title: 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.
authors: Key Laboratory of Structure-Based Drug Design & Discovery, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
authors: Yun-rong
authors: YR
authors: Jing
authors: Chem-Pharm R&D Institute, Tianjin Tasly Group Co., Ltd, Tasly TCM Garden, No. 2, Pujihe East Road, Beichen District, Tianjin 300402, PR China.
authors: Wei
authors: W
authors: Zhou
authors: Chem-Pharm R&D Institute, Tianjin Tasly Group Co., Ltd, Tasly TCM Garden, No. 2, Pujihe East Road, Beichen District, Tianjin 300402, PR China.
authors: Wan-liang
authors: WL
authors: Li
authors: Key Laboratory of Structure-Based Drug Design & Discovery, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China. Electronic address: linxiang.zhao@vip.sina.com.
authors: Lin-xiang
authors: LX
authors: Zhao
authors: Chem-Pharm R&D Institute, Tianjin Tasly Group Co., Ltd, Tasly TCM Garden, No. 2, Pujihe East Road, Beichen District, Tianjin 300402, PR China; Zhuhai Oxforston PharmTech Co., Ltd, Zhuhai, Guangdong 519085, China. Electronic address: yonkenafil@yahoo.co.uk.
authors: Yong-feng
authors: YF
authors: Wang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D006801:Humans; D017239:Paclitaxel / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry; D043823:Taxoids / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D043823:Taxoids; D017239:Paclitaxel
keywords: 1,14-Carbonate baccatin III; Bi-directional Caco-2 cells permeability; MDCK-MDR1 monolayers; Oral bioavailability; P-gp substrate; Paclitaxel