Regulators of Microtubule Assembly : Molecular Recognition Mechanism and Developement of New Regulators.

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In the course of our studies on the antimitotic agents, inhibitors of microtubule assembly, we have discovered a number of inhibitors as the natural and synthetic compounds. Their action mechanisms have also been clarified. In this research project, the followings have been achieved.Ustiloxins A-D,13-membered cyclic peptides, were isolated from the water extract of false smut balls (ina-kouji), and their structures were determined. Ustiloxins A-D strongly inhibited microtubule assembly. The IC_<50> values were ; A (0.7 uM), B (2.8 uM), C (4.4 uM), D (6.6 uM). Competitive binding assys revealed that their binding site on tubulin is identical to that of rhizoxin/phomopsin. Approaches to find the minimal structure of ustiloxin/phomopsin class antibiotics to bind to tubulin have been attempted by both chemical transformation of ustiloxin D and total synthasis.Aza-analogs of combretastatin were deviced as the colchicine-site ligands to study the function of this drug-binding site. Some compounds synthesized were postent inhibitors of microtubule assembly.Synthesis of the partial structure of curacin A,a novel colchicine site ligand having potent antimitotic activity, were attempted to clarify its stereochemistry and action mechanism, and also to develope new cytotoxic agents.