title: Discovery of alkoxyl biphenyl derivatives bearing dibenzo[c,e]azepine scaffold as potential dual inhibitors of P-glycoprotein and breast cancer resistance protein.
abstract: We recently reported alkoxyl biphenyl derivatives bearing dibenzo[c,e]azepine scaffold as novel P-glycoprotein (P-gp, ABCB1) inhibitors. In this study, their ability to reverse breast cancer resistance protein (BCRP, ABCG2)-mediated multidrug resistance was tested in HEK293/BCRP cells which was BCRP-transfected stable HEK293 cells. It was observed that compounds 4d, 4h, 4i increased mitoxantrone accumulation in HEK293/BCRP cells via inhibiting BCRP efflux function. Notably, the inhibitory activity of 4i was comparable to that of the classical BCRP inhibitor Ko143 at an equimolar concentration. Interestingly, 4i had little inhibitory effect on multidrug resistance-associated protein 1 (MRP1, ABCC1), another drug efflux transporter. These results, together with the previous findings, suggest that 4i may be a dual inhibitor of P-gp and BCRP to warrant further investigation.
authors.affiliation: School of Pharmacy, Xuzhou Medical College, Xuzhou 221004, People's Republic of China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Environmental Pharmacy, Tianjin Institute of Health and Environmental Medicine, Tianjin 300050, People's Republic of China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Environmental Pharmacy, Tianjin Institute of Health and Environmental Medicine, Tianjin 300050, People's Republic of China. Electronic address: p_h2002@hotmail.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
authors.forename: Sixun
authors.initials: S
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, People's Republic of China. Electronic address: zyhtgd@hotmail.com.
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; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D003024:Clozapine / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001713:Biphenyl Compounds; D003024:Clozapine; D009363:Neoplasm Proteins; D012333:RNA, Messenger; C116614:ABCG2 protein, human; C586625:dibenzo(c,e)azepine; C010574:biphenyl
keywords: Alkoxyl biphenyl; BCRP inhibitor; Dibenzo[c,e]azepine; Multidrug resistance