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Aberrant cyclization affords a C-6 modified cyclic adenosine 5'-diphosphoribose analogue with biological activity in Jurkat T cells.

Moreau C, Kirchberger T, Zhang B, Thomas MP, Weber K, Guse AH, Potter BV - J. Med. Chem. (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, United Kingdom.

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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C-6 modified cADPR analogues and numbering system.
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fig1: C-6 modified cADPR analogues and numbering system.

Mentions: Cyclic adenosine 5′-diphosphoribose(cADPR, 1, Figure 1), discoveredby Lee et al. in 1987,1 is one of the principalsecond messenger molecules that mobilize intracellular Ca2+ in a different way to the well-established d-myo-inositol 1,4,5-trisphosphate (Ins(1,4,5)P3),2 by gating the ryanodine receptor.3,4 The cADPR/Ca2+ signaling system is active in diverse mammalian cellularsystems such as cardiac muscle, acinar cells, and plant cells.5 cADPR is a metabolite of nicotinamide adeninedinucleotide (NAD+) and is produced enzymatically by ADP-ribosylcyclases (ADPRC). Its structure was fully characterized by Lee etal.6 as a cyclic 18-membered dinucleotidefeaturing two glycosidic bonds and a pyrophosphate linkage. Severalexcellent reviews dealing with the chemistry of cADPR and the cADPR/Ca2+ signaling system have appeared in recent years.3,5,7−11


Aberrant cyclization affords a C-6 modified cyclic adenosine 5'-diphosphoribose analogue with biological activity in Jurkat T cells.

Moreau C, Kirchberger T, Zhang B, Thomas MP, Weber K, Guse AH, Potter BV - J. Med. Chem. (2012)

C-6 modified cADPR analogues and numbering system.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3285147&req=5

fig1: C-6 modified cADPR analogues and numbering system.
Mentions: Cyclic adenosine 5′-diphosphoribose(cADPR, 1, Figure 1), discoveredby Lee et al. in 1987,1 is one of the principalsecond messenger molecules that mobilize intracellular Ca2+ in a different way to the well-established d-myo-inositol 1,4,5-trisphosphate (Ins(1,4,5)P3),2 by gating the ryanodine receptor.3,4 The cADPR/Ca2+ signaling system is active in diverse mammalian cellularsystems such as cardiac muscle, acinar cells, and plant cells.5 cADPR is a metabolite of nicotinamide adeninedinucleotide (NAD+) and is produced enzymatically by ADP-ribosylcyclases (ADPRC). Its structure was fully characterized by Lee etal.6 as a cyclic 18-membered dinucleotidefeaturing two glycosidic bonds and a pyrophosphate linkage. Severalexcellent reviews dealing with the chemistry of cADPR and the cADPR/Ca2+ signaling system have appeared in recent years.3,5,7−11

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, United Kingdom.

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.

Show MeSH
Related in: MedlinePlus