Design, synthesis and biological evaluation of novel inhibitors of NAD kinase

Nicotinamide adenine dinucleotide kinase (NADK) is an ubiquitous enzyme that catalyzes a magnesium-dependent phosphorylation of the 2’-hydroxyl group of the adenosine ribose moiety of NAD using ATP or inorganic polyphosphates as phosphoryl donors to produce NADP. To our knowledge this reaction represents the only route leading to de novo NADP biosynthesis, which is a crucial pathway for many cellular processes in living organism. Particularly it was demonstrated that NAD kinase is essential for the survival of Mycobacterium tuberculosis, becoming an appealing new target for the development of potential drugs against multi-drug resistant and extensively drug resistant tuberculosis (TB). With the recent discovery of NAD analogues as molecular probes, a number of nucleobase and sugar modified analogues have been synthesized, such as diadenosine disulfide (DTA) (1), and they were found to be moderate inhibitors of Mycobacterium tuberculosis and human NADKs. Locking the conformation of adenine moiety to syn by substitution with a bulky bromine atom at C8 in one or two adenine rings of DTA, the NADK inhibitory activity has been improved.1 On this basis, we report the synthesis and the inhibitory activity of NAD analogues modified in the sugar and adenine moiety, maintaining the short di-sulfur linker instead of the pyrophosphate linkage of NAD. The results of this study will be presented. 1Petrelli, R.; Cappellacci, L. et al. Bioorg. Med. Chem., 2009, 17(15), 5656-5664.