4,5-Diaryl-3H-1,2-dithiole-3-thiones and related compounds as combretastatin A-4/oltipraz hybrids: Synthesis, molecular modelling and evaluation as antiproliferative agents and inhibitors of tubulin

• The combretastatin A-4/oltipraz hybrids were first introduced into CA-4 analogues.
• A set of 4,5-diaryl-3H-1,2-dithiole-3-thiones and related compounds were synthesized.
• 4d and 5c showed potent antiproliferative activities at sub-micromolar IC50 values.
• 4d inhibited tubulin polymerization and caused cellular arrest in the G2/M phase.
• 4d was docked with a superimposed docked pose of CA-4.

A new series of 4,5-diaryl-3H-1,2-dithiole-3-thiones and related compounds were designed and synthesised as combretastatin A-4/oltipraz hybrids. We evaluated the antiproliferative activities, inhibition of tubulin polymerization, and cell-cycle effects of these compounds. Several compounds in this series, such as 4d and 5c, displayed significant activity against SGC-7901, KB and HT-1080 cell lines, as determined using MTT assays. The most active compound, 4d, markedly inhibited tubulin polymerization, with an IC50 value of 4.44 μM being observed. In mechanistic studies, 4d caused cell arrest in G2/M phase, induced apoptotic cell death, and disrupted microtubule formation. Molecular docking studies revealed that 4d interacts and binds efficiently with the tubulin protein.

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