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Epothilone Analogues with Benzimidazole and Quinoline Side Chains: Chemical Synthesis, Antiproliferative Activity, and Interactions with Tubulin
Author(s) -
Dietrich Silvia Anthoine,
Lindauer Renate,
Stierlin Claire,
Gertsch Jürg,
Matesanz Ruth,
Notararigo Sara,
Díaz José Fernando,
Altmann KarlHeinz
Publication year - 2009
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200901376
Subject(s) - benzimidazole , tubulin , quinoline , stereochemistry , chemistry , microtubule , in vitro , prodrug , epothilone , side chain , biochemistry , biology , microbiology and biotechnology , organic chemistry , polymer
A series of epothilone B and D analogues bearing isomeric quinoline or functionalized benzimidazole side chains has been prepared by chemical synthesis in a highly convergent manner. All analogues have been found to interact with the tubulin/microtubule system and to inhibit human cancer cell proliferation in vitro, albeit with different potencies (IC 50 values between 1 and 150 n M ). The affinity of quinoline‐based epothilone B and D analogues for stabilized microtubules clearly depends on the position of the N‐atom in the quinoline system, while the induction of tubulin polymerization in vitro appears to be less sensitive to N‐positioning. The potent inhibition of human cancer cell growth by epothilone analogues bearing functionalized benzimidazole side chains suggests that these systems might be conjugated with tumor‐targeting moieties to form tumor‐targeted prodrugs.