Esperamicin

Abstract: Enediyne Antitumor Antibiotics, Terrence W. Doyle and Donald B. Borders Calicheamicins The Biochemical Induction Assay and Its Application in the Detection of the Calicheamicins, Michael Greenstein, Mary Jo Wildey, and William M. Maiese Taxonomy, Fermentation, and Yield Improvement, Amedeo A. Fantini and Raymond T. Testa Identification, Isolation, and Structure Determination, May D. Lee Disulfide Calicheamicins and the Chemistry of the Allylic Trisulfide Group, William J. McGahren, Wei-Dong Ding, and George A. Ellestad Preparation of Conjugates to Monoclonal Antibodies, Lois M. Hinman, Philip R. Hamann, and Janis Upeslacis Genetic Analysis of Calicheamicin Biosynthesis, David M. Rothstein Biological Activities of Calicheamicin, Frederick E. Durr, Roslyn E. Wallace, Raymond T. Testa, and Nydia A. Kuck DNA-Cleaving Properties of Calicheamicing, George A. Ellestad, Wei-Dong ding, Nada Zein, and Craig A. Townsend Esperamicins Fermentation and Isolation of Esperamicins, Kin Sing Lam and Salvatore Forenza Structure Determination of the Esperamicins, Jerzy Golik Biosynthesis of Esperamicin, Kin Sing Lam and Judith A. Veitch Mechanism of Action and Molecular Modeling for Esperamicin A1, Calicheamicing, and Dynemicin A, David R. Langley Biological Properties of Esperamicin and Other Enediyne Antibodies, Anna Maria Casazza and Susan L. Kelley Dynemicins Dynemicin, Masataka Konishi and Toshikazu Oki Neocarzinostatin Neocarzinostatin: Chemical and Biological Basis of Oxidative DNA Damage, Irving H. Goldberg and Lizzy S. Kappen The Clinical Effects of Neocarzinostatin and Its Polymer Conjugate, SMANCS, Hiroshi Maeda Synthetic Methodologies Synthetic Studies of the Enediyne Antibiotics, Randall L. Halcomb

Abstract: The esperamicins represent a class of antitumor antibiotics characterized by an unusual chemical core structure and extremely potent cytotoxicity. The mechanism by which these drugs produce cytotoxicity was investigated and found to be related to the formation of single- and double-strand DNA breaks. Using five structurally related analogs, we defined a structure-activity relationship for cytotoxicity in various eukaryotic and DNA-repair-deficient prokaryotic cell lines, for DNA breakage in a human colon carcinoma cell line, and for DNA breakage in vitro in pBR322 DNA. Mild reducing agents such as dithiothreitol greatly increased the DNA breakage potency of these analogs in vitro. Results suggest that the pendant aromatic chromophore of esperamicin A1 may contribute to the uptake of the drug into cells but may also hinder double-strand DNA break formation. Little DNA breakage specificity was observed for the drug in a 139-base-pair fragment of pBR322 DNA. Evidence supports a previously proposed mechanism whereby esperamicins may produce the observed DNA breaks through reduction of the methyl trisulfide group to a thiolate anion followed by a Michael addition of the anion across the alpha,beta-unsaturated ketone. This addition may result in the saturation of the bridgehead double bond, thus allowing the two triple bonds to approach each other, causing cyclization of the diyn-ene to form a phenylene diradical. It is likely that this diradical is the active form of the drug responsible for single- and double-strand DNA breakage produced by this class of antitumor agents.