Synthesis of a methylenebis(phosphonate) analogue of mycophenolic adenine dinucleotide: a glucuronidation-resistant MAD analogue of NAD.
Mycophenolic alcohol (MPAlc), obtained by reduction of the carboxylic group of mycophenolic acid (MPA), was coupled with 2',3'-O-isopropylideneadenosine 5'-methylenebis(phosphonate) (4) in the presence of diisopropylcarbodiimide (DIC) to give P1-(2',3'-O-isopropylideneadenosin-5'-yl)-P2-(mycophenolic alcohol-6'-yl)methylenebis(phosphonate) (8) in 32% yield. Deisopropy-lidenation of 8 with CF3COOH/H2O afforded the methylenebis(phosphonate) analogue 3 of mycophenolic adenine dinucleotide (MAD). Compound 3, beta-methylene-MAD, was found to be a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) type II (Ki = 0.3 microM) as well as an inhibitor of growth of K562 cells (IC50 = 1.5 microM). In contrast to MPA and mycophenolic alcohol, beta-methylene-MAD was not converted into the glucuronide when incubated with uridine 5'-diphosphoglucuronyltransferase.
Lesiak
K
K
Division of Medicinal Chemistry, Codon Pharmaceuticals, Inc., Gaithersburg, Maryland 20877, USA.
Watanabe
K A
KA
Majumdar
A
A
Powell
J
J
Seidman
M
M
Vanderveen
K
K
Goldstein
B M
BM
Pankiewicz
K W
KW
D000227:Adenine Nucleotides; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001711:Biotransformation; D002455:Cell Division / Q000187:drug effects; D005965:Glucuronates; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors*; D007202:Indicators and Reagents; D015394:Molecular Structure; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D009243:NAD / Q000031:analogs & derivatives*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D005965:Glucuronates; D007202:Indicators and Reagents; C110807:beta-methylene-mycophenolic adenine dinucleotide; C110804:mycophenolic adenine dinucleotide; D009243:NAD; D007168:IMP Dehydrogenase; D014453:Glucuronosyltransferase; D009173:Mycophenolic Acid