Synthesis and multidrug resistance reversal activity of 1,2-disubstituted tetrahydroisoquinoline derivatives

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. Cytotoxicily 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 AC(50) 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'-dimetho xy-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