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

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.

• Authors: L I Kruse, D L Ladd, P B Harrsch, F L McCabe, S M Mong, L Faucette, R Johnson
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 32 Issue 2 Pg. 409-17 (Feb 1989) ISSN: 0022-2623 [Print] United States
• PMID: 2913301 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Benzimidazoles
• Tubulin
• Nocodazole

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, metabolism, pharmacology)
• Benzimidazoles (chemical synthesis, metabolism, pharmacology)
• Leukemia P388 (drug therapy)
• Mice
• Nocodazole
• Structure-Activity Relationship
• Tubulin (metabolism)