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

Christelle Moreau, Tanja Kirchberger, Bo Zhang, Mark P. Thomas, Karin Weber, Andreas H. Guse, Barry V. L. Potter

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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.
Original languageEnglish
Pages (from-to)1478-1489
JournalJournal of Medicinal Chemistry
Volume55
Issue number4
DOIs
Publication statusPublished - 2012

Fingerprint

Adenosine Diphosphate Ribose
Jurkat Cells
Cyclization
T-Lymphocytes
NAD
Thioinosine
ADP-ribosyl Cyclase
Aplysia
6-Mercaptopurine
Niacinamide
Adenosine
Pharmacology

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Aberrant cyclization affords a C-6 modified cyclic adenosine 5′-diphosphoribose analogue with biological activity in Jurkat T cells. / Moreau, Christelle; Kirchberger, Tanja; Zhang, Bo; Thomas, Mark P.; Weber, Karin; Guse, Andreas H.; Potter, Barry V. L.

In: Journal of Medicinal Chemistry, Vol. 55, No. 4, 2012, p. 1478-1489.

Research output: Contribution to journalArticle

Moreau, Christelle ; Kirchberger, Tanja ; Zhang, Bo ; Thomas, Mark P. ; Weber, Karin ; Guse, Andreas H. ; Potter, Barry V. L. / Aberrant cyclization affords a C-6 modified cyclic adenosine 5′-diphosphoribose analogue with biological activity in Jurkat T cells. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 4. pp. 1478-1489.
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