[Total synthesis and biological evaluation of a C(10)/C(12)-phenylene-bridged analog of epothilone D.]
>>Chem Biodivers. 2004 Nov;1(11):1771-84.
Total synthesis and biological evaluation of a C(10)/C(12)-phenylene-bridged analog of epothilone D.
End N, Furet P, van Campenhout N, Wartmann M, Altmann KH.
Novartis Institutes for Biomedical Research, DA Oncology, CH-4002 Basel.
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.<<
I've had pubcrawler looking for epothilone D news for well over two years. But it just found this abstract from two years ago . . . or the actual publication date is very different from the one given in the abstract. Whatever, Novartis does some modeling, finds a promising lead. But they had some difficulty in getting a good yield, and the compound turned out to have no activity. So the authors, knowing they aren't giving away any secrets, publish to pad their resumes (Look, Ma! I can do total synthesis with Suzuki reactions!). It seems to underscore the difficulty with epothilones, and while Epo D may be kind of dead, it perhaps shows there is some value in Kosan's platform. Kosan at least got an Epo D out there with some activity, and were able to produce it with reasonable yields, while these big pharma guys basically whiffed.
Cheers, Tuck |
