On the Importance of the Thiazole Nitrogen in Epothilones: Semisynthesis and Microtubule-Binding Affinity of Deaza-Epothilone C

Autor: Edenharter, Adriana, Ryckewaert, Lucie, Cintulová, Daniela, Estévez-Gallego, Juan, Díaz, José F., Altmann, Karl-Heinz
Přispěvatelé: Ministerio de Economía y Competitividad (España), European Commission
Rok vydání: 2020
Předmět:
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
instname
Chemistry
Volume 2
Issue 2
Pages 30-509
Chemistry, 2 (2)
Popis: © 2020 by the authors.
Deaza-epothilone C, which incorporates a thiophene moiety in place of the thiazole heterocycle in the natural epothilone side chain, has been prepared by semisynthesis from epothilone A, in order to assess the contribution of the thiazole nitrogen to microtubule binding. The synthesis was based on the esterification of a known epothilone A-derived carboxylic acid fragment and a fully synthetic alcohol building block incorporating the modified side chain segment and subsequent ring-closure by ring-closing olefin metathesis. The latter proceeded with unfavorable selectivity and in low yield. Distinct differences in chemical behavior were unveiled between the thiophene-derived advanced intermediates and what has been reported for the corresponding thiazole-based congeners. Compared to natural epothilone C, the free energy of binding of deaza-epothilone C to microtubules was reduced by ca. 1 kcal/mol or less, thus indicating a distinct but non-decisive role of the thiazole nitrogen in the interaction of epothilones with the tubulin/microtubule system. In contrast to natural epothilone C, deaza-epothilone C was devoid of antiproliferative activity in vitro up to a concentration of 10 μM, presumably due to an insufficient stability in the cell culture medium.
This work was supported by institutional funding from ETH Zürich (A.E., K.-H.A., L.R., D.C.) and by Ministerio de Economia y Competitividad grants BFU2016-75319-R to J.F.D. (both AEI/FEDER, UE) and H2020-MSCA-ITN-2019 860070 TUBINTRAIN to J.F.D. and a donation from Club deportivo Escuela Hungaresa de Pontevedra. No funds were received to cover the costs for publication in open access.
Databáze: OpenAIRE
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