The synthesis of novel taxoids for oral administration

Abstract

A group of novel taxoids, with modifications at C-7, C-10, C-3' and C-14 positions of paclitaxel, was synthesized in order to improve their biological profile by decreasing their affinity with P-glycoprotein (P-gp) and increasing cellular permeability. Most of the new taxoids demonstrated the similar potent cytotoxic activities in MCF-7 human tumor cell line as paclitaxel in vitro. In the permeability assay with monolayers of Caco-2 cells, most of the compounds demonstrated an increased trans-cellular transport in A-to-B direction in comparison with paclitaxel. Among them the compounds T-13, T-15 and T-26 showed the highest permeability, and with efflux ratios better than that of ortataxel. The interaction of the compounds T-13 and T-26 with P-gp was evaluated using Madin-Darby canine kidney (MDCK)-multidrug resistance-1(MDR1) and MDCK-wild-type (WT). The results indicated that T-13 and T-26 were poor substrates for P-gp and possessed inhibiting effects of P-gp mediated efflux. It was thus clear that simultaneous modifications at the C-7, C-10 and C-3' positions of paclitaxel significantly impaired its interactions with P-gp and interfered with P-gp mediated efflux.

Keywords: 1,14-Carbonate baccatin III; Bi-directional Caco-2 cells permeability; MDCK-MDR1 monolayers; Oral bioavailability; P-gp substrate; Paclitaxel.