Tubulin inhibitors(University of Stellenbosch)

The current review discusses the importance of combretastatin A-4 (CA-4) as a lead compound of microtubule targeting agents. CA-4 holds a unique place among naturally occurring compounds having cytotoxic activity. In this review an overall picture of design strategies, structure-activity relationship, synthesis, cytotoxic activity, and binding interactions of promising CA-4 analogues, are discussed and arranged chronologically from 2016 to early 2023. Also, this review emphasizes their biological activity as anticancer agents, within an overview of clinical application limitation and suggested strategies to overcome. Dual targeting tubulin inhibitors showed highpotentialto surpass medication resistance and provide synergistic efficacy. Linking platinum (IV), amino acids, and HDAC targeting moieties to active tubulin inhibitorsproduced potent active compounds. Analogues of CA-4 bridged with azetidin-2-one, pyrazole, sulfide, or carrying selenium atom exhibited cytotoxic action against a variety of malignant cell lines through different pathways.

As our ongoing work, a novel series of the amide-based CA-4 analogues were successfully designed, synthesized, and explored for their biological evaluation. Among these compounds, 7d and 8a illustrated most potent antiproliferative activity toward A549, HeLa, HCT116, and HT-29 cell lines. Most importantly, these two compounds didn't display noticeable cytotoxic activity on the non-tumoural cell line HEK-293. Further mechanism studies revealed that analogue 8a was identified as a novel tubulin polymerization inhibitor with an IC₅₀ value of 6.90 μM, which is comparable with CA-4. The subsequent investigations unveiled that analogue 8a not only effectively caused cell cycle arrest at the G₂/M phase but also induced apoptosis in A549 cells via a concentration-dependent manner. The molecular docking revealed that 8a could occupy well the colchicine-binding site of tubulin. Collectively, these findings indicate that amide-based CA-4 scaffold could be worthy of further evaluation for development of novel tubulin inhibitors with improved safety profile.