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.

Graphical abstractA 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 full-size imageDownload 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.