TY - JOUR
T1 - Complex target-oriented total synthesis in the drug discovery process
T2 - The discovery of a highly promising family of second generation epothilones
AU - Rivkin, Alexey
AU - Yoshimura, Fumihiko
AU - Gabarda, Ana E.
AU - Chou, Ting Chao
AU - Dong, Huajin
AU - Tong, William P.
AU - Danishefsky, Samuel J.
PY - 2003/3/12
Y1 - 2003/3/12
N2 - The total synthesis of a family of (E)-9,10-dehydro derivatives of epothilone D (i.e., 12,13-desoxyepothilone B) is described. The route is particularly concise and amenable to production of new congeners. Furthermore, the chemistry described herein constitutes a major simplification in the total synthesis of EpoD, which is in human clinical trials. This new family of epothilones shows major advantages in terms of their potency and pharmacostability relative to the wild-type saturated analogues in the D series. From the perspective of compound availability through synthesis, potency, and pharmacokinetic properties, these compounds could well warrant advancement to clinical evaluation in humans.
AB - The total synthesis of a family of (E)-9,10-dehydro derivatives of epothilone D (i.e., 12,13-desoxyepothilone B) is described. The route is particularly concise and amenable to production of new congeners. Furthermore, the chemistry described herein constitutes a major simplification in the total synthesis of EpoD, which is in human clinical trials. This new family of epothilones shows major advantages in terms of their potency and pharmacostability relative to the wild-type saturated analogues in the D series. From the perspective of compound availability through synthesis, potency, and pharmacokinetic properties, these compounds could well warrant advancement to clinical evaluation in humans.
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U2 - 10.1021/ja029695p
DO - 10.1021/ja029695p
M3 - Article
C2 - 12617656
AN - SCOPUS:0037433593
SN - 0002-7863
VL - 125
SP - 2899
EP - 2901
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 10
ER -