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β-1,2,3-Triazolyl-Nucleosides as Nicotinamide Riboside Mimics a
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E. J. Amigues , E. Armstrong , M. Dvorakova , M. E. Migaud & M. Huang
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School of Chemistry and Chemical Engineering, Queen's University Belfast, Belfast, Northern Ireland Available online: 30 Mar 2009
To cite this article: E. J. Amigues, E. Armstrong, M. Dvorakova, M. E. Migaud & M. Huang (2009): β-1,2,3-Triazolyl-Nucleosides as Nicotinamide Riboside Mimics, Nucleosides, Nucleotides and Nucleic Acids, 28:3, 238-259 To link to this article: http://dx.doi.org/10.1080/15257770902865415
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Nucleosides, Nucleotides and Nucleic Acids, 28:238–259, 2009 C Taylor & Francis Group, LLC Copyright ISSN: 1525-7770 print / 1532-2335 online DOI: 10.1080/15257770902865415
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β-1,2,3-TRIAZOLYL-NUCLEOSIDES AS NICOTINAMIDE RIBOSIDE MIMICS
E. J. Amigues, E. Armstrong, M. Dvorakova, M. E. Migaud, and M. Huang School of Chemistry and Chemical Engineering, Queen’s University Belfast, Belfast, Northern Ireland
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The synthesis of a series of pyridine- and piperidine-substituted 1,2,3-triazolides linked to a riboside moiety is described. The presence of a triazolide substituent on the pyridine moiety permitted the facile reduction of the latter under mild hydrogenation conditions. These analogues were modelled as to define their similarity to nicotinamide riboside and quantify their ability to bind NAD-dependent protein deacetylases. Keywords
Nucleoside; nucleotide; sirtuin; inhibition
One family of protein deacetylases catalyzes the removal of the acetate moiety from acetylated lysine residues on proteins, such as histones, using nicotinamide adenine dinucleotide (NAD) as a co-substrate.[1] Upon catalysis, in addition to the deacetylated protein being released, NAD is converted into 2 /3 -O-acetylated-adenosine diphosphate ribose and Received 3 February 2009; accepted 4 March 2009. M. E. Migaud and M. Huang share joint authorship this article. The authors thank Professor R. Marmorstein and Ms. B. Sanders (from the Wistar Institute, Philadelphia, USA) for carrying out the preliminary inhibition studies and extensive discussions, and the EPSRC/MRC GR0100461 and the EC-FP6-EST program, which financially supported this work. Address correspondence to M. E. Migaud and M. Huang, School of Chemistry and Chemical Engineering, David Keir Building, Queen’s University Belfast, Stranmillis Road, Belfast, BT9 5AG, Northern Ireland. E-mail:
[email protected] and
[email protected]
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β-1,2,3-Triazolyl-Nucleosides
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SCHEME 1 Currently proposed mechanisms of deacetylation catalyzed by NAD-dependent protein deacetylases.
nicotinamide. In cells, these deacetylases are regulated by endogenous nicotinamide which acts as a non-competitive enzyme inhibitor.[2,3] Considering that regulation of such NAD-dependent deacetylases is implicated in numerous biological processes including life-span expansion and p53 expression in eukaryotes,[4] identifying structural and chemical features that molecules should possess in order to attain potent inhibition is the first step to developing a robust program toward drug discovery targeting such enzymes.[5,6] Two mechanisms can be proposed to explain the early steps of the NADdependent enzyme catalyzed deacetylation (Scheme 1). The first proposed pathway results in the formation of a stabilized oxycarbocation reaction intermediate, hence is defined as the SN 1 mechanism. Such intermediate has been observed in enzymatic reactions involving a nicotinamide-riboside bond cleavage.[7,8] The second predicted pathway involves a transition state intermediate resulting from the nucleophilic attack of the carbonyl group from the acetyl-lysine moiety and the simultaneous breakage of the nicotinamide bound via an SN 2 mechanism.[9] As a starting point in our search for chemical scaffolds that could lead to NAD-dependent deacetylase inhibition, we decided to investigate the possibilities of mimicking the increased distance between the nicotinamide and the C1 -carbon of the nicotinamide riboside of NAD occurring for either of these mechanisms. While many nucleoside analogues, mimicking both the adenosine and the nicotinamide moieties, have been synthesized thus far, compounds simulating the elongation of the nucleosidic bond between the C1 of the northern riboside and the nitrogen of the pyridine ring, have been under less scrutiny.[10, 11] Developing an effective synthetic programme of work that would allow the identification of inhibitors of NAD-dependent
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E. J. Amigues et al. TABLE 1 Optimization of the 1,3-dipolar cycloaddition reaction conditions
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Product
n-ethynylpyridine
Reaction conditions
Yield
6a
5a: n = 2
6b
5b: n = 3
6c
5c: n = 4
8a
5a: n = 2
8b
5b: n = 3
8c
5c: n = 4
A B C A B C A B C A B A B A B
41% – – 85% 47%
