title: Aberrant cyclization affords a C-6 modified cyclic adenosine 5'-diphosphoribose analogue with biological activity in Jurkat T cells.
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.
authors.affiliation: Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, United Kingdom.
authors.forename: Christelle
authors.initials: C
authors.lastname: Moreau
authors.forename: Tanja
authors.initials: T
authors.lastname: Kirchberger
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Mark P
authors.initials: MP
authors.lastname: Thomas
authors.forename: Karin
authors.initials: K
authors.lastname: Weber
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Guse
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000737:chemistry; D000818:Animals; D001048:Aplysia; D002118:Calcium / Q000378:metabolism; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D003500:Cyclization; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019169:Jurkat Cells; D008958:Models, Molecular; D008968:Molecular Conformation; D010539:Permeability; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: C572346:cyclic 6-thioinosine 5'-diphosphate ribose; D036563:Cyclic ADP-Ribose; D013868:Thioinosine; D036541:ADP-ribosyl Cyclase; D002118:Calcium