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.
Bibliographical noteFunding Information:
These studies were funded by the Center for Drug Design, University of Minnesota.
Copyright 2011 Elsevier B.V., All rights reserved.
- Benzamide adenine dinucleotide (BAD)
- M. tuberculosis
- NAD analogues
- NAD kinase