title: Design and Synthesis of New α-Naphthoflavones as Cytochrome P450 (CYP) 1B1 Inhibitors To Overcome Docetaxel-Resistance Associated with CYP1B1 Overexpression.
abstract: CYP1B1 is recognized as a new target in cancer prevention and therapy. Taking α-naphthoflavone as a lead, a series of 6,7,10-trimethoxy-α-naphthoflavones (4a-o) were synthesized and evaluated for their inhibitory potency against CYP1B1 and selectivity over CYP1A1 and 1A2. SAR analysis indicated that introducing methoxy groups at C(6), C(7), and C(10) on the naphthalene part and a fluoro atom at C(3') on the B-ring, could sharply increase the efficiency toward CYP1B1 inhibition. Among the prepared derivatives, compound 4c is the most potent and selective CYP1B1 inhibitor ever reported. More effort was taken to acquire water-soluble α-naphthoflavone derivatives for further cell-based study of overcoming anticancer drug-resistance. Finally, we obtained water-soluble naphthoflavone (11f) which could obviously eliminate the docetaxel-resistance caused by the enhanced expression of CYP1B1 in MCF-7/1B1 cells. It could be envisaged that the discovery of new α-naphthoflavones as CYP1B1 inhibitors is clinically important for overcoming CYP1B1-mediated drug-resistance in cancer therapeutics.
authors: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, China.
authors: Jiahua
authors: J
authors: Cui
authors: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, China.
authors: Qingqing
authors: Q
authors: Meng
authors: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, China.
authors: Xu
authors: X
authors: Zhang
authors: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, China.
authors: Qing
authors: Q
authors: Cui
authors: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, China.
authors: Wen
authors: W
authors: Zhou
authors: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, China.
authors: Shaoshun
authors: S
authors: Li
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001571:Benzoflavones / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D065633:Cytochrome P-450 CYP1B1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001571:Benzoflavones; D043823:Taxoids; D000077143:Docetaxel; C011512:alpha-naphthoflavone; D065633:Cytochrome P-450 CYP1B1