霉酚酸腺嘌呤二核苷酸的亚甲基双（膦酸酯）类似物的合成：一种抗葡萄糖醛酸化的NAD的MAD类似物。

Synthesis of a methylenebis(phosphonate) analogue of mycophenolic adenine dinucleotide: a glucuronidation-resistant MAD analogue of NAD.

作者信息

Lesiak K, Watanabe K A, Majumdar A, Powell J, Seidman M, Vanderveen K, Goldstein B M, Pankiewicz K W

机构信息

Division of Medicinal Chemistry, Codon Pharmaceuticals, Inc., Gaithersburg, Maryland 20877, USA.

出版信息

J Med Chem. 1998 Feb 12;41(4):618-22. doi: 10.1021/jm970705k.

DOI:10.1021/jm970705k

PMID:9484510

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.

摘要

麦考酚醇（MPAlc）是通过还原麦考酚酸（MPA）的羧基得到的，在二异丙基碳二亚胺（DIC）存在下，它与2',3'-O-异丙叉腺苷5'-亚甲基双膦酸酯（4）偶联，得到P1-(2',3'-O-异丙叉腺苷-5'-基)-P2-(麦考酚醇-6'-基)亚甲基双膦酸酯（8），产率为32%。用CF3COOH/H2O对8进行去异丙叉基化反应，得到麦考酚腺嘌呤二核苷酸（MAD）的亚甲基双膦酸酯类似物3。化合物3，β-亚甲基-MAD，被发现是II型肌苷单磷酸脱氢酶（IMPDH）的有效抑制剂（Ki = 0.3 microM），也是K562细胞生长的抑制剂（IC50 = 1.5 microM）。与MPA和麦考酚醇不同，β-亚甲基-MAD与尿苷5'-二磷酸葡萄糖醛酸转移酶孵育时不会转化为葡萄糖醛酸苷。