Development of a novel series of thiazole-based compounds with enhanced antiproliferative properties as tubulin polymerization inhibitors

In cancer therapy, inhibiting tubulin polymerization is a key approach for modifying microtubule dynamics required for cell survival and proliferation. Microtubule destabilizing agents (MDAs), also known as tubulin polymerization inhibitors, prevent tubulin heterodimers from forming microtubules, resulting in catastrophic cellular collapse.

A novel series of thiazole-based compounds 8a-o was developed to inhibit tubulin polymerization and assess for its antiproliferative efficacy against the NCI 60 cell line. The structures of the newly synthesized compounds were confirmed using ¹H NMR, ¹³C NMR, and elemental microanalyses. All 15 compounds (8a-o) were assessed for antiproliferative action at a single dosage (10 μM) and analyzed against the comprehensive 60-cell panel at five concentrations (0.01, 0.1, 1, 10, and 100 μM).

The results from the one-dose and five-dose studies demonstrate that 8b, 8c, 8d, 8m, and 8o are the most prominent antiproliferative agents, exhibiting the most favourable low-micromolar GI₅₀ values across various cell lines, frequently advancing to low-micromolar TGI, and, in numerous sensitive cell lines, achieving LC₅₀ values within the single-digit micromolar range. Compounds 8b, 8d and 8m showed significant anti-tubulin activity, with IC50 values ranging from 3.86 to 7.19 μM, compared to the reference CA-4 (IC50 = 2.40 μM). In the MCF-7 breast cancer cell line, compound 8m drove a significant accumulation of cells in the G2/M phase, increasing from 13.74% to 45.35%. G2/M arrest is frequently associated with DNA damage or the inhibition of microtubule dynamics, which aligns with Western blot results demonstrating a decrease in tubulin (50 kDa) expression following treatment with 8m. Apoptotic and necrotic experiments indicate that 8m stimulates a defined programmed cell death pathway rather than inducing non-specific toxic necrosis. Molecular docking corroborated their binding at the colchicine site, while in silico ADMET profiling indicated a promising drug-like profile for compound 8m.