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

Abstract A diverse array of polyheterocyclic annulated 1,2,3‐triazolo‐fused‐tetrahydro‐β‐carboline derivatives have been synthesized via an intramolecular azide‐alkyne cycloaddition (1,3‐dipolar) reaction. Among the hexaheterocyclic series 5 a – r , the compound 5 b (14,15‐dimethoxy‐6,7,12,12 b ‐tetrahydro‐4 H ‐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 μM; whereas, among the pentaheterocyclic series 14 a – l , the derivative 14 b ((6 R ,12a S )‐6‐(3,4‐dimethoxyphenyl)‐7,12,12a,13‐tetrahydro‐4 H ,6 H ‐[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 μM on the B16F10 cell line. Treatment of MCF‐7 and B16F10 cells with 5 b and 14 b 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.