Biphasic Dose-Dependent G0/G1 and G2/M Cell-Cycle Arrest by Synthetic 2,3-Arylpyridylindole Derivatives in A549 Lung Cancer Cells

A collection of 2,3-arylpyridylindole derivatives were synthesized via the Larock heteroannulation and evaluated for their in vitro cytotoxic activity against A549 human lung cancer cells. Two derivatives expressed good cytotoxicity with IC50 values of 1.18 +/- 0.25 mu M and 0.87 +/- 0.10 mu M and inhibited tubulin polymerization in vitro, with molecular docking studies suggesting the binding modes of the compounds in the colchicine binding site. Both derivatives have biphasic cell cycle arrest effects depending on their concentrations. At a lower concentration (0.5 mu M), the two compounds induced G0/G1 cell cycle arrest by activating the JNK/p53/p21 pathway. At a higher concentration (2.0 mu M), the two derivatives arrested the cell cycle at the G2/M phase via Akt signaling and inhibition of tubulin polymerization. Additional cytotoxic mechanisms of the two compounds involved the decreased expression of Bcl-2 and Mcl-1 antiapoptotic proteins through inhibition of the STAT3 and Akt signaling pathways.

Automated summary

A series of compounds synthesized by Larock heteroannulation showed good cytotoxic activity against human lung cancer cells, through inhibition of tubulin polymerization, modulation of cell cycle, and downregulation of apoptosis-related proteins.