Author:

Keywords:

Adenocarcinoma, Breast Neoplasms, Cell Line, Tumor, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Hela Cells, Humans, Inhibitory Concentration 50, P-Glycoprotein, Rhodamines, Structure-Activity Relationship, Tetrahydroisoquinolines, Verapamil, Science & Technology, Life Sciences & Biomedicine, Oncology, tetrahydroisoquinolines, multidrug resistance, P-glycoprotein, P-GLYCOPROTEIN, CELL-LINE, DRUG-RESISTANCE, CANCER-CELLS, INHIBITORS, ANALOGS, GROWTH, ALPHA, MDR, ATP Binding Cassette Transporter, Subfamily B, Member 1, HeLa Cells, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, 3211 Oncology and carcinogenesis

Abstract:

BACKGROUND: Cancer treatment often fails due to multidrug resistance (MDR) of the tumor cells. One of the major causes is overexpression of P-glycoprotein (P-gp). MATERIALS AND METHODS: By N-substitution reactions of diamine, amino acid and amino alcohol derivatives with 1-substituted tetrahydroisoquinoline skeleton, structurally diverse 1,2-disubstituted 1,2,3,4-tetrahydroisoquinolines were synthesized. The compounds were assayed as P-gp inhibitors using a standard functional assay with rhodamine (6G) on MCF-7/Adr cells. Cytotoxicity was investigated on HeLa cells using an antiproliferative assay. RESULTS: Five of the 24 compounds showed greater P-gp inhibition than the control compound verapamil with AC50 values (concentration of the compound eliciting 50% of the maximal rhodamine 6G accumulation) significantly lower than that of verapamil. CONCLUSION: Novel compounds were synthesized that showed MDR-reversal effect. One of them, (1'R*,2R*)-2-[2'-[2''-hydroxy-3''-(alpha-naphthyloxy)propyl]-6',7'-dimethoxy-1',2',3',4'-tetrahydro-1'-isoquinolyl]propan-1-ol hydrochloride, showed two times higher efficacy than verapamil at 10 times lower concentrations. The outcome makes this molecule an attractive subject for further investigation and development.