title: Synthesis and bioevaluation of novel benzodipyranone derivatives as P-glycoprotein inhibitors for multidrug resistance reversal agents.
abstract: Multidrug resistance (MDR) is a phenomenon in which cells become resistant to structurally and mechanistically unrelated drugs, and it is one of the emerging problems in cancer therapy today. The relation between overexpression of the ABC transporter subfamily B member 1 (ABCB1/P-glycoprotein) and resistant cancers has been well characterized. In the present study, we successfully synthesized 52 novel benzodipyranone analogs and evaluated for their P-gp inhibitory activity in a P-gp transfected cell line, ABCB1/Flp-In™-293. Among these derivatives, 5a bearing on the 3-methylphenyl substituent, displayed the most potent P-gp inhibitory activity, which can enable the increase of the intracellular accumulation of P-gp substrate Calcein-AM. 5a exhibited more potency on promoted anticancer drugs cytotoxicity by reversing P-gp-mediated drug resistance in both ABCB1/Flp-In™-293 and KBvin cell lines. In particular, the compound 5a sensitized ABCB1/Flp-In™-293 cells toward paclitaxel, vincristine, and doxorubicin by 16.1, 21.0, and 1.6-fold at 10 μM, respectively. Further, 5a dramatically sensitized the resistant cell line KBvin toward paclitaxel and vincristine by 23.1 and 29.7-fold at 10 μM, respectively. It's possible that its mechanism of MDR inhibition can restore the intracellular accumulation of drugs and eventually chemosensitize cancer cells to anticancer drugs and reduce ABCB1 mRNA expression level.
authors.affiliation: School of Pharmacy, College of Pharmacy, China Medical University, 91, Hsueh-Shih Road, Taichung 404, Taiwan, ROC.
authors.forename: Chien-Yu
authors.initials: CY
authors.lastname: Chen
authors.affiliation: School of Pharmacy, College of Pharmacy, China Medical University, 91, Hsueh-Shih Road, Taichung 404, Taiwan, ROC.
authors.forename: Nai-Yu
authors.initials: NY
authors.lastname: Liu
authors.affiliation: School of Pharmacy, College of Pharmacy, China Medical University, 91, Hsueh-Shih Road, Taichung 404, Taiwan, ROC.
authors.forename: Hui-Chang
authors.initials: HC
authors.lastname: Lin
authors.affiliation: School of Pharmacy, College of Pharmacy, China Medical University, 91, Hsueh-Shih Road, Taichung 404, Taiwan, ROC.
authors.forename: Chih-Yu
authors.initials: CY
authors.lastname: Lee
authors.affiliation: School of Pharmacy, College of Pharmacy, China Medical University, 91, Hsueh-Shih Road, Taichung 404, Taiwan, ROC. Electronic address: cc0206hung@gmail.com.
authors.forename: Chin-Chuan
authors.initials: CC
authors.lastname: Hung
authors.affiliation: School of Pharmacy, College of Pharmacy, China Medical University, 91, Hsueh-Shih Road, Taichung 404, Taiwan, ROC. Electronic address: chihshiang@mail.cmu.edu.tw.
authors.forename: Chih-Shiang
authors.initials: CS
authors.lastname: Chang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D011487:Protein Conformation; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011714:Pyrans; D012333:RNA, Messenger
keywords: Benzodipyranone; Multidrug resistance; P-glycoprotein; Reversal agent