Development of S-aryl dithiocarbamate derived novel antiproliferative compound exhibiting tubulin bundling

Abstract

Cancer is a leading cause of human death, and there is a need to identify efficient and novel chemical scaffolds which could provide flexibility to cancer chemotherapeutics. This work introduces S-aryl dithiocarbamates belonging to a versatile group of organo-sulfur containing compounds as a hitherto unexplored class of effective anticancer drugs with promising pharmacophore properties. We synthesized a series of N-Boc piperazine containing S-aryl dithiocarbamates and identified compound 1 as a potent antiproliferative agent in lung, cervical, and breast cancer cell lines. Compound 1 exhibited best inhibitory activity against cervical cancer cells, HeLa with an IC₅₀ of 0.432 ± 0.138 μM for 72 h, and lung cancer cells, A549 with an IC₅₀ of 0.447 ± 0.051 μM for 72 h. We further demonstrate that HeLa cells treated with this compound result in G₂/M phase cell cycle arrest, causing cell apoptosis due to the upregulation of the p53-p21 signaling pathway. Importantly, cells treated with compound 1 showed a novel tubulin bundling phenotype in fluorescence microscopy, which is a characteristic of microtubule-stabilizing anticancer drugs like paclitaxel. Interestingly, molecular docking analysis revealed reasonable binding of compound 1 in the taxol-binding pocket of β-tubulin, making it a promising candidate for microtubule stabilization based anticancer drug discovery.

Keywords: Apoptosis; Cancer; Cell cycle; Dithiocarbamate; Tubulin.