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

详细信息    查看全文

• 作者：Riccardo Petrelli ; Yuk Yin Sham ; Liqiang Chen ; Krzysztof Felczak ; Eric Bennett ; Daniel Wilson ; Courtney Aldrich ; Jose S. Yu ; Loredana Cappellacci ; Palmarisa Franchetti ; Mario Grifantini ; Francesca Maz
• 关键词：NAD kinase ; NADP ; Enzyme inhibition ; Tiazofurin ; Dithioadenosine analogues ; NAD conformation
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2009
• 出版时间：1 August 2009
• 年：2009
• 卷：17
• 期：15
• 页码：5656-5664
• 全文大小：431 K

文摘

Diadenosine disulfide (5) was reported to inhibit NAD kinase from Lysteria 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 (IC₅₀ = 110 μM and IC₅₀ = 87 μM, respectively) and Mycobacterium tuberculosis NAD kinase (IC₅₀ = 80 μM and IC₅₀ = 45 μM, 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 (IC₅₀ = 6 μM) and mycobacterium NAD kinase (IC₅₀ = 14–19 μΜ 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.