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

1
ETH Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, CH-8093 Zürich, Switzerland
2
Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas, 28040 Madrid, Spain
*
Author to whom correspondence should be addressed.
Chemistry 2020, 2(2), 499-509; https://doi.org/10.3390/chemistry2020030
Received: 18 April 2020 / Revised: 19 May 2020 / Accepted: 21 May 2020 / Published: 23 May 2020
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. View Full-Text
Keywords: binding affinity; epothilones; deaza-epothilone; microtubules; structure-activity relationship; thiophene binding affinity; epothilones; deaza-epothilone; microtubules; structure-activity relationship; thiophene
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Edenharter, A.; Ryckewaert, L.; Cintulová, D.; Estévez-Gallego, J.; Díaz, J.F.; Altmann, K.-H. On the Importance of the Thiazole Nitrogen in Epothilones: Semisynthesis and Microtubule-Binding Affinity of Deaza-Epothilone C. Chemistry 2020, 2, 499-509.

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