Nucleotide analogues with immunobiological properties: 9-[2-Hydroxy-3-(phosphonomethoxy)propyl]-adenine (HPMPA), -2,6-diaminopurine (HPMPDAP), and their N6-substituted derivatives.
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.
Potmesil
Petr
P
Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Centre for New Antivirals and Antineoplastics, Vídenská 1083, 142 20 Prague 4, Czech Republic. potmesil@biomed.cas.cz
Krecmerová
Marcela
M
Kmonícková
Eva
E
Holý
Antonín
A
Zídek
Zdenek
Z
D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002110:Caffeine / Q000031:analogs & derivatives / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000235:genetics; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D009711:Nucleotides / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D063065:Organophosphonates / Q000737:chemistry / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000276:immunology / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014230:Triazoles / Q000494:pharmacology
D016207:Cytokines; D004095:Dihydropyridines; D008070:Lipopolysaccharides; C107728:MRS 1191; D009711:Nucleotides; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D058915:Purinergic P1 Receptor Antagonists; D011799:Quinazolines; D012333:RNA, Messenger; D018047:Receptors, Purinergic P1; D014230:Triazoles; C091173:9-(3-hydroxy-2-phosphonomethoxypropyl)-2,6-diaminopurine; C081320:8-(3-chlorostyryl)caffeine; D009569:Nitric Oxide; D002110:Caffeine; D007371:Interferon-gamma; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D052247:Nitric Oxide Synthase Type II; D000225:Adenine; C052410:9-chloro-2-(2-furyl)-(1,2,4)triazolo(1,5-c)quinazolin-5-imine