Pocket-based lead optimization strategy for the design and synthesis of tubulin polymerization inhibitors

Microtubules play an indispensable role in numerous cellular processes. Targeting the colchicine binding site on tubulin to destabilize microtubules is a promising strategy for cancer chemotherapy. Our group has previously developed a SMART analogue, 9, in which the thiazole of SMART was replaced with triazole ring. The results of biological evaluation indicated that 9 exhibited moderate anti-proliferative activity targeting at microtubules. Based on the predicted binding mode of 9, the pocket-based lead optimization strategy was implemented. A series of 9 analogues were designed, synthesized, and subsequently assessed for their anti-proliferative activities against three distinct human tumor cell lines. The compound 12b, featuring a 5-methoxy group on the 1,2,3-triazol ring, demonstrated potent anti-proliferative activity against SGC-7901 cell lines with an IC50 value of 15 nM. The structure-activity relationships suggest that the presence of a specific steric hindrance at the C5-position on the 1,2,3-triazol ring confers a greater advantageous in terms of inhibitory activity due to its stronger interactions with surrounding amino acids. This work presents a pioneering approach to augment their biological activities by optimizing the structure of CBSIs.