Probing binding requirements of NAD kinase with modified substrate (NAD) analogues

Synthesis of novel NAD+ analogues that cannot be phosphorylated by NAD kinase is reported. In these analogues the C2′ hydroxyl group of the adenosine moiety was replaced by fluorine in the ribo or arabino configuration (1 and 2, respectively) or was inverted into arabino configuration to give compound 3. Compounds 1 and 2 showed inhibition of human NAD kinase, whereas analogue 3 inhibited both the human and Mycobacterium tuberculosis NAD kinase. An uncharged benzamide adenine dinucleotide (BAD) was found to be the most potent competitive inhibitor (Ki = 90 μM) of the human enzyme reported so far.

Graphical abstractSynthesis of novel nicotinamide adenine dinucleotides (NAD+ analogues) containing 2′-fluorine in the ribo or arabino configuration of the adenosine ribose moiety, or the 2′-OH group in the arabino configuration, is reported. These compounds as well benzamide adenine dinucleotide (BAD) were evaluated as potential inhibitors of human and Mycobacterium tuberculosis NAD kinase, which converts NAD to NADP.Figure optionsDownload full-size imageDownload as PowerPoint slide