TY - JOUR
T1 - Synthesis of a methylenebis(phosphonate) analogue of mycophenolic adenine dinucleotide
T2 - A glucuronidation-resistant MAD analogue of NAD
AU - Lesiak, Krystyna
AU - Watanabe, Kyoichi A.
AU - Majumdar, Alokes
AU - Powell, James
AU - Seidman, Michael
AU - Vanderveen, Kristen
AU - Goldstein, Barry M.
AU - Pankiewicz, Krzysztof W.
PY - 1998/2/12
Y1 - 1998/2/12
N2 - 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. 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.
AB - 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. 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.
UR - http://www.scopus.com/inward/record.url?scp=0032510138&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032510138&partnerID=8YFLogxK
U2 - 10.1021/jm970705k
DO - 10.1021/jm970705k
M3 - Article
C2 - 9484510
AN - SCOPUS:0032510138
SN - 0022-2623
VL - 41
SP - 618
EP - 622
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 4
ER -