title: Structure-activity relationship study of permethyl ningalin B analogues as P-glycoprotein chemosensitizers.
abstract: A novel series of permethyl ningalin B analogues were synthesized and evaluated for their P-glycoprotein (P-gp)-modulating activities in a P-gp-overexpressing breast cancer cell line (LCC6MDR). Compounds 35 and 37, which possess one methoxy group and one benzyloxy group at aryl ring C, displayed the most potent P-gp-modulating activity. A 1 μM concentration of 35 and 37 resensitized LCC6MDR cells toward paclitaxel by 42.7-fold, with respective EC50 values of 93.5 and 110.0 nM. Their mechanism of P-gp modulation is associated with an increase in intracellular drug accumulation. Their advantages also include low cytotoxicity (IC50 for L929 fibroblast >100 μM) and high therapeutic indexes (>909 after normalization with their EC50 values). 35 is not a substrate of P-gp. They are potentially dual-selective modulators for both P-gp and breast cancer resistance protein transporters. The present study demonstrates that these new compounds can be employed as effective and safe modulators of P-gp-mediated drug resistance in cancer cells.
authors.affiliation: Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China , Qingdao, 266003 Shandong, China.
authors.forename: Jin Wen
authors.initials: JW
authors.lastname: Bin
authors.forename: Iris L K
authors.initials: IL
authors.lastname: Wong
authors.forename: Xuesen
authors.initials: X
authors.lastname: Hu
authors.forename: Zhang Xiao
authors.initials: ZX
authors.lastname: Yu
authors.forename: Li Fu
authors.initials: LF
authors.lastname: Xing
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.forename: Larry M C
authors.initials: LM
authors.lastname: Chow
authors.forename: Wan Sheng
authors.initials: WS
authors.lastname: Biao
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D012449:Safety; 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; D004317:Doxorubicin; D006575:Heterocyclic Compounds, 3-Ring; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D017239:Paclitaxel; C116614:ABCG2 protein, human; C409782:ningalin B; C421109:multidrug resistance-associated protein 1