Azinomycins A and B are potent and effective antitumor agents isolated from Streptomyces. Their biological activity resides in their ability to covalently alkylate and subsequently cross-link double stranded DNA. There has been no developmental work on the natural agents because of their poor availability from natural sources and because of their chemical instability.
The aim of this proposal is to elucidate the molecular details involved in the expression of cytotoxicity and antitumor activity by these agents through total synthesis of the natural products and a rationally designed series of structurally and functionally related agents. The unprecedented structure, intricate functionalization, unique molecular mechanism of action, and effective antitumor activity make the azinomycins attractive targets for study. The major rationale for synthetic efforts lies in the construction of structurally and functionally related agents for use in elucidation of the details of covalent interaction of these agents with DNA. Methodology developed in the course of synthetic efforts will be used to design and synthesize agents with which to explore the chemical events surrounding DNA cross-linking. A convergent synthetic approach brings together five small fragments in a series of ester, amide, and olefin bond formation events and will be the key to the modular construction of a variety of molecules with which to explore structure-function relationships based of the azinomycin skeleton.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Medicinal Chemistry Study Section (MCHA)
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Lees, Robert G
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Ohio State University
Schools of Medicine
United States
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Shi, Wei; Coleman, Robert S; Lowary, Todd L (2009) Synthesis and DNA-binding affinity studies of glycosylated intercalators designed as functional mimics of the anthracycline antibiotics. Org Biomol Chem 7:3709-22
Coleman, Robert S; Tierney, Mark T; Cortright, Sarah B et al. (2007) Synthesis of functional ""top-half"" partial structures of azinomycin a and B. J Org Chem 72:7726-35
Coleman, Robert S; Woodward, Robert L; Hayes, Amy M et al. (2007) Dependence of DNA sequence selectivity and cell cytotoxicity on azinomycin A and B epoxyamide stereochemistry. Org Lett 9:1891-4
Kelly, Gilbert T; Liu, Chaomin; Smith 3rd, Roger et al. (2006) Cellular effects induced by the antitumor agent azinomycin B. Chem Biol 13:485-92
Alcaro, Stefano; Ortuso, Francesco; Coleman, Robert S (2005) Molecular modeling of DNA cross-linking analogues based on the azinomycin scaffold. J Chem Inf Model 45:602-9
Coleman, Robert S; Burk, Christopher H; Navarro, Antonio et al. (2002) Role of the azinomycin naphthoate and central amide in sequence-dependent DNA alkylation and cytotoxicity of epoxide-bearing substructures. Org Lett 4:3545-8
Alcaro, Stefano; Ortuso, Francesco; Coleman, Robert S (2002) DNA cross-linking by azinomycin B: Monte Carlo simulations in the evaluation of sequence selectivity. J Med Chem 45:861-70
Coleman, Robert S; Perez, Ronelito J; Burk, Christopher H et al. (2002) Studies on the mechanism of action of azinomycin B: definition of regioselectivity and sequence selectivity of DNA cross-link formation and clarification of the role of the naphthoate. J Am Chem Soc 124:13008-17
Coleman, R S; Chen, W (2001) A convergent approach to the mitomycin ring system. Org Lett 3:1141-4
Coleman, R S; Garg, R (2001) Stereocontrolled synthesis of the diene and triene macrolactones of oximidines I and II: organometallic coupling versus standard macrolactonization. Org Lett 3:3487-90

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