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Issue 3, 2020
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Synthesis of phosphonoacetate analogues of the second messenger adenosine 5′-diphosphate ribose (ADPR)

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Abstract

Adenosine 5′-diphosphate ribose (ADPR) is an intracellular signalling molecule generated from nicotinamide adenine dinucleotide (NAD+). Synthetic ADPR analogues can shed light on the mechanism of activation of ADPR targets and their downstream effects. Such chemical biology studies, however, are often challenging due to the negatively charged pyrophosphate that is also sensitive to cellular pyrophosphatases. Prior work on an initial ADPR target, the transient receptor potential cation channel TRPM2, showed complete pyrophosphate group replacement to be a step too far in maintaining biological activity. Thus, we designed ADPR analogues with just one of the negatively charged phosphate groups removed, by employing a phosphonoacetate linker. Synthesis of two novel phosphonoacetate ADPR analogues is described via tandem N,N′-dicyclohexylcarbodiimide coupling to phosphonoacetic acid. Neither analogue, however, showed significant agonist or antagonist activity towards TRPM2, underlining the importance of a complete pyrophosphate motif in activation of this particular receptor.

Graphical abstract: Synthesis of phosphonoacetate analogues of the second messenger adenosine 5′-diphosphate ribose (ADPR)

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Supplementary files

Article information


Submitted
08 Nov 2019
Accepted
16 Dec 2019
First published
09 Jan 2020

This article is Open Access

RSC Adv., 2020,10, 1776-1785
Article type
Paper

Synthesis of phosphonoacetate analogues of the second messenger adenosine 5′-diphosphate ribose (ADPR)

O. Baszczyňski, J. M. Watt, M. D. Rozewitz, R. Fliegert, A. H. Guse and B. V. L. Potter, RSC Adv., 2020, 10, 1776
DOI: 10.1039/C9RA09284F

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