Design, synthesis and bioevaluation of antitubulin agents carrying diaryl-5,5-fused-heterocycle scaffold

Abstract

A series of 3,6-diaryl-1H-pyrazolo[5,1-c][1,2,4]triazoles (I) and 3,6-diaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (II) as antitubulin agents were designed, synthesized and bioevaluated. Compounds (II) 4a, 4d, 4f, 4j, 4l and 4n showed potent antiproliferative activity at sub-micromolar or nanomolar concentrations against SGC-7901, A549 and HT-1080 cell lines, indicating that the bioisosteric replacement of the carbonyl group and B-ring of SMART and ABI with a 5,5-fused-heterocycle scaffold successfully maintained potent antiproliferative activity. Compound 4f exhibited the most excellent antiproliferative activity against the three cancer cell lines (IC₅₀ = 0.022-0.029 μM). Consistent with its potent antiproliferative activity, 4f also displayed excellent antitubulin activity (IC₅₀ = 0.77 μM). Furthermore, compound 4f could dramatically affect cell morphology and microtubule networking, while cell cycle studies demonstrated that 4f significantly induced SGC-7901 cells arrest in G2/M phase. In addition, molecular docking studies supported the biological assay data and suggested that 4f may be a potential antitubulin agent.

Keywords: Antiproliferative activity; Cell cycle arrest; Immunofluorescence; Molecular modeling; Tubulin.