Design, synthesis, and antiproliferative activity of novel thiazole-based derivatives as tubulin polymerization...

The development of novel microtubule-targeting medicines (MTAs) remains a crucial strategy in cancer treatment, as they combat drug resistance and systemic toxicity. A novel series of thiazole-based derivatives was synthesized, characterized, and evaluated as antitubulin agents endowed with antiproliferative action. An IC₅₀ experiment was performed to assess the efficacy of novel compounds 9a-o in suppressing tubulin activity. The antiproliferative effects of the most potent compounds were evaluated. The levels of initiator caspases (Caspase-8 and Caspase-9) and executioner caspase (Caspase-3) were examined to ascertain the degree of apoptosis. Additionally, the expression levels of the mitochondrial regulatory proteins Bax and Bcl-2 were examined to ascertain the importance of the intrinsic apoptotic pathway. Compound 9k exhibited significant inhibition of tubulin with an IC₅₀ of 1.56 µM and showed potent activity against HeLa (cervical), HCT-116 (colorectal), and A-549 (lung) cancer cell lines. The apoptotic assays revealed that 9k effectively triggered the apoptotic cascade, leading to a ninefold increase in Caspase-3 and a significant twenty-onefold rise in Caspase-9, surpassing the effects of the reference Staurosporine. Caspase-8 was activated by an elevenfold increase, primarily via the intrinsic pathway. This was confirmed by a substantial change in the mitochondrial "rheostat": 9k induced a 38-fold increase in pro-apoptotic Bax and a 5-fold decrease in anti-apoptotic Bcl-2. Molecular docking studies showed that 9k exhibited a favorable binding mode consistent with its tubulin-inhibition profile. In silico ADMET predictions further supported 9k as a drug-like lead with acceptable oral exposure and a beneficial P-gp-related transporter profile. The enhanced apoptotic effects of 9k compared with Staurosporine make 9k an attractive lead candidate for further development as an anti-cancer drug targeting the colchicine-binding site.