Synthesis of 1,2,3-Triazolo-fused-tetrahydro-b-carboline Derivatives via 1,3-Dipolar Cycloaddition Reaction: Cytotoxicity Evaluation and DNA-Binding studies

摘要

A diverse array of polyheterocyclic annulated 1,2,3-triazolofused- tetrahydro-b-carboline derivatives have been synthesized via an intramolecular azide-alkyne cycloaddition (1,3-dipolar) reaction. Among the hexaheterocyclic series 5a–r, the compound 5b (14,15-dimethoxy-6,7,12,12b-tetrahydro-4H-benzo[ 5’,6’][1,2,3]triazolo[5’’,1’’:3’,4’][1,4]diazepino[1’,7’:1,2]pyrido[ 3,4-b]indole) displayed significant cytotoxicity against the MCF-7 cell line with an IC-(50) value of 6.45 ± 0.37 mM; whereas, among the pentaheterocyclic series 14a–l, the derivative 14b ((6R,12aS)-6-(3,4-dimethoxyphenyl)-7,12,12a,13-tetrahydro- 4H,6H-[1,2,3]triazolo[1’’,5’’:4’,5’]pyrazino[1’,2’:1,6]pyrido[3,4- b]indole) has shown potent cytotoxicity with an IC_(50) value of 4.01 ± 0.39 mM on the B16F10 cell line. Treatment of MCF-7 and B16F10 cells with 5b and 14b respectively resulted in cell cycle arrest, inhibition of cell migration and colony formation as well as induction of apoptosis. DNA binding affinity estimation by viscometry experiment and molecular modeling revealed their efficient minor groove binding.