Synthesis, Profiling, and Bioactive Conformation of trans-Cyclopropyl Epothilones

Article abstract of DOI:10.1002/hlca.201900078

A series of new 3-deoxy-C(12),C(13)-trans-cyclopropyl-epothilones have been prepared, bearing benzothiazole, quinoline, thiazol-5-ylvinyl, or isoxazol-3-ylvinyl side chains. For analogs with fused aromatic side chains, macrocyclic ring-closure was based on ring-closing olefin metathesis (RCM) of a precursor incorporating the fully elaborated heavy atom framework of the target structure (including the side chain moiety), while side chain attachment for the thiazole and isoxazole-containing 16-desmethyl analogs was performed only after establishment of the macrolactone core. Two approaches were elaborated for a macrocyclic aldehyde as the common precursor for the latter analogs that involved ring-closure either by RCM or by macrolactonization. Benzothiazole- and quinoline-based analogs were found to be highly potent antiproliferative agents; the two analogs with a thiazol-5-ylvinyl or an isoxazol-3-ylvinyl side chain likewise showed good antiproliferative activity but were significantly less potent than the parent epothilone A. Surprisingly, the desaturation of the C(10)?C(11) bond in these analogs was associated with a virtually complete loss in antiproliferative activity, which likely reflects a requirement for a ca. 60 ° C(10)?C(11) torsion angle in the tubulin-bound conformation of 12,13-trans-epothilones.

Full text of DOI:10.1002/hlca.201900078

HELVETICA
chimica acta
Accepted Article
Title: Synthesis, Profiling and Bioactive Conformation of trans-
Cyclopropyl Epothilones
Authors: Karl-Heinz Altmann, Christian Nicolas Kuzniewski, Simon
Glauser, Fabienne Zdenka Gaugaz, Raphael Schiess, Stefan
Vetterli, Javier Rodríguez-Salarichs, Jürg Gertsch, Mariano
Redondo-Horcajo, Oliver Philip Horlacher, Angeles Canales,
Jesus Jimenez-Barbero, and Jose Fernando Díaz
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To be cited as: Helv. Chim. Acta 10.1002/hlca.201900078
Link to VoR: http://dx.doi.org/10.1002/hlca.201900078
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10.1002/hlca.201900078
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Schmidt, S.
Hauke, S. Krehl, O. Kunz, 'Ring-closing metathesis', In Comprehensive Organic
Synthesis, 2nd ed.; Vol. 5; Elsevier: Amsterdam, 2014, pp. 1400–1482.
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10.1002/hlca.201900078
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This article is protected by copyright. All rights reserved.