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Synthesis, Profiling, and Bioactive Conformation of trans ‐Cyclopropyl Epothilones
Author(s) -
Kuzniewski Christian N.,
Glauser Simon,
Gaugaz Fabienne Z.,
Schiess Raphael,
RodríguezSalarichs Javier,
Vetterli Stefan,
Horlacher Oliver P.,
Gertsch Jürg,
RedondoHorcajo Mariano,
Canales Angeles,
JiménezBarbero Jesús,
Díaz José Fernando,
Altmann KarlHeinz
Publication year - 2019
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.201900078
Subject(s) - chemistry , side chain , stereochemistry , benzothiazole , moiety , epothilones , quinoline , thiazole , ring (chemistry) , ring closing metathesis , metathesis , organic chemistry , polymerization , polymer
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.