Design, synthesis and cytotoxicity of novel 3'-N-alkoxycarbonyl docetaxel analogs.

Abstract By-product 9a exhibited potent cytotoxicity against both SK-OV-3 and A549 cell lines. The structure of 9a was characterized using 1D and 2D NMR experiments and confirmed by synthesis to afford a diastereomeric mixture ( 16a ) that was identical to 9a , as well as a pair of diastereomers ( R )- 16b and ( S )- 16c . The preliminary SAR study demonstrated that analogs with an ( R )-configuration were slightly more potent than analogs with an ( S )-configuration. In addition, α,α-gem-dimethyl analogs 16g – i were the most potent analogs in this series, exhibiting similar potency to docetaxel and greater potency than Taxol against the SK-OV-3 cell line. For the A549 cell line, analogs 16g – i were more potent (>65-fold) than both docetaxel and Taxol.