Tubulin inhibitors(University of Münster)

As the key components and elements of the cytoskeleton, tubulin play a fundamental and essential role in multiple biological processes. In this work, we designed and synthesized a series of deoxypodophyllotoxin derivatives by strategy of introducing nitrogen into the C-4 position of deoxypodophyllotoxin. Among them, compounds A7 and A8 exhibited the potent antiproliferative activity against five cancer cell lines and paclitaxel-resistant A549 cells. Specially, both compounds A7 and A8 showed the best antiproliferative activities against MCF-7 cells with an IC₅₀ value of 4 nM. Further investigation indicated that both compounds could inhibit the polymerization of tubulin by targeting the colchicine binding site of tubulin, destroy the microtubule network, induce MCF-7 cell cycle arrest in the G2/M phase, and induce MCF-7 cell apoptosis, accompanied by the decrease of mitochondrial membrane potential and increase the accumulation of reactive oxygen species. Meanwhile, compounds A7 and A8 were able to inhibit the migration of cancer cells and destroy the angiogenesis of human umbilical vein endothelial cells. All the results suggested that compounds A7 and A8 may be promising inhibitors of tubulin polymerization for the treatment of breast cancer.