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Selective inhibition of nicotinamide adenine dinucleotide kinases by dinucleoside disulfide mimics of nicotinamide adenine dinucleotide analogues.

机译:烟酰胺腺嘌呤二核苷酸类似物的二核苷二硫键模拟物选择性抑制烟酰胺腺嘌呤二核苷酸激酶。

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摘要

Diadenosine disulfide (5) was reported to inhibit NAD kinase from Listeria monocytogenes and the crystal structure of the enzyme-inhibitor complex has been solved. We have synthesized tiazofurin adenosine disulfide (4) and the disulfide 5, and found that these compounds were moderate inhibitors of human NAD kinase (IC(50)=110 microM and IC(50)=87 microM, respectively) and Mycobacterium tuberculosis NAD kinase (IC(50)=80 microM and IC(50)=45 microM, respectively). We also found that NAD mimics with a short disulfide (-S-S-) moiety were able to bind in the folded (compact) conformation but not in the common extended conformation, which requires the presence of a longer pyrophosphate (-O-P-O-P-O-) linkage. Since majority of NAD-dependent enzymes bind NAD in the extended conformation, selective inhibition of NAD kinases by disulfide analogues has been observed. Introduction of bromine at the C8 of the adenine ring restricted the adenosine moiety of diadenosine disulfides to the syn conformation making it even more compact. The 8-bromoadenosine adenosine disulfide (14) and its di(8-bromoadenosine) analogue (15) were found to be the most potent inhibitors of human (IC(50)=6 microM) and mycobacterium NAD kinase (IC(50)=14-19 microM reported so far. None of the disulfide analogues showed inhibition of lactate-, and inosine monophosphate-dehydrogenase (IMPDH), enzymes that bind NAD in the extended conformation.
机译:据报道,二硫化腺苷(5)会抑制单核细胞增生性李斯特菌(Listeria monocytogenes)的NAD激酶,并且酶-抑制剂复合物的晶体结构已得到解决。我们已经合成了噻唑呋林二硫腺苷(4)和二硫化物5,发现这些化合物是人NAD激酶(分别为IC(50)= 110 microM和IC(50)= 87 microM)和结核分枝杆菌NAD激酶的中度抑制剂(分别为IC(50)= 80 microM和IC(50)= 45 microM)。我们还发现具有短二硫键(-S-S-)部分的NAD模拟物能够以折叠(紧密)构象结合,但不能以常见的延伸构象结合,这需要更长的焦磷酸盐(-O-P-O-P-O-)连接。由于大多数NAD依赖性酶以扩展构象结合NAD,因此已观察到二硫键类似物对NAD激酶的选择性抑制。在腺嘌呤环的C8处引入溴将二腺苷二硫化物的腺苷部分限制为顺式构象,使其更加紧密。发现8-溴腺苷二硫腺苷(14)及其二(8-溴腺苷)类似物(15)是人类(IC(50)= 6 microM)和分枝杆菌NAD激酶(IC(50)=迄今为止报道了14-19 microM,没有任何二硫键类似物显示出抑制乳酸和肌苷单磷酸脱氢酶(IMPDH)的作用,这些酶以扩展的构象结合NAD。

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