O Oh O Zkepo

Hundreds of epothilone analogs have been prepared using conventional solution chemistry or combinatorial strategies. Their screening has allowed to establish a detailed SAR profile,49,57,58 which is summarized below:

a. The configuration at the stereocentres C-6, C-8, C-13, and C-15 is important and must be that of the natural products (1).

b. The epoxide function is not essential, and it may be replaced by a C12-C13 double bond or a cyclopropane ring (2). Analogs incorporating a trans epoxide or trans olefin structure at C12-C13 appear to be almost equipotent with the corresponding cis isomers.

c. A methyl group at C-12 enhances activity (3).

d. Expansion to a 17-membered ring, created by the presence of a trans C11-C12 double bond and an additional methylene, leads to a compound where anti-proliferative activity is substantially maintained (4).

e. Z can be O or NH. In the latter case, the molecule is metabolically more stable.

f. A correct location for the nitrogen in the side chain at C-15 is significant for activity. However, the replacement of the thiazole ring either by an oxazole or various pyridine moieties is well tolerated (6).

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