Disease relevance of NCI60_002100

• The inhibition of herpes simplex virus (HSV) replication by 2'-deoxyadenosine (dAdo) is greatly potentiated by the presence of the inhibitor of adenosine deaminase, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) [1].
• We measured the changes in pial arteriolar diameter and CSF concentrations of adenosine, inosine, and hypoxanthine during hypoxia in the absence and presence of topically applied dipyridamole (10(-6) M) and erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA; 10(-5) M) [2].
• In an open chest canine model, dipyridamole (0.5 mg/kg/h) and EHNA (5 mg/kg/h) were infused intra-atrially during a coronary occlusion period of 45 min and a reperfusion period of 180 min [3].
• Neither pertussis toxin treatment nor exposure to the cGMP-stimulated phosphodiesterase (PDE2) inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine or the nonselective PDE inhibitor 3-isobutyl-1-methylxanthine nor the phosphatase inhibitors okadaic acid or calyculin A unmasked an ISO-mimicking response of GLP-1 [4].
• The uptake of adenosine by an adenosine kinase deficient variant of C1300 murine neuroblastoma cells has been studied in the absence and in the presence of erythro-9-(2-hydroxy-3-nonyl)adenine, a potent adenine deaminase inhibitor [5].

High impact information on NCI60_002100

• Whereas an inhibitor of cyclic nucleotide phosphodiesterase (PDE) 3A (milrinone) mimicked the effect of NO, inhibitors of PDE2 (erythro-9-(2-hydroxy-3-nonyl)adenine) and PDE5 (dipyridamole) were poorly effective [6].
• Concentrations required to inhibit growth of CCRF-CEM human T-lymphoblastoid cells by 50% (IC50) are: 2-CldAdo, 0.045 microM; 2-BrdAdo, 0.068 microM; dAdo, 0.9 microM in the presence of 5 microM erythro-9-(2-hydroxy-3-nonyl)adenine [7].
• HSV replication is inhibited by dAdo [in the presence of EHNA] or by 2'-deoxyguanosine (dGuo) at concentrations slightly lower than are necessary to inhibit growth of uninfected HeLa cells [1].
• Under conditions where virus replication is inhibited by greater than 99% with dAdo and EHNA, the level of dATP increases 50-fold or more, and synthesis of HSV DNA is inhibited [1].
• Reactivation of intracellular enzyme was inhibited by adenosine deaminase inhibitors [2'-deoxycoformycin and erythro-9-(2-hydroxy-3-nonyl)adenine] and the synthetic substrate for AdoHcy hydrolase, 3-deazaadenosine [8].

Biological context of NCI60_002100

• A low concentration of erythro-9-(2-hydroxy-3-nonyl)adenine, which did not inhibit cell growth, nevertheless retarded the cells in G2 + M phase of the cell cycle and increased reductase activity [9].
• Adenosine deaminase inhibitors: synthesis and structure-activity relationships of imidazole analogues of erythro-9-(2-hydroxy-3-nonyl)adenine [10].
• Pharmacokinetics of inhibition of adenosine deaminase by erythro-9-(2-hydroxy-3-nonyl)adenine in CBA mice [11].
• Erythro-9-(2-hydroxy-3-nonyl)adenine inhibits cyclic-3',5'-guanosine monophosphate-stimulated phosphodiesterase to reverse hypoxic pulmonary vasoconstriction in the perfused rat lung [12].
• We tested the hypothesis that inhibition of adenosine transport by dipyridamole and inhibition of adenosine deamination by erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) prevents nucleoside loss and stimulates postischemic ATP-repletion [3].

Anatomical context of NCI60_002100

• In comparative growth rate experiments, the APHID-D2 cell line is less sensitive than the parental cell line to growth inhibition by deoxyadenosine in the presence of 10 microM erythro-9-(2-hydroxy-3-nonyl)adenine, an inhibitor of adenosine deaminase [13].
• Erythro-9-(2-hydroxy-3-nonyl)adenine inhibits cyclic GMP-stimulated phosphodiesterase in isolated cardiac myocytes [14].
• Culture pretreatment with Ado deaminase (ADA), that converts Ado into inosine, reduced but did not abolish Guo-induced astrocyte proliferation whereas erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), that inhibits ADA activity, amplified Guo effect [15].
• Neither the ATPase activity nor microtubule gelation-contraction is affected by high magnesium concentrations (up to 8 mM) or by the anti-ATPase drugs ouabain, oligomycin, sodium azide, and erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) [16].
• 3-Isobutyl-1-methylxanthine, a nonspecific phosphodiesterase (PDE) inhibitor, and erythro-9-(2-hydroxy-3-nonyl)adenine, a specific inhibitor of the cGMP-stimulated PDE (PDE2), completely restore cAMP accumulation in sodium nitroprusside-treated fibroblasts and largely reverse the attenuated response in IL-1beta-treated fibroblasts [17].

Associations of NCI60_002100 with other chemical compounds

• Specific inhibition of adenosine deaminase by nontoxic concentrations of erythro-9-(2-hydroxy-3-nonyl)adenine greatly potentiates the biological activity of both ara-A and 3'-deoxyadenosine (cordycepin) [18].
• Incubation of cells with a combination of deoxyadenosine, deoxycytidine, and erythro-9-(2-hydroxy-3-nonyl)adenine produced a selective depletion of dGTP to levels similar to that produced by mycophenolic acid, but did not affect cell growth [19].
• Local inhibition of adenosine kinase with iodotubercidin (10 micromol/l in perfusate) or inhibition of adenosine deaminase with erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA; 100 micromol/l in perfusate) did not change adenosine concentrations in the nonischemic kidneys (0.18 +/- 0.04 and 0.24 +/- 0.05 micromol/l, respectively) [20].
• In the presence of 10 microM erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) to block intracellular adenosine deaminase (ADA) activity, 2'-deoxyformycin A and dAdo both gave IC50's of 5-10 microM [21].
• The nucleoside transport inhibitor nitrobenzylthioinosine attenuated CBA and CPA metabolism in rat blood as did the inhibitor of adenosine deaminase erythro-9-(2-hydroxy-3-nonyl)adenine, albeit at relatively high concentrations [22].

Gene context of NCI60_002100

• When we evaluated an in vitro cell model of ADA deficiency using an ADA inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), we found that the inhibitory effect of EHNA plus deoxyadenosine on mitogen-stimulated PBMC could not be prevented by IL-2 [23].
• In this study, we evaluated the biochemical and pharmacological actions of several novel erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) analogs to identify new reversible adenosine deaminase (ADA) inhibitors with potential clinical utility [24].
• A series of erythro-1-(2-hydroxy-3-nonyl)imidazole derivatives have been synthesized and evaluated for adenosine deaminase (ADA) inhibitory activity, in order to introduce simplifications in the ADA inhibitors erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, 1a) and 3-deaza-EHNA (1c) [10].
• In addition to having the lowest efficiency with A134U, the bacterial ADA was also distinguished by its lack of binding of the mammalian ADA inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine and by its weak binding to the 9-(p-aminobenzyl)adenine-agarose affinity column [25].
• Neither the inhibition of LMC by c9Ado nor the metabolic formation of c9ATP in lymphocytes was affected by erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), indicating that c9Ado is not a substrate for adenosine deaminase [26].

Analytical, diagnostic and therapeutic context of NCI60_002100

• Left ventricular contractility fully recovered within 30 minutes of reperfusion in the groups treated with erythro-9-(2-hydroxy-3-nonyl)adenine and p-nitrobenzyl-thioinosine (p < 0.05 versus control group) [27].
• Adenosine or erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase inhibitor, was administered by perilymphatic perfusion to albino guinea pigs that were subjected to cochlear ischemic episodes of 30-minute duration [28].

References