title: Potent and Nontoxic Chemosensitizer of P-Glycoprotein-Mediated Multidrug Resistance in Cancer: Synthesis and Evaluation of Methylated Epigallocatechin, Gallocatechin, and Dihydromyricetin Derivatives.
abstract: We are interested in developing novel natural product-derived P-gp inhibitors to reverse cancer drug resistance. Here, we have synthesized 55 novel derivatives of methylated epigallocatechin (EGC), gallocatechin (GC), and dihydromyricetin (DHM). Three EGC derivatives (23, 35, and 36) and three GC derivatives (50, 51, and 53) are significantly better than epigallocatechin gallate (EGCG) with a relative fold (RF) ranging from 31.4 to 53.6. The effective concentration (EC50) of 23 and 51 ranges from 102 to 195 nM. Compounds 23 and 51 are noncytotoxic to fibroblasts with IC50 > 100 μM. Compound 23 is specific for P-gp without modulating activity toward MRP1 or BCRP. Compounds 23 and 51 are non-P-gp substrates. Important pharmacophores for P-gp modulation were identified. In summary, methylated EGC and GC derivatives represent a new class of potent, specific, noncytotoxic, and nonsubstrate P-gp modulators.
authors.affiliation: †Department of Applied Biology and Chemical Technology, and State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China.
authors.forename: Iris L K
authors.initials: IL
authors.lastname: Wong
authors.forename: Bao-Chao
authors.initials: BC
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Yuan
authors.forename: Liang-Xing
authors.initials: LX
authors.lastname: Duan
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Xue-Min
authors.initials: XM
authors.lastname: Li
authors.affiliation: †Department of Applied Biology and Chemical Technology, and State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China.
authors.forename: Xuesen
authors.initials: X
authors.lastname: Hu
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.forename: Sheng-Biao
authors.initials: SB
authors.lastname: Wan
authors.affiliation: †Department of Applied Biology and Chemical Technology, and State Key Laboratory of Chirosciences, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR, China.
authors.forename: Larry M C
authors.initials: LM
authors.lastname: Chow
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D044948:Flavonols / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008745:Methylation; D008958:Models, Molecular; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D044948:Flavonols; D009363:Neoplasm Proteins; D002392:Catechin; C045651:epigallocatechin gallate; C057580:gallocatechol; C472036:dihydromyricetin