COMPARISON OF BIOCHEMICAL PARAMETERS OF BENZAMIDE RIBOSIDE, A NEW INHIBITOR OF IMP DEHYDROGENASE, WITH TIAZOFURIN AND SELENAZOFURIN
COMPARISON OF BIOCHEMICAL PARAMETERS OF BENZAMIDE RIBOSIDE, A NEW INHIBITOR OF IMP DEHYDROGENASE, WITH TIAZOFURIN AND SELENAZOFURIN
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DOI：
10.1016/0006-2952(94)90565-7
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发表时间：
1994-10-07
影响因子：
5.8
通讯作者：
JAYARAM, HN
中科院分区：
文献类型：
--
作者：
GHAREHBAGHI, K;SREENATH, A;JAYARAM, HN
比较了IMP脱氢酶（IMPDH）抑制剂苯甲酰胺核苷、硫唑弗林和硒唑弗林的生化和细胞毒性活性。这三种C-核苷通过形成NAD的类似物发挥其细胞毒性，其中烟酰胺被C-核苷碱基取代。在一组60个人癌细胞系中比较这三种药物的抗增殖活性。为了研究苯甲酰胺核苷和硒偶氮弗林与硫偶氮弗林的关系，进行了计算机比较分析，得到苯甲酰胺核苷和硒偶氮弗林的相关系数分别为0.761和0.815。在人髓性白血病K562细胞中检测了这些药物的生化活性。将K562细胞与各10 μ M的苯甲酰胺核苷孵育4小时。硒唑弗林和硫唑弗林导致IMPDH活性降低49%、71%和26%，同时细胞内IMP库增加。作为IMPDH抑制的结果，GTP和dGTP浓度减少。这些研究表明，硒唑弗林是最有效的三种代理。为了比较这些试剂的NAD类似物的细胞合成，在用[2，8-H-3]腺苷预标记细胞后，将Kj 62细胞与苯甲酰胺核苷、硫唑弗林和硒唑弗林各10 μ M孵育。结果表明，苯甲酰胺核苷产生的NAD类似物（BAD）是硫唑弗林和硒唑弗林的2倍和3倍。为了阐明这三种化合物对其他利用NAD的酶的影响，在市售的乳酸脱氢酶、谷氨酸脱氢酶和苹果酸脱氢酶的纯化制剂中研究了纯化的苯甲酰胺腺嘌呤二核苷酸（BAD）、噻唑-4-甲酰胺腺嘌呤二核苷酸（TAD）和硒唑-4-甲酰胺腺嘌呤二核苷酸（SAD）的抑制活性。SAD和Escherichia coli对这三种酶均无抑制作用。虽然BAD没有影响乳酸和谷氨酸脱氢酶，它选择性地抑制50%的苹果酸脱氢酶活性在3.2 μ M的浓度。这些研究证明了三种C-核苷的生化作用的相似性和差异，即使它们具有相似的作用机制。
The biochemical and cytotoxic activities of the IMP dehydrogenase (IMPDH) inhibitors benzamide riboside, tiazofurin, and selenazofurin were compared. These three C-nucleosides exert their cytotoxicity by forming an analogue of NAD, wherein nicotinamide is replaced by the C-nucleoside base. The antiproliferative activities of these three agents were compared in a panel of 60 human cancer cell lines. To examine the relationship of benzamide riboside and selenazofurin to tiazofurin, COMPARE computer analysis was performed, and correlation coefficients of 0.761 and 0.815 were obtained for benzamide riboside and selenazofurin, respectively. The biochemical activities of these agents were examined in human myelogenous leukemia K562 cells. Incubation of K562 cells for 4 hr with 10 mu M each of benzamide riboside. selenazofurin and tiazofurin resulted in a 49, 71, and 26% decrease in IMPDH activity with a concurrent increase in intracellular IMP pools. As a consequence of IMPDH inhibition, GTP and dGTP concentrations were curtailed. These studies demonstrated that selenazofurin was the most potent of the three agents. To compare the cellular synthesis of NAD analogues of these agents, Kj62 cells were incubated with 10 mu M each of benzamide riboside, tiazofurin and selenazofurin after prelabeling the cells with [2, 8-H-3]adenosine. The results demonstrated that benzamide riboside produced 2- and 3-fold more of NAD analogue (BAD) than tiazofurin and selenazofurin did. To elucidate the effects of the three compounds on other NAD-utilizing enzymes, the inhibitory activities of purified benzamide adenine dinucleotide (BAD), thiazole-4-carboxamide adenine dinucleotide (TAD) and selenazole-4-carboxamide adenine dinucleotide (SAD) were studied in commercially available purified preparations of lactate dehydrogenase, glutamate dehydrogenase and malate dehydrogenase. TAD and SAD did not inhibit these three dehydrogenases. Although BAD did not influence lactate and glutamate dehydrogenases, it selectively inhibited 50% of malate dehydrogenase activity at a 3.2 mu M concentration. These studies demonstrate similarities and differences in the biochemical actions of the three C-nucleosides, even though they share similar mechanisms of action.