title: Design, synthesis and X-ray crystallographic study of NAmPRTase inhibitors as anti-cancer agents.
abstract: 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.
authors.affiliation: School of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea.
authors.forename: Hyun
authors.initials: H
authors.lastname: You
authors.forename: Hyung-Seop
authors.initials: HS
authors.lastname: Youn
authors.forename: Isak
authors.initials: I
authors.lastname: Im
authors.forename: Man-Ho
authors.initials: MH
authors.lastname: Bae
authors.forename: Sang-Kook
authors.initials: SK
authors.lastname: Lee
authors.forename: Hyojin
authors.initials: H
authors.lastname: Ko
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Eom
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Kim
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D057075:Enzyme Assays; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D012266:Ribose / Q000737:chemistry
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; D012266:Ribose; D054409:Nicotinamide Phosphoribosyltransferase