Design, synthesis and X-ray crystallographic study of NAmPRTase inhibitors as anti-cancer agents
- Eur J Med Chem. 2011 Apr;46(4):1153-64. doi: 10.1016/j.ejmech.2011.01.034.
- 1. School of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea.
NAmPRTase (PBEF/Visfatin) plays a pivotal role in the salvage pathway of NAD(+) biosynthesis. NAmPRTase has been an attractive target for anti-cancer agents that induce Apoptosis of tumor cells via a declining plasma NAD(+) level. In this report, a series of structural analogs of FK866 (1), a known NAmPRTase inhibitor, was synthesized and tested for inhibitory activities against the proliferation of Cancer cells and human NAmPRTase. Among them, compound 7 showed similar anti-cancer and enzyme inhibitory activities to compound 1. Further investigation of compound 7 with X-ray analysis revealed a co-crystal structure in complex with human NAmPRTase, suggesting that Asp219 in the active site of the enzyme could contribute to an additional interaction with the pyrrole nitrogen of compound 7.