Robert S. Coleman
Professor
Dept. of Chemistry
Ohio State University
100 W. 18th Avenue
Columbus, Ohio 43210-1185
phone: 614-292-4548
fax: 614-292-1685
AZINOMYCINS A & B
One of the natural products of current focus is azinomycin B. The mechanism of action of this antitumor agent is the result of cross-linking of the DNA bases, via the reactive epoxide and aziridine moieties. We have synthesized the highly functionalized aziridine-containing portion of the molecule with excellent control of stereochemistry, and we recently completed the first total synthesis of azinomycin A.1 We use information obtained in our synthetic and computer modeling programs to rationally design new anticancer drugs, which are tested for cytotoxic activity in our group.2
We have examined the interaction of azinomycin B with DNA, both experimentally3 with the natural agents obtained from bacterial fermentation broths and using molecular mechanics and ab initio calculations4 (in collaboration with Stefano Alcaro). We demonstrated that the preferred (most reactive) sequence for azinomycin B/DNA binding is 5'-GCC-3'/3'-CGG-5', where cross-linking occurs between the aziridine and epoxide of the agent and the dG-N7 positions of the two 5'-disposed guanine bases. A major focus of research is the examination of azinomycin partial structures5 for reactivity with duplex DNA correlated with cytotoxic activity.6 We are also examining the effect of DNA lesions produced by azinomycin B on gene expression in collaboration with Coran Watanabe at Texas A&M University.7
[1] Coleman, R. S.; Li, J.; Navarro, A. Angew. Chem. Int. Ed. 2001, 40, 1736.
[3] Alcaro, S.; Ortuso, F.; Coleman, R. S. J. Med. Chem. 2002, 45, 861.
[4] Coleman, R. S.; Perez, R. J.; Burk, C. H.; Navarro, A. J. Am. Chem. Soc. 2002, 124, 13008.