title: Synthesis and biological evaluation of bifendate-chalcone hybrids as a new class of potential P-glycoprotein inhibitors.
abstract: Overexpression of P-glycoprotein (P-gp) is one of the major problems to successful cancer chemotherapy. To find novel effective P-gp inhibitors, a series of bifendate-chalcone hybrids were synthesized and evaluated. Among them, the most active compound 8g had little intrinsic cytotoxicity (IC(50)>200 μM), and could increase accumulation of Rhodamine 123 in K562/A02 cells more potently than bifendate and verapamil (VRP) by inhibiting P-gp efflux function. And 8g displayed potent chemo-sensitizing effect and persisted for much longer time (>24h) compared with VRP (<6h). In addition, 8g, unlike VRP, showed no stimulation on the P-gp ATPase activity, suggesting it is not a P-gp substrate. Therefore, 8g may represent a promising lead to develop MDR reversal agents for cancer chemotherapy.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Gu
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Ren
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Tang
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Ma
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Lai
authors.forename: Sixun
authors.initials: S
authors.lastname: Peng
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002599:Chalcone / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020014:K562 Cells; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; C465548:bifendate; D002599:Chalcone