One-pot synthesis and biological evaluation of N-(aminosulfonyl)-4-podophyllotoxin carbamates as potential anticancer agents
- Bioorg Med Chem Lett. 2017 Jul 1;27(13):2890-2894. doi: 10.1016/j.bmcl.2017.04.082.
- 1. School of Pharmacy, Lanzhou University, Lanzhou 730000, China; Lanzhou Institutes for Food and Drug Control, Gansu Province, Lanzhou 730000, China.
- 2. School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
- 3. School of Pharmacy, Lanzhou University, Lanzhou 730000, China. Electronic address: [email protected].
- 4. Experimental Center of Medicine, General Hospital of Lanzhou Military Command, Lanzhou 730050, China; Key Laboratory of Stem Cells and Gene Drug of Gansu Province, General Hospital of Lanzhou Military Command, Lanzhou 730050, China. Electronic address: [email protected].
A series of N-(aminosulfonyl)-4-podophyllotoxin carbamates were synthesized via the Burgess-type intermediate, and their antiproliferative activities were evaluated. Most of them possessed more potent cytotoxic effects against four human tumor cell lines (HeLa, A-549, HCT-8 and HepG2) and less toxic to normal human fetal lung fibroblast WI-38 cells than etoposide. In particular, N-(morpholinosulfonyl)-4-podophyllotoxin carbamate (9) exhibited the most potent activity towards these four tumor cells with IC50 values in the range of 0.5-16.5μM. Furthermore, immunofluorescence analysis revealed that 9 induced cell Apoptosis by up-regulating the expression of p53 and ROS. Meanwhile, 9 effectively inhibited tubulin polymerization and microtubule assembly at cellular levels in HeLa cells. In addition, 9 could induce cell cycle arrest in the G2/M phase in HeLa cells by up-regulating levels of cyclinB1 and cdc2 and decreasing the expression of p-cdc2. These results indicated that 9 had potential for further development as Anticancer agents.