Design, synthesis and X-ray crystallographic study of NAmPRTase inhibitors as anti-cancer agents

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.

A NAmPRTase inhibitor, compound 7 showed anti-proliferative activity and the analysis of X-ray co-crystal structure suggested that Asp219 could contribute to an additional interaction with the pyrrole nitrogen of 7.Figure optionsDownload as PowerPoint slideResearch highlights
► We designed and synthesized new FK866 analogs as NAmPRTase inhibitors.
► The new compounds were evaluated for the anti-cancer and enzyme inhibitory activities.
► X-ray co-crystal structure with the most potent compound, 7 was analyzed.
► Asp219 could contribute to an additional ionic interaction with the pyrrole nitrogen of compound 7.