Aberrant cyclization affords a C-6 modified cyclic adenosine 5′-diphosphoribose analogue with biological activity in Jurkat T cells

Reference:

Moreau, C., Kirchberger, T., Zhang, B., Thomas, M. P., Weber, K., Guse, A. H. and Potter, B. V. L., 2012. Aberrant cyclization affords a C-6 modified cyclic adenosine 5′-diphosphoribose analogue with biological activity in Jurkat T cells. Journal of Medicinal Chemistry, 55 (4), pp. 1478-1489.

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Official URL:

http://dx.doi.org/10.1021/jm201127y

Related URLs:

• http://dx.doi.org/10.1021/jm201127y

Abstract

Two nicotinamide adenine dinucleotide (NAD +) analogues modified at the 6 position of the purine ring were synthesized, and their substrate properties toward Aplysia californica ADP-ribosyl cyclase were investigated. 6-N-Methyl NAD + (6-N-methyl nicotinamide adenosine 5′-dinucleotide 10) hydrolyzes to give the linear 6-N-methyl ADPR (adenosine 5′-diphosphoribose, 11), whereas 6-thio NHD + (nicotinamide 6-mercaptopurine 5′-dinucleotide, 17) generates a cyclic dinucleotide. Surprisingly, NMR correlation spectra confirm this compound to be the N1 cyclic product 6-thio N1-cIDPR (6-thio cyclic inosine 5′-diphosphoribose, 3), although the corresponding 6-oxo analogue is well-known to cyclize at N7. In Jurkat T cells, unlike the parent cyclic inosine 5′-diphosphoribose N1-cIDPR 2, 6-thio N1-cIDPR antagonizes both cADPR- and N1-cIDPR-induced Ca 2+ release but possesses weak agonist activity at higher concentration. 3 is thus identified as the first C-6 modified cADPR (cyclic adenosine 5′-diphosphoribose) analogue antagonist; it represents the first example of a fluorescent N1-cyclized cADPR analogue and is a new pharmacological tool for intervention in the cADPR pathway of cellular signaling.

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