the Food and Drug Administration for the treatment of ovarian, breast, and lung cancer, as well as Kaposi's sarcoma. It is used off-label to treat gastroesophageal, endometrial, cervical, prostate, and head and neck cancers, in addn. to sarcoma, lymphoma, and leukemia. Paclitaxel has long been recognized to induce mitotic arrest, which leads to cell death in a subset of the arrested population. However, recent evidence demonstrates that intratumoral concns. of paclitaxel are too low to cause mitotic arrest and result in multipolar divisions instead. It is hoped that this insight can now be used to develop a biomarker to identify the ∼50% of patients that will benefit from paclitaxel therapy. Here I discuss the history of paclitaxel and our recently evolved understanding of its mechanism of action.
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    Ji, Z.; Ahmed, A. A.; Albert, D. H.; Bouska, J. J.; Bousquet, P. F.; Cunha, G. A.; Diaz, G.; Glaser, K. B.; Guo, J.; Harris, C. M.; Li, J.; Marcotte, P. A.; Moskey, M. D.; Oie, T.; Pease, L.; Soni, N. B.; Stewart, K. D.; Davidsen, S. K.; Michaelides, M. R. 3-amino-benzo[d]isoxazoles as novel multitargeted inhibitors of receptor tyrosine kinases. J. Med. Chem. 2008, 51, 1231– 1241,  DOI: 10.1021/jm701096v

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    3-Amino-benzo[d]isoxazoles as Novel Multitargeted Inhibitors of Receptor Tyrosine Kinases

    Ji, Zhiqin; Ahmed, Asma A.; Albert, Daniel H.; Bouska, Jennifer J.; Bousquet, Peter F.; Cunha, George, A.; Diaz, Gilbert; Glaser, Keith B.; Guo, Jun; Harris, Christopher M.; Li, Junling; Marcotte, Patrick A.; Moskey, Maria D.; Oie, Tetsuro; Pease, Lori; Soni, Nirupama B.; Stewart, Kent D.; Davidsen, Steven K.; Michaelides, Michael R.

    Journal of Medicinal Chemistry (2008), 51 (5), 1231-1241CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)

    A series of benzoisoxazoles, e.g., I, and benzoisothiazoles have been synthesized and evaluated as inhibitors of receptor tyrosine kinases (RTKs). Structure-activity relationship studies led to the identification of 3-amino benzo[d]isoxazoles, incorporating a N,N'-diphenyl urea moiety at the 4-position that potently inhibited both the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor families of RTKs. Within this series, orally bioavailable compds. possessing promising pharmacokinetic profiles were identified, and a no. of compds. demonstrated in vivo efficacy in models of VEGF-stimulated vascular permeability and tumor growth. In particular, I exhibited an ED50 of 2.0 mg/kg in the VEGF-stimulated uterine edema model and 81% inhibition in the human fibrosarcoma (HT1080) tumor growth model when given orally at a dose of 10 mg/kg/day.
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    Ramalingam, S. S.; Shtivelband, M.; Soo, R. A.; Barrios, C. H.; Makhson, A.; Segalla, J. G. M.; Pittman, K. B.; Kolman, P.; Pereira, J. R.; Srkalovic, G.; Belani, C. P.; Axelrod, R.; Owonikoko, T. K.; Qin, Q.; Qian, J.; McKeegan, E. M.; Devanarayan, V.; McKee, M. D.; Ricker, J. L.; Carlson, D. M.; Gorbunova, V. A. Randomized phase II study of carboplatin and paclitaxel with either linifanib or placebo for advanced nonsquamous non-small-cell lung cancer. J. Clin. Oncol. 2015, 33, 433– 441,  DOI: 10.1200/JCO.2014.55.7173

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    Randomized phase II study of carboplatin and paclitaxel with either linifanib or placebo for advanced nonsquamous non-small-cell lung cancer

    Ramalingam, Suresh S.; Shtivelband, Mikhail; Soo, Ross A.; Barrios, Carlos H.; Makhson, Anatoly; Segalla, Jose G. M.; Pittman, Kenneth B.; Kolman, Petr; Pereira, Jose R.; Srkalovic, Gordan; Belani, Chandra P.; Axelrod, Rita; Owonikoko, Taofeek K.; Qin, Qin; Qian, Jiang; McKeegan, Evelyn M.; Devanarayan, Viswanath; McKee, Mark D.; Ricker, Justin L.; Carlson, Dawn M.; Gorbunova, Vera A.

    Journal of Clinical Oncology (2015), 33 (5), 433-441CODEN: JCONDN; ISSN:0732-183X. (American Society of Clinical Oncology)

    Purpose: Linifanib, a potent, selective inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, has single-agent activity in non-small-cell lung cancer (NSCLC). We evaluated linifanib with carboplatin and paclitaxel as first-line therapy of advanced nonsquamous NSCLC. Patients and Methods: Patients with stage IIIB/IV nonsquamous NSCLC were randomly assigned to 3-wk cycles of carboplatin (area under the curve 6) and paclitaxel (200 mg/m2) with daily placebo (arm A), linifanib 7.5 mg (arm B), or linifanib 12.5 mg (arm C). The primary end point was progression-free survival (PFS); secondary efficacy end points included overall survival (OS) and objective response rate. Results: One hundred thirty-eight patients were randomly assigned (median age, 61 years; 57% men; 84% smokers). Median PFS times were 5.4 mo (95% CI, 4.2 to 5.7 mo) in arm A (n = 47), 8.3 mo (95% CI, 4.2 to 10.8 mo) in arm B (n = 44), and 7.3 mo (95% CI, 4.6 to 10.8 mo) in arm C (n = 47). Hazard ratios (HRs) for PFS were 0.51 for arm B vs. A (P = .022) and 0.64 for arm C vs. A (P = .118). Median OS times were 11.3, 11.4, and 13.0 mo in arms A, B, and C, resp. HRs for OS were 1.08 for arm B vs. A (P = .779) and 0.88 for arm C vs. A (P = .650). Both linifanib doses were assocd. with increased toxicity, including a higher incidence of adverse events known to be assocd. with VEGF/PDGF inhibition. Baseline plasma carcinoembryonic antigen/cytokeratin 19 fragments biomarker signature was assocd. with PFS improvement and a trend toward OS improvement with linifanib 12.5 mg. Conclusion: Addn. of linifanib to chemotherapy significantly improved PFS (arm B), with a modest trend for survival benefit (arm C) and increased toxicity reflective of known VEGF/PDGF inhibitory effects.
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    Yoon, J.; Ryu, J.-S. A rapid synthesis of lavendustin-mimetic small molecules by click fragment assembly. Bioorg. Med. Chem. Lett. 2010, 20, 3930– 3935,  DOI: 10.1016/j.bmcl.2010.05.014

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    A rapid synthesis of lavendustin-mimetic small molecules by click fragment assembly

    Yoon, Jieun; Ryu, Jae-Sang

    Bioorganic & Medicinal Chemistry Letters (2010), 20 (13), 3930-3935CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)

    Lavendustin-mimetic small mols. modifying the linker -CH2-NH- with an 1,2,3-triazole ring have been synthesized via a click chem. Two pharmacophoric fragments of lavendustin were varied to investigate chem. space and the auxophoric -CH2-NH- was altered to an 1,2,3-triazole for rapid click conjugation. The small mols. were evaluated against HCT116 colon cancer and CCRF-CEM leukemia cell lines. Among the 28 analogs, 3-phenylpropyl ester I inhibited CCRF-CEM leukemia cell growth with GI50 value of 0.9 μM.
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    Meher, N.; Iyer, P. K. Functional group engineering in naphthalimides: a conceptual insight to fine-tune the supramolecular self-assembly and condensed state luminescence. Nanoscale 2019, 11, 13233– 13242,  DOI: 10.1039/C9NR04593G

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    Functional group engineering in naphthalimides: a conceptual insight to fine-tune the supramolecular self-assembly and condensed state luminescence

    Meher, Niranjan; Iyer, Parameswar Krishnan

    Nanoscale (2019), 11 (28), 13233-13242CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)

    Engineering well-defined supramol. fluorescent nano-architectures based on org. conjugated small mols. has been an essential scientific challenge. Herein, a library of sixteen naphthalimide congeners (1-15 and HNI) has been strategically designed that unveils a conceptual insight into the functional group controlled condensed state emission and aggregation-induced enhanced emission (AIEE) in conventional strong aggregation-caused quenching (ACQ) active fluorophores. Along with the regulation of ACQ-to-AIEE transformation and tailoring of the condensed state emission, a simple yet potential design strategy of functional group engineering has been established for the first time to spontaneously generate and systematically tailor the supramol. self-assembly of org. small mols. into highly defined nano-architectures. Single-crystal XRD anal. of six congeners revealed that, unlike the well-established electronic contribution of the functional groups in the molecularly dispersed state, the condensed state photophys. and morphol. properties are dictated by the distinct intermol. π-π stacking interaction of the planar arom. core. This work demonstrates an unconventional influence of the functional motif in the condensed state that could emerge as a promising route to build a fluorescent supramol. nanoassembly from non-fluorescent conjugated mols. for a variety of future applications.
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    Gude, M.; Ryf, J.; White, P. D. An accurate method for the quantitation of Fmoc-derivatized solid phase supports. Lett. Pept. Sci. 2002, 9, 203– 206,  DOI: 10.1023/A:1024148619149

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    An accurate method for the quantitation of Fmoc-derivatized solid phase supports

    Gude, Markus; Ryf, Jeannine; White, Peter D.

    Letters in Peptide Science (2003), 9 (4-5), 203-206CODEN: LPSCEM; ISSN:0929-5666. (Kluwer Academic Publishers)

    By performing the Fmoc resin loading detn. with DBU instead of piperidine, highly reproducible results were obtained that showed excellent correlation with data obtained by independent anal. methods.
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    Yan, B. Analytical Methods in Combinatorial Chemistry; CRC Press, 1999; p 131.

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