Synthesis and SAR of C12-C13-oxazoline derivatives of epothilone A.
The SAR of a series of new epothilone A derivatives with a 2-substituted-1,3-oxazoline moiety trans-fused to the C12-C13 bond of the deoxy macrocycle have been investigated with regard to tubulin polymerization induction and cancer cell growth inhibition. Significant differences in antiproliferative activity were observed between different analogs, depending on the nature of the substituent at the 2-position of the oxazoline ring. The most potent compounds showed comparable activity with the natural product epothilone A. Modeling studies provide a preliminary rationale for the observed SAR.
Swiss Federal Institute of Technology (ETH) Zürich, Zürich, Switzerland.
Bernhard
B
Pfeiffer
Kurt
K
Hauenstein
Philipp
P
Merz
Jürg
J
Gertsch
Karl-Heinz
KH
Altmann
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003198:Computer Simulation; D034261:Epothilones / Q000737:chemistry*; D006801:Humans; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D034261:Epothilones; D010080:Oxazoles; D014404:Tubulin; D050257:Tubulin Modulators; C093787:epothilone A