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Chemical and Enzymatic Reductive Activation of Acylfulvene to Isomeric Cytotoxic Reactive Intermediates

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Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, United States
Institute of Food, Nutrition and Health, ETH Zurich, 8092 Zurich, Switzerland
§ Cancer Cell and Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20814, United States
Cite this: Chem. Res. Toxicol. 2011, 24, 11, 2044–2054
Publication Date (Web):September 22, 2011
Copyright © 2011 American Chemical Society

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    Abstract Image

    Acylfulvenes (AFs), a class of semisynthetic analogues of the sesquiterpene natural product illudin S, are cytotoxic toward cancer cells. The minor structural changes between illudin S and AFs translate to an improved therapeutic window in preclinical cell-based assays and xenograft models. AFs are, therefore, unique tools for addressing the chemical and biochemical basis of cytotoxic selectivity. AFs elicit cytotoxic responses by alkylation of biological targets, including DNA. While AFs are capable of direct alkylation, cytosolic reductive bioactivation to an electrophilic intermediate is correlated with enhanced cytotoxicity. Data obtained in this study illustrate chemical aspects of the process of AF activation. By tracking reaction mechanisms with stable isotope-labeled reagents, enzymatic versus chemical activation pathways for AF were compared for reactions involving the NADPH-dependent enzyme prostaglandin reductase 1 (PTGR1) or sodium borohydride, respectively. These two processes resulted in isomeric products that appear to give rise to similar patterns of DNA modification. The chemically activated isomer has been newly isolated and chemically characterized in this study, including an assessment of its relative stereochemistry and stability at varying pH and under bioassay conditions. In mammalian cancer cells, this chemically activated analogue was shown to not rely on further cellular activation to significantly enhance cytotoxic potency, in contrast to the requirements of AF. On the basis of this study, we anticipate that the chemically activated form of AF will serve as a useful chemical probe for evaluating biomolecular interactions independent of enzyme-mediated activation.

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    Mass spectra of d-2, NMR spectra of 5 and 6, NMR arrays of acid-mediated conversion of 5 to 2, cytotoxicity curves of 5, and models of AF hydride reduction (Figures S1–S8). This material is available free of charge via the Internet at

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    Cited By

    This article is cited by 10 publications.

    1. Claudia Otto, Graciela Spivak, Claudia M.N. Aloisi, Mirco Menigatti, Hanspeter Naegeli, Philip C. Hanawalt, Marina Tanasova, and Shana J. Sturla . Modulation of Cytotoxicity by Transcription-Coupled Nucleotide Excision Repair Is Independent of the Requirement for Bioactivation of Acylfulvene. Chemical Research in Toxicology 2017, 30 (3) , 769-776.
    2. Paul M. van Midwoud and Shana J. Sturla . Improved Efficacy of Acylfulvene in Colon Cancer Cells When Combined with a Nuclear Excision Repair Inhibitor. Chemical Research in Toxicology 2013, 26 (11) , 1674-1682.
    3. Kathryn E. Pietsch, Paul M. van Midwoud, Peter W. Villalta, and Shana J. Sturla . Quantification of Acylfulvene– and Illudin S–DNA Adducts in Cells with Variable Bioactivation Capacities. Chemical Research in Toxicology 2013, 26 (1) , 146-155.
    4. Marina Tanasova and Shana J. Sturla . Chemistry and Biology of Acylfulvenes: Sesquiterpene-Derived Antitumor Agents. Chemical Reviews 2012, 112 (6) , 3578-3610.
    5. Rie Kanao, Hidehiko Kawai, Toshiyasu Taniguchi, Minoru Takata, Chikahide Masutani. RFWD3 and translesion DNA polymerases contribute to PCNA modification–dependent DNA damage tolerance. Life Science Alliance 2022, 5 (12) , e202201584.
    6. Melanie M. Erzinger, Cédric Bovet, Katrin M. Hecht, Sabine Senger, Pascale Winiker, Nadine Sobotzki, Simona Cristea, Niko Beerenwinkel, Jerry W. Shay, Giancarlo Marra, Bernd Wollscheid, Shana J. Sturla, . Sulforaphane Preconditioning Sensitizes Human Colon Cancer Cells towards the Bioreductive Anticancer Prodrug PR-104A. PLOS ONE 2016, 11 (3) , e0150219.
    7. Xianping Huang, Weihe Zhou, Yuefeng Zhang, Yong Liu. High Expression of PTGR1 Promotes NSCLC Cell Growth via Positive Regulation of Cyclin-Dependent Protein Kinase Complex. BioMed Research International 2016, 2016 , 1-12.
    8. Ricardo Sánchez-Rodríguez, Julia Esperanza Torres-Mena, Monica De-la-Luz-Cruz, Gloria Alejandra Bernal-Ramos, Saúl Villa-Treviño, Victoria Chagoya-Hazas, Luis Landero-López, Rebeca García-Román, Patrick Rouimi, Luis Del-Pozo-Yauner, Jorge Meléndez-Zajgla, Julio Isael Pérez-Carreón. Increased expression of prostaglandin reductase 1 in hepatocellular carcinomas from clinical cases and experimental tumors in rats. The International Journal of Biochemistry & Cell Biology 2014, 53 , 186-194.
    9. Hansruedi Glatt, Kathryn E. Pietsch, Shana J. Sturla, Walter Meinl. Sulfotransferase-independent genotoxicity of illudin S and its acylfulvene derivatives in bacterial and mammalian cells. Archives of Toxicology 2014, 88 (1) , 161-169.
    10. Dilani D. De Silva, Sylvie Rapior, Enge Sudarman, Marc Stadler, Jianchu Xu, S. Aisyah Alias, Kevin D. Hyde. Bioactive metabolites from macrofungi: ethnopharmacology, biological activities and chemistry. Fungal Diversity 2013, 62 (1) , 1-40.

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