Novel methylenephosphophosphonate analogues of mycophenolic adenine dinucleotide. Inhibition of inosine monophosphate dehydrogenase.
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.
Rejman
Dominik
D
Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Olesiak
Magda
M
Chen
Liqiang
L
Patterson
Steven E
SE
Wilson
Daniel
D
Jayaram
Hiramagalur N
HN
Hedstrom
Lizbeth
L
Pankiewicz
Krzysztof W
KW
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
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