Discovery of tetrandrine derivatives as tumor migration, invasion and angiogenesis inhibitors.

Metastatic progression of cancer is a complex and clinically daunting process, with migration, invasion and angiogenesis being the key features. Tetrandrine (TET) is a typical dibenzylisoquinoline alkaloid with promising anti-tumor activity. In our previous work, a number of TET derivatives were designed and synthesized with obvious anti-proliferation activities against cancer cells, however, the anti-metastatic effects of these compounds were not evaluated. In the current investigation, five TET derivatives (8, 18, 32, 71, and 72) with pronounced anti-proliferative activities (IC values of 1.00, 1.91, 3.43, 3.78, and 1.93 μM, respectively) against human umbilical vein endothelial cells (HUVECs) were screened out. Scratch assays showed that these compounds significantly suppressed the migration of HUVECs and induced their apoptosis. Among them, derivatives 8 and 72 obviously inhibited the proliferation, colony formation and invasion of HCT-15 cells. Tube formation assays revealed that 4 μM of 8 or 72 remarkably inhibited the tube forming capacity of HUVECs. Moreover, 8 and 72 surpressed the formation of filopodia in HUVECs and severely impaired their motility. Both compounds effectively inhibited the angiogenesis in the zebrafish model with low toxicities in vivo. These results indicated that TET derivatives 8 and 72 are promising anti-metastatic inhibitors.