Epothilone analogues with benzimidazole and quinoline side chains: chemical synthesis, antiproliferative activity, and interactions with tubulin.
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.
Dietrich
Silvia Anthoine
SA
Swiss Federal Institute of Technology (ETH) Zürich, Department of Chemistry and Applied Biosciences, HCI H405, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland.
Lindauer
Renate
R
Stierlin
Claire
C
Gertsch
Jürg
J
Matesanz
Ruth
R
Notararigo
Sara
S
Díaz
José Fernando
JF
Altmann
Karl-Heinz
KH
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
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D001688:Biological Products; D034261:Epothilones; D011804:Quinolines; D014404:Tubulin; C037219:quinoline