title: Synthesis and biological activity of new functionalized epothilones for prodrug design and tumor targeting.
abstract: Epothilones are potent antiproliferative agents, which have served as successful lead structures for anticancer drug discovery. However, their therapeutic efficacy would benefit greatly from an increase in their selectivity for tumor cells, which may be achieved through conjugation with a tumor-targeting moiety. Three novel epothilone analogs bearing variously functionalized benzimidazole side chains were synthesized using a strategy based on palladium-mediated coupling and macrolactonization. The synthesis of these compounds is described and their in vitro biological activity is discussed with respect to their interactions with the tubulin/microtubule system and the inhibition of human cancer cell proliferation. The additional functional groups may be used to synthesize conjugates of epothilone derivatives with a variety of tumor-targeting moieties.
authors.affiliation: Swiss Federal Institute of Technology (ETH) Zürich, Institute of Pharmaceutical Sciences, ETH Hönggerberg, HCI H 405, CH-8093 Zürich.
authors.forename: Silvia Anthoine
authors.initials: SA
authors.lastname: Dietrich
authors.forename: Linda
authors.initials: L
authors.lastname: Riediker
authors.forename: Jürg
authors.initials: J
authors.lastname: Gertsch
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Altmann
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D034261:Epothilones / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D034261:Epothilones; D011355:Prodrugs; D014404:Tubulin; D050257:Tubulin Modulators