Novel Tetrazole Derivatives Targeting Tubulin Endowed with Antiproliferative Activity against Glioblastoma Cells

Increasing awareness of the structure of microtubules has made tubulin a relevant target for the research of novel chemotherapies. Furthermore, the particularly high sensitivity of glioblastoma multiforme (GBM) cells to microtubule disruption could open new doors in the search for new anti-GBM treatments. However, the difficulties in developing potent anti-tubulin drugs endowed with improved pharmacokinetic properties necessitates the expansion of medicinal chemistry campaigns. The application of an ensemble pharmacophore screening methodology helped to optimize this process, leading to the development of a new tetrazole-based tubulin inhibitor. Considering this scaffold, we have synthesized a new family of tetrazole derivatives that achieved remarkable antimitotic effects against a broad panel of cancer cells, especially against GBM cells, showing high selectivity in comparison with non-tumor cells. The compounds also exerted high aqueous solubility and were demonstrated to not be substrates of efflux pumps, thus overcoming the main limitations that are usually associated with tubulin binding agents. Tubulin polymerization assays, immunofluorescence experiments, and flow cytometry studies demonstrated that the compounds target tubulin and arrest cells at the G2/M phase followed by induction of apoptosis. The docking experiments agreed with the proposed interactions at the colchicine site and explained the structure-activity relationships.

Automated summary

Increasing awareness of the structure of microtubules has driven research on targeting tubulin for novel chemotherapies, particularly for glioblastoma multiforme (GBM) cells. Optimization of potently anti-tubulin drugs with improved pharmacokinetic properties is challenging, but the use of ensemble pharmacophore screening has led to the development of a new tetrazole-based tubulin inhibitor. This inhibitor demonstrated remarkable antimitotic effects against various cancer cells, especially GBM cells, with high selectivity and overcome the limitations typically associated with tubulin binding agents.