Total synthesis and biological evaluation of a C(10)/C(12)-phenylene-bridged analog of epothilone D.
The total synthesis of compound 8, a conformationally constrained analog of epothilone D (2), has been achieved through a convergent strategy based on three key fragments comprising C(1)-C(6) (26), C(7)-C(12) (16), and C(13)-O(16) (19) of the macrocyclic framework. Construction of the C(12)-C(13) bond involved Pd(0)-mediated B-alkyl Suzuki coupling between aryl bromide 16 and olefin 19, and proceeded in excellent yield, while formation of the C(6)-C(7) bond through aldol reaction was somewhat less efficient. Surprisingly, macrolactonization was rather low-yielding and gave protected 8 only in 39% yield. Although 8 had been suggested by pharmacophore modeling to adopt a conformation similar to the bioactive conformation of epothilone B, the compound was devoid of any significant antiproliferative activity.
End
Nicole
N
Novartis Institutes for Biomedical Research, DA Oncology, CH-4002 Basel.
Furet
Pascal
P
van Campenhout
Nathalie
N
Wartmann
Markus
M
Altmann
Karl-Heinz
KH
D004353:Drug Evaluation, Preclinical / Q000379:methods; D034261:Epothilones / Q000138:chemical synthesis*; D015394:Molecular Structure
D034261:Epothilones; C114026:desoxyepothilone B