SYNTHESIS OF BRIDGED AND POLYCYCLIC ANTITUMOR AGENTS

点击翻译按钮获取中文摘要

The long-term objective of our research are to discover new chemical strategies and tactics for the synthesis of complex natural products. Our focus is on the synthesis of molecules known or likely to have in vivo anticancer activity. We propose to carry out the first type synthesis of two such substances. One such target is the ansa-macrolide pyrandione antibiotic Lankacidin C, reported to have good in vivo antitumor activity in mice bearing L1210 leukemia, 6C3HED/OG lymphosarcoma and B16 melanoma. We propose an enantiospecific approach based on the intramolecular rearrangement of an enantiopure beta-lactam intermediate, a reaction already demonstrated in our laboratory during the previous grant period. Our second target molecule is the C35H47O9N oxazole polyene ansa-macrolide rhizoxin. This complex, polyfunctional molecule shows high in vivo activity against L1210 and P388 leukemia and B16 melanoma in mice, and against certain vincristine- and andriamycin-resistant tumor lines. Recent studies suggest that rhizoxin and some of its congeners are potent inhibitors of microtubule assembly, with a receptor binding mechanism somewhat resembling that of maytansine. Our proposed synthesis is enantiospecific and highly convergent, so as to provide maximum modular flexibility for structural modifications and analog synthesis. The proposed target molecules will serve as demanding frameworks to test a variety of new, chemoselective and stereoselective synthetic methodologies. These include the use of novel functionalized and sometimes chiral vinylstannane nucleophiles, development of vinylogous beta-ketophosphonate dianons or their equivalents as bifunctional lynch- pin reagents, enantioselective constructions of polyfunctional lactones, an enantioselective Darzens condensation and stereoselective elaboration of an oxazoletriene chromophore. Advanced intermediates and new analogs of the two target molecules, uniquely accessible by our synthetic protocols, will be screened for antineoplastic activity. Structural modifications observed to enhance potency will be further investigated to generate therapeutically improved drugs based on these two frameworks.