title: 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.affiliation: Department of Medicinal Chemistry, Smith Kline & French Laboratories, Swedeland, Pennsylvania 19406.
authors.forename: L I
authors.initials: LI
authors.lastname: Kruse
authors.forename: D L
authors.initials: DL
authors.lastname: Ladd
authors.forename: P B
authors.initials: PB
authors.lastname: Harrsch
authors.forename: F L
authors.initials: FL
authors.lastname: McCabe
authors.forename: S M
authors.initials: SM
authors.lastname: Mong
authors.forename: L
authors.initials: L
authors.lastname: Faucette
authors.forename: R
authors.initials: R
authors.lastname: Johnson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D015739:Nocodazole; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D014404:Tubulin; D015739:Nocodazole