Nucleotide analogues with immunobiological properties: 9-[2-Hydroxy-3-(phosphonomethoxy)propyl]-adenine (HPMPA), -2,6-diaminopurine (HPMPDAP), and their N6-substituted derivatives
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
16733050
DOI
10.1016/j.ejphar.2006.04.018
PII: S0014-2999(06)00422-5
Knihovny.cz E-resources
- MeSH
- Adenine analogs & derivatives chemistry pharmacology MeSH
- Purinergic P1 Receptor Antagonists MeSH
- Quinazolines pharmacology MeSH
- Cytokines metabolism MeSH
- Dihydropyridines pharmacology MeSH
- Gene Expression genetics MeSH
- Interferon-gamma pharmacology MeSH
- Caffeine analogs & derivatives pharmacology MeSH
- Lipopolysaccharides pharmacology MeSH
- RNA, Messenger genetics metabolism MeSH
- Molecular Structure MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Nucleotides chemistry immunology pharmacology MeSH
- Organophosphonates chemistry pharmacology MeSH
- Organophosphorus Compounds chemistry pharmacology MeSH
- Nitric Oxide biosynthesis MeSH
- Macrophages, Peritoneal cytology drug effects metabolism MeSH
- Reverse Transcriptase Polymerase Chain Reaction MeSH
- Receptors, Purinergic P1 immunology physiology MeSH
- Nitric Oxide Synthase Type II genetics MeSH
- Triazoles pharmacology MeSH
- Cell Survival drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 8-(3-chlorostyryl)caffeine MeSH Browser
- 9-(3-hydroxy-2-phosphonomethoxypropyl)-2,6-diaminopurine MeSH Browser
- 9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine MeSH Browser
- 9-chloro-2-(2-furyl)-(1,2,4)triazolo(1,5-c)quinazolin-5-imine MeSH Browser
- Adenine MeSH
- Purinergic P1 Receptor Antagonists MeSH
- Quinazolines MeSH
- Cytokines MeSH
- Dihydropyridines MeSH
- Interferon-gamma MeSH
- Caffeine MeSH
- Lipopolysaccharides MeSH
- RNA, Messenger MeSH
- MRS 1191 MeSH Browser
- Nucleotides MeSH
- Organophosphonates MeSH
- Organophosphorus Compounds MeSH
- Nitric Oxide MeSH
- Receptors, Purinergic P1 MeSH
- Nitric Oxide Synthase Type II MeSH
- Triazoles MeSH
Newly developed acyclic nucleoside phosphonates, derivatives of adenine and 2,6-diaminopurine bearing the 2-hydroxy-3-(phosphonomethoxy)propyl (HPMP) moiety at the N9-side chain (i.e., HPMPA and HPMPDAP, respectively) were screened for in vitro immunobiological activity, using mouse resident peritoneal macrophages and splenocytes. Both HPMPA and HPMPDAP augmented the interferon-gamma-triggered production of NO as well as expression of inducible nitric oxide synthase (iNOS) mRNA in macrophages. HPMPDAP activated secretion of tumor necrosis factor-alpha (TNF-alpha), chemokines "regulated-upon-activation, normal T cell expressed and secreted" (RANTES) and macrophage inflammatory protein-1alpha (MIP-1alpha), and marginally also secretion of interleukin-10 (IL-10) in both macrophages and splenocytes. The HPMPA, less prominently than HPMPDAP, elevated only secretion of RANTES and TNF-alpha. The compounds also activated secretion of TNF-alpha (HPMPDAP > HPMPA) in human peripheral blood mononuclear cells (PBMC). Distinct N6-substituted derivatives, i.e., N6-dimethyl-, N6-cyclopropyl-, N6-piperidin-1-yl-, N6-(2-methoxyethyl)-, N6-(2-hydroxyethyl)-, N6-allyl- and N6-2-(dimethylamino)ethyl-HPMPA/HPMPDAP as well as 6-thio and 6-hydroxy derivatives usually showed loss of the activity compared to the parent compounds. The immunomodulatory effects were found to be at least in part dependent on P1 purinoreceptors, and mediated by transcriptional factor nuclear factor-kappaB.
References provided by Crossref.org
