title: Synthesis and evaluation of furoxan-based nitric oxide-releasing derivatives of tetrahydroisoquinoline as anticancer and multidrug resistance reversal agents.
abstract: Multidrug resistance in tumor cells poses a major obstacle to efficient chemotherapy. Several types of agents have been recognized as multidrug resistance inhibitors, among which the tetrahydroisoquinolines is the most studied. In current study 16 furoxan-based nitric oxide-releasing derivatives of tetrahydroisoquinoline were synthesized. Their cytotoxic activities and effects in reversing multidrug resistance have been evaluated. The results revealed that these compounds had moderate cytotoxic effects. Compounds 7a-f, 7h, and 7l showed higher cytotoxicities than the rest, but lower than adriamycin on K562 cell line. Compounds 7d, 7f, and 7l exhibited potent MDR reversal activities on K562/A02 cell line. The accumulation assay indicated that compounds 7d, 7f, and 7l significantly increased the intracellular accumulation of rhodamine123 in K562/A02 cells. Furthermore, these three compounds produced high concentrations of NO in K562/A02 cells. Potentially, the high concentrations of NO produced by NO donor moieties will lead to an increased cytotoxicity to K562/A02 cells. Our results suggested that compounds 7d, 7f, and 7l had anticancer effects, as well as multidrug resistance reversal effects.
authors.affiliation: Centre of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu 210009, China.
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Zou
authors.forename: Xiao-Bu
authors.initials: XB
authors.lastname: Lan
authors.forename: Hai
authors.initials: H
authors.lastname: Qian
authors.forename: Wen-Long
authors.initials: WL
authors.lastname: Huang
authors.forename: Yun-Man
authors.initials: YM
authors.lastname: Li
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D058990:Molecular Targeted Therapy; D009569:Nitric Oxide / Q000378:metabolism; D020112:Rhodamine 123 / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014230:Triazoles / Q000737:chemistry / Q000378:metabolism; D014700:Verapamil / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; C467221:N-(1,2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl)-1-(4-chlorobenzyl)-2-(4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl)piperidin-1-yl)-2-oxoethylamine; D044005:Tetrahydroisoquinolines; D014230:Triazoles; D020112:Rhodamine 123; D009569:Nitric Oxide; D004317:Doxorubicin; D014700:Verapamil