Document Report Card

ID: ALA1124613

Journal: J Med Chem

Title: Synthesis, tubulin binding, antineoplastic evaluation, and structure-activity relationship of oncodazole analogues.

Authors: Kruse LI, Ladd DL, Harrsch PB, McCabe FL, Mong SM, Faucette L, Johnson R.

Abstract: In an attempt to identify a soluble oncodazole analogue that could be easily formulated, a series of substituted oncodazoles was synthesized and evaluated for tubulin binding affinity, in vitro cytotoxicity against cultured mouse B-16 cells, and ability to prolong lifespan at the maximally tolerated dose in the P388 mouse leukemia model. Biological evaluation of all the isomeric methyloncodazoles demonstrated the thiophene 4'-position to be the only site of significant bulk tolerance, although substitution of this position with polar or charged functional groups abolished biological activity. Simple esters of the 4'-carboxymethyloncodazole were shown to have enhanced antitumor activity and tubulin binding affinity relative to oncodazole. Despite a failure of this study to identify a water-soluble oncodazole with antitumor activity, the structure-activity relationship developed led to a derivative with enhanced activity in the P388 leukemia model and facilitated the preparation of a biologically active photolabile analogue.

CiteXplore: 2913301

DOI: 10.1021/jm00122a020