title: Epothilone analogues with benzimidazole and quinoline side chains: chemical synthesis, antiproliferative activity, and interactions with tubulin.
abstract: 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 nM). 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.
authors.affiliation: Swiss Federal Institute of Technology (ETH) Zürich, Department of Chemistry and Applied Biosciences, HCI H405, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland.
authors.forename: Silvia Anthoine
authors.initials: SA
authors.lastname: Dietrich
authors.forename: Renate
authors.initials: R
authors.lastname: Lindauer
authors.forename: Claire
authors.initials: C
authors.lastname: Stierlin
authors.forename: Jürg
authors.initials: J
authors.lastname: Gertsch
authors.forename: Ruth
authors.initials: R
authors.lastname: Matesanz
authors.forename: Sara
authors.initials: S
authors.lastname: Notararigo
authors.forename: José Fernando
authors.initials: JF
authors.lastname: Díaz
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Altmann
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D034261:Epothilones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008870:Microtubules / Q000187:drug effects*; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D001688:Biological Products; D034261:Epothilones; D011804:Quinolines; D014404:Tubulin; C037219:quinoline