Novel derivatives of nicotinamide adenine dinucleotide (NAD) and their biological evaluation against NAD-consuming enzymes

Pergolizzi, Giulia (2012) Novel derivatives of nicotinamide adenine dinucleotide (NAD) and their biological evaluation against NAD-consuming enzymes. Doctoral thesis, University of East Anglia.

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Nicotinamide adenine dinucleotide (β-NAD+) is a primary metabolite involved in fundamental biological processes. Its molecular structure with characteristic functional groups, such as the quaternary nitrogen of the nicotinamide ring, and the two high-energy pyrophosphate and nicotinamide N-glycosidic bonds, allows it to undergo different reactions depending on the reactive moiety. Well known as a redox substrate owing to the redox properties of the nicotinamide ring, β-NAD+ is also fundamental as a substrate of NAD+-consuming enzymes that cleave either high-energy bonds to catalyse their reactions. In this study, a panel of novel adenine-modified NAD+ derivatives was synthesized and biologically evaluated against different NAD+-consuming enzymes. The synthesis of NAD+ derivatives, modified in position 2, 6 or 8 of the adenine ring with aryl/heteroaryl groups, was accomplished by Suzuki-Miyaura cross-couplings. Their biological activity as inhibitors and/or non-natural substrates was assessed against a selected range of NAD+-consuming enzymes. The fluorescence of 8-aryl/heteroaryl NAD+ derivatives allowed their use as biochemical probes for the development of continuous biochemical assays to monitor NAD+-consuming enzyme activities. The introduction of different substituents in position 8 on the adenine ring allowed the modulation of their fluorescence, resulting in the development of more sensitive and alternative probes compared to the known fluorophore ε-NAD+. The different substitutions introduced on the adenine ring also allowed us to probe the active site of an NAD+-dependent bacterial DNA ligase. The selective activity of 8-aryl/heteroaryl NAD+ derivatives against different NAD+-consuming enzymes offers excellent opportunities for their application as tool compounds in in-vitro/in-vivo studies, and as inhibitor templates for drug discovery.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Users 2593 not found.
Date Deposited: 28 May 2013 14:31
Last Modified: 10 Jun 2013 15:39

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