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 P -(2‘,3‘-O-isopropylideneadenosin-5‘-yl)-P -(mycophenoli...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1998-02, Vol.41 (4), p.618-622
Main Authors: Lesiak, Krystyna, Watanabe, Kyoichi A, Majumdar, Alokes, Powell, James, Seidman, Michael, Vanderveen, Kristen, Goldstein, Barry M, Pankiewicz, Krzysztof W
Format: Article
Language:English
Subjects:
Adenine Nucleotides
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - toxicity
Biological and medical sciences
Biotransformation
Cell Division - drug effects
General aspects
Glucuronates
Glucuronosyltransferase - metabolism
Humans
IMP Dehydrogenase - antagonists & inhibitors
Indicators and Reagents
Medical sciences
Molecular Structure
Mycophenolic Acid - analogs & derivatives
Mycophenolic Acid - chemical synthesis
Mycophenolic Acid - chemistry
Mycophenolic Acid - pharmacology
Mycophenolic Acid - toxicity
NAD - analogs & derivatives
Pharmacology. Drug treatments
Structure-Activity Relationship
Tumor Cells, Cultured
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Summary: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 P -(2‘,3‘-O-isopropylideneadenosin-5‘-yl)-P -(mycophenolic alcohol-6‘-yl)methylenebis(phosphonate) (8) in 32% yield. Deisopropylidenation of 8 with CF3COOH/H2O afforded the methylenebis(phosphonate) analogue 3 of mycophenolic adenine dinucleotide (MAD). Compound 3, β-methylene-MAD, was found to be a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) type II (K i = 0.3 μM) as well as an inhibitor of growth of K562 cells (IC50 = 1.5 μM). In contrast to MPA and mycophenolic alcohol, β-methylene-MAD was not converted into the glucuronide when incubated with uridine 5‘-diphosphoglucuronyltransferase.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm970705k