Journal of Medicinal Chemistry p. 409 - 417 (1989)
Update date:2022-08-03
Topics: Synthesis Structure-Activity Relationship Tubulin Binding Antineoplastic Evaluation
Kruse, Lawrence I.
Ladd, David L.
Harrsch, Peter B.
McCabe, Francis L.
Mong, Shau-Ming
et al.
n 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 cyctotoxicity 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 enhanched 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.
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