Structural Determinants for N1/N7 Cyclization of Nicotinamide Hypoxanthine 5'-dinucleotide (Nhd+) Derivatives by Adp-ribosyl Cyclase from Aplysia Californica: Ca2+-mobilizing Activity of 8-substituted Cyclic Inosine 5'-diphosphoribose Analogues in T-lymphocytes.
From: Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, United Kingdom.
Journal of medicinal chemistry
- Publish Date: Aug 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 17
- Pages: 5162-76
- Medium: Print
- Language: English
- Citation (JAMA): Moreau Christelle, Wagner Gerd K, Weber Karin, et al. Structural Determinants for N1/N7 Cyclization of Nicotinamide Hypoxanthine 5'-dinucleotide (Nhd+) Derivatives by Adp-ribosyl Cyclase from Aplysia Californica: Ca2+-mobilizing Activity of 8-substituted Cyclic Inosine 5'-diphosphoribose Analogues in T-lymphocytes.. J. Med. Chem. Aug 2006;49:5162-76
Abstract
A series of nicotinamide hypoxanthine 5’-dinucleotide (NHD+) analogues modified at C-8 (2-5) and 7-deaza-NHD+ were synthesized, and cyclization in the presence of Aplysia ADP-ribosyl cyclase was studied. All 8-substituted NHD+ analogues were converted into their N1-cyclic forms by the enzyme, while in contrast, 7-deaza-NHD+ 17 was hydrolyzed into 7-deazainosine 5’-diphosphoribose (7-deaza-IDPR) 25. Correlations are made showing that the conformation of the NHD+ substrate is the key to successful cyclization. The pharmacological activities of these novel cIDPR derivatives were evaluated in both permeabilized and intact Jurkat T-lymphocytes. The results show that in permeabilized cells both 8-iodo 1g and 8-N3-N1-cIDPR 1d have an activity comparable to that of cADPR, while 8-iodo 1g and 8-phenyl-N1-cIDPR 1c have a small but significant effect in intact cells and can therefore be regarded as membrane-permeant; thus, cIDPR derivatives are emerging as important novel biological tools to study cADPR-mediated Ca2+ release in T-cells.
Mesh Headings (Keywords): ADP-ribosyl Cyclase, Animals, Aplysia, Calcium, Cyclic IMP, Cyclization, Humans, Hydrolysis, Inosine Diphosphate, Jurkat Cells, Molecular Conformation, Stereoisomerism, Structure-Activity Relationship, T-Lymphocytes
Check for Full Text / PubMed Unique Identifier (PMID): 16913705
This abstract is part of PubMed, a service of the U.S. National Library of Medicine. PubMed includes more than 17 million citations from MEDLINE and other life science journals for biomedical articles. See Copyright and Disclaimers.
Linked medical terms appearing on this page are added by Healia to help readers find more information and are not part of the original PubMed document.
The data herein was last updated on July 8th, 2008 and may not reflect the most current and accurate data available from NLM.