title: Novel methylenephosphophosphonate analogues of mycophenolic adenine dinucleotide. Inhibition of inosine monophosphate dehydrogenase.
abstract: Novel methylenephosphophosphonate analogues of mycophenolic adenine dinucleotide (MAD) have been prepared as potential inhibitors of IMP dehydrogenase. A coupling of the mycophenolic (hydroxymethyl)phosphonate 6 with the phosphitylated adenosine analogue 11 followed by oxidation and deprotection afforded the phosphophosphonate 8. A similar coupling between adenosine (hydroxymethyl)phosphonate 10 and phosphitylated mycophenolic alcohol 5 gave the corresponding phosphophosphonate 13. Both 8 and 13 (Ki = 20-87 nM) were found to be the most potent cofactor type inhibitors of IMP dehydrogenase.
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Dominik
authors.initials: D
authors.lastname: Rejman
authors.forename: Magda
authors.initials: M
authors.lastname: Olesiak
authors.forename: Liqiang
authors.initials: L
authors.lastname: Chen
authors.forename: Steven E
authors.initials: SE
authors.lastname: Patterson
authors.forename: Daniel
authors.initials: D
authors.lastname: Wilson
authors.forename: Hiramagalur N
authors.initials: HN
authors.lastname: Jayaram
authors.forename: Lizbeth
authors.initials: L
authors.lastname: Hedstrom
authors.forename: Krzysztof W
authors.initials: KW
authors.lastname: Pankiewicz
mesh_terms: D000227:Adenine Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry; D000249:Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000227:Adenine Nucleotides; D063065:Organophosphonates; C513373:P(1)-(7-hydroxy-6-(ethyl-2-yl)-5-methoxy-4-methylphthalan-1-one)methylenephospho-P(2)-(adenosin-5'-yl)phosphonate; C513372:P(1)-(adenosin-5'-yl)methylenephospho-P(2)-(7-hydroxy-6-(ethyl-2-yl)-5-methoxy-4-methylphthalan-1-one)phosphonate; C110804:mycophenolic adenine dinucleotide; D000249:Adenosine Monophosphate; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid