Epothilone Analogues with Benzimidazole and Quinoline Side Chains:Chemical Synthesis, Antiproliferative Activity, and Interactions with Tubulin

摘要

A series of epothilone B andD analogues bearing isomeric quino-line or functionalized benzimidazoleside chains has been prepared bychemical synthesis in a highly conver-gent manner. All analogues have beenfound to interact with the tubulin/mi-crotubule system and to inhibit humancancer cell proliferation in vitro, albeitwith different potencies (IC,values between 1 and 150 nm). The affinity ofquinoline-based epothilone B and Danalogues for stabilized microtubulesclearly depends on the position of the N-atom in the quinoline system, whilethe induction of tubulin polymerizationin vitro appears to be less sensitive toN-positioning. The potent inhibition ofhuman cancer cell growth by epothi-lone analogues bearing functionalizedbenzimidazole side chains suggests thatthese systems might be conjugated withtumor-targeting moieties to formtumor-targeted prodrugs.