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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adenine Nucleotides / chemical synthesis*
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Adenine Nucleotides / chemistry
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Adenosine Monophosphate / analogs & derivatives*
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Adenosine Monophosphate / chemical synthesis
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Adenosine Monophosphate / chemistry
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Humans
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IMP Dehydrogenase / antagonists & inhibitors*
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IMP Dehydrogenase / chemistry*
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Mycophenolic Acid / analogs & derivatives*
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Mycophenolic Acid / chemical synthesis
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Mycophenolic Acid / chemistry
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Organophosphonates / chemical synthesis*
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Organophosphonates / chemistry
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Structure-Activity Relationship
Substances
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Adenine Nucleotides
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Organophosphonates
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P(1)-(7-hydroxy-6-(ethyl-2-yl)-5-methoxy-4-methylphthalan-1-one)methylenephospho-P(2)-(adenosin-5'-yl)phosphonate
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P(1)-(adenosin-5'-yl)methylenephospho-P(2)-(7-hydroxy-6-(ethyl-2-yl)-5-methoxy-4-methylphthalan-1-one)phosphonate
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mycophenolic adenine dinucleotide
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Adenosine Monophosphate
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IMP Dehydrogenase
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Mycophenolic Acid