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.

Agents that cause apoptotic cell death by interfering with tubulin dynamics, such as vinblastine and paclitaxel, are an important class of chemotherapeutics. Unfortunately, these compounds are substrates for multidrug resistance (MDR) pumps, allowing cancer cells to gain resistance to these chemotherapeutics. The indolesulfonamide family of tubulin inhibitors are not excluded by MDR pumps and have a promising activity profile, although their high lipophilicity is a pharmacokinetic limitation for their clinical use. Here we present a new family of N-indolyl-3,4,5-trimethoxybenzenesulfonamide derivatives with modifications on the indole system at positions 1 and 3 and on the sulfonamide nitrogen. We synthesized and screened against HeLa cells 34 novel indolic benzenesulfonamides. The most potent derivatives (1.7-109 nM) were tested against a broad panel of cancer cell lines, which revealed that substituted benzenesulfonamides analogs had highest potency. Importantly, these compounds were only moderately toxic to non-tumorigenic cells, suggesting the presence of a therapeutic index. Consistent with known clinical anti-tubulin agents, these compounds arrested the cell cycle at G₂/M phase. Mechanistically, they induced apoptosis via caspase 3/7 activation, which occurred during M arrest. The substituents on the sulfonamide nitrogen appeared to determine different mechanistic results and cell fates. These results suggest that the compounds act differently depending on the bridge substituents, thus making them very interesting as mechanistic probes as well as potential drugs for further development.