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).


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.


CONCLUSIONS
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.
Institute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, POB 121, Hungary.
Attila
A
Mihályi
Róbert
R
Gáspár
Zita
Z
Zalán
László
L
Lázár
Ferenc
F
Fülöp
Peter A M
PA
de Witte
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D012235:Rhodamines / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012235:Rhodamines; D044005:Tetrahydroisoquinolines; C026188:rhodamine 6G; D014700:Verapamil