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

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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.

Details

Item Type Articles
CreatorsMoreau, C., Kirchberger, T., Zhang, B., Thomas, M. P., Weber, K., Guse, A. H. and Potter, B. V. L.
DOI10.1021/jm201127y
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URLURL Type
http://dx.doi.org/10.1021/jm201127yFree Full-text
DepartmentsFaculty of Science > Pharmacy & Pharmacology
RefereedYes
StatusPublished
ID Code29418

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