STUDIES ON THE ANTIMITOTIC AGENTS-TUBULIN INTERACTION AND DRUG DESIGN

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The research project concern with the discovery of novel antimitotic agents, studies on the structure-acvtivity relationships of the ligands binding at both the colchicine site and the vinca-alkaloids site, as well as molecular design for new medicinal and agrochemical chemicals, based on the knowledges on the modes of their action mechanisms.In the last year, following results were obtained in this research project : (1)Ustiloxin F,having the simplest structure among ustiloxins, rhizoxin/maytansine site ligands from the false smut balls caused on panicles of rice plant (in Japanese, Ina-kouji), was isolated, and its structure and potent anti-tubulin activity was clarified.(2)Total synthesis of curacin A,a novel colchicine site ligand isolated from marine blue-algae, was accomplished. Various analogues with modified side chains have also been prepared synthetically, and their anti-tubulin and antimicrobial activities were examined.(3)The activity of arenastatin A,a potent cytotoxic compound isolated from marine sponge, against the microtubule system was evaluated. A potent inhibitory activity of microtubule assembly (IC_<50> : 2.8 muM) and binding to tubulin in a competitive manner to rhizoxin binding were verified. Activities of several synthetic analogues of arenastatin A against microtubule assembly were also evaluated, and showed that their anti-tubulin activities were parallel to their cytotoxicity on KB cells.(4)Activities of various Taxane compounds isolated from Japanese Yew Trees were evaluated for microtubule stabilizing actibity against Ca^<2+> induced microtubule depolymerisation. It was shown that several compounds lacking the oxatane ring and the acyl side chain, indicated as the essential factors for the taxol's bioactivity, showed also the microtubule stabilizing actvity.