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Epothilone Analogues with Benzimidazole and Quinoline Side Chains: Chemical Synthesis,Antiproliferative Activity,and Interactions with Tubulin
Authors:Silvia Anthoine Dietrich  Renate Lindauer  Claire Stierlin  Jürg Gertsch Dr.  Ruth Matesanz Dr.  Sara Notararigo  José Fernando Díaz Dr.  Karl‐Heinz Altmann Prof. Dr.
Affiliation:1. Swiss Federal Institute of Technology (ETH) Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, HCI H405, Wolfgang‐Pauli‐Str. 10, 8093 Zürich (Switzerland), Fax: (+41)?44‐6331369 http://www.pharma.ethz.ch/institute_groups/institute_groups/pharmaceutical_biology/;2. Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid (Spain)
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 (IC50 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.
Keywords:antitumor agents  epothilone  microtubules  natural products  structure–  activity relationships  total synthesis
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