Nucleoside and non-nucleoside IMP dehydrogenase inhibitors as antitumor and antiviral agents.
Nucleoside and non-nucleoside IMP dehydrogenase inhibitors as antitumor and antiviral agents.
复制标题
核苷和非核苷 IMP 脱氢酶抑制剂作为抗肿瘤和抗病毒药物。
DOI：
10.1002/chin.199940260
复制
发表时间：
1999
影响因子：
4.1
通讯作者：
M. Grifantini
中科院分区：
文献类型：
--
作者：
P. Franchetti;M. Grifantini
IMP脱氢酶（IMPDH）是一种在嘌呤核苷酸合成途径的代谢分支点催化肌苷5 -单磷酸（IMP）转化为5 -单磷酸黄嘌呤（XMP）的酶。IMPDH在癌细胞中显著增加，因此被认为是癌症化疗的敏感靶点。通过阻断IMP到XMP的转化，IMPDH抑制剂导致鸟苷酸（GMP， GDP， GTP和dGTP）池的耗尽。人类IMPDH的两种异构体，设计为I型和II型，已被鉴定和测序。I型是组成型表达，在正常细胞中占主导地位，而II型在肿瘤细胞和复制细胞中选择性上调。目前已发现两种具有抗肿瘤、抗病毒和免疫抑制活性的IMPDH抑制剂：核苷类抑制剂，如利巴韦林和噻唑呋喃；非核苷类抑制剂，如霉酚酸。利巴韦林通过其合成代谢物5 -单磷酸产生抑制IMPDH。Tiazofurin在代谢转化为噻唑-4-羧酰胺腺嘌呤二核苷酸（TAD）后抑制酶，TAD是辅助因子NAD的类似物。假设噻唑呋喃的抑制活性是由于杂环硫原子与呋喃糖氧1之间的吸引静电相互作用，限制了噻唑呋喃及其活性合成代谢产物TAD中c -糖苷键的旋转。为了验证这一假设，我们研究了几种与噻唑呋喃及其NAD类似物相关的c -核苷。非核苷类IMPDH抑制剂也进行了综述。
IMP dehydrogenase (IMPDH) is an enzyme which catalyzes the NAD-dependent conversion of inosine 5 -monophosphate (IMP) to xanthosine 5 -monophosphate (XMP) at the metabolic branch point in the de novo purine nucleotide synthetic pathway. IMPDH was shown to be increased significantly in cancer cells and therefore considered to be a sensitive target for cancer chemotherapy. By blocking the conversion of IMP to XMP, IMPDH inhibitors lead to depletion of the guanylate (GMP, GDP, GTP and dGTP) pools. Two isoforms of human IMPDH, designed type I and type II, have been identified and sequenced. Type I is constitutively expressed and is the predominant isoform in normal cells, while type II is selectively up-regulated in neoplastic and replicating cells. Two types of IMPDH inhibitors, endowed with antineoplastic, antiviral and immunosoppressive activity, have been discovered so far: nucleoside inhibitors, such as ribavirin and tiazofurin, and non-nucleoside, such as mycophenolic acid. Ribavirin produces IMPDH inhibition via its anabolite 5 -monophosphate. Tiazofurin inhibits the enzyme after metabolic conversion into thiazole-4-carboxamide adenine dinucleotide (TAD), an analogue of the cofactor NAD. It was hypothesized that the inhibitory activity of tiazofurin is due to an attractive electrostatic interaction between the heterocyclic sulphur atom and the furanose oxygen 1 which constrain rotation about the C-glycosidic bond in tiazofurin and in its active anabolite TAD. To check this hypothesis, we studied several C-nucleosides related to tiazofurin and their NAD analogues. Non-nucleoside IMPDH inhibitors are also reviewed.