title: Synthesis of a methylenebis(phosphonate) analogue of mycophenolic adenine dinucleotide: a glucuronidation-resistant MAD analogue of NAD.
abstract: 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.
authors.affiliation: Division of Medicinal Chemistry, Codon Pharmaceuticals, Inc., Gaithersburg, Maryland 20877, USA.
authors.forename: K
authors.initials: K
authors.lastname: Lesiak
authors.forename: K A
authors.initials: KA
authors.lastname: Watanabe
authors.forename: A
authors.initials: A
authors.lastname: Majumdar
authors.forename: J
authors.initials: J
authors.lastname: Powell
authors.forename: M
authors.initials: M
authors.lastname: Seidman
authors.forename: K
authors.initials: K
authors.lastname: Vanderveen
authors.forename: B M
authors.initials: BM
authors.lastname: Goldstein
authors.forename: K W
authors.initials: KW
authors.lastname: Pankiewicz
mesh_terms: 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
chemical_list: 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