title: Design and syntheses of permethyl ningalin B analogues: potent multidrug resistance (MDR) reversal agents of cancer cells.
abstract: A series of novel N-arylalkyl-3,4-diaryl-substituted pyrrole-2,5-diones were synthesized. They exhibited promising P-gp modulating activity in a P-gp overexpressing breast cancer cell line (LCC6MDR). Compound 6 (with three methoxy groups at D-ring) displayed the highest P-gp modulating activity. 6 at 1 microM can sensitize LCC6MDR cells toward paclitaxel by 18.2-fold. Interestingly, a synergy on modulating P-gp was noted when 6 and 25 were used together (fractional inhibitory concentration index FICI = 0.42). Combination of 6 (0.5 microM) and 25 (0.5 microM) resulted in a 66-fold sensitization of LCC6MDR cells toward paclitaxel. They also reversed P-gp mediated doxorubicin (DOX) and vincristine resistance. Kinetic characterization suggests that permethyl ningalin B analogues likely act as a noncompetitive inhibitor of P-gp-mediated DOX transport (K(i) = 5.4-5.8 microM). The present study demonstrates that synthetic analogues of permethyl ningalin B 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, China.
authors.forename: Pu Yong
authors.initials: PY
authors.lastname: Zhang
authors.forename: Iris L K
authors.initials: IL
authors.lastname: Wong
authors.forename: Clare S W
authors.initials: CS
authors.lastname: Yan
authors.forename: Xiao Yu
authors.initials: XY
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.forename: Larry M C
authors.initials: LM
authors.lastname: Chow
authors.forename: Sheng Biao
authors.initials: SB
authors.lastname: Wan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D015195:Drug Design; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014750:Vincristine / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; D011758:Pyrroles; C409782:ningalin B; D014750:Vincristine; D004317:Doxorubicin; D017239:Paclitaxel