title: Novel fluorinated docetaxel analog for anti-hepatoma: Molecular docking and biological evaluation.
abstract: N-De-tert-butoxycarbonyl-N-[2-(1,1,1-trifluoro-2-methyl)propyloxycarbonyl]-2-debenzoyl-2-(m-fluorobenzoyl)-docetaxel (4FDT), a novel fluorinated docetaxel analog, was evaluated for its anti-hepatoma effect and possible druggability. In molecular docking studies, 4FDT coincided with paclitaxel in a part of the nucleus. In in vitro studies, 4FDT demonstrated higher anti-hepatoma activity approximately 1.5 times greater than that of docetaxel. More interestingly, 4FDT had been determined to have better anticancer effects, even 90 times greater in patient-derived xenografts (PDX) liver cancer cell lines than sorafenib. In the in vivo studies, 4FDT could effectively reduce the growth rate of liver cancer H22 and HepG2 cells. Furthermore, in a preliminary study on the ex vivo distribution of 4FDT, 4FDT-IR783 was primarily concentrated in the liver 1h after injection, and most of it was metabolized from the liver in 24h. Finally, the acute toxicity test revealed fewer side effects for 4FDT (approximately 16% than docetaxel). The water solubility, which was 11 times greater than that of docetaxel, confirmed the good druggability of 4FDT. All of these results demonstrated 4FDT's great potential to be a candidate drug for liver cancer treatment.
authors.affiliation: Department of Natural Products Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Yun-Peng
authors.initials: YP
authors.lastname: Hao
authors.affiliation: Department of Natural Products Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Zheng-Yu
authors.initials: ZY
authors.lastname: Liu
authors.affiliation: Department of Natural Products Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Xie
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Natural Products Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai 200040, China. Electronic address: sunxunf@shmu.edu.cn.
authors.forename: Xun
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D003198:Computer Simulation; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D008113:Liver Neoplasms / Q000188:drug therapy*; D008954:Models, Biological; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D043823:Taxoids / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel
keywords: 4FDT; Anti-hepatoma; Docetaxel; Ex vivo distribution; Patient-derived xenografts