8-aminoguanosine and 8-aminoguanine

In vivo, guanine moieties in DNA, RNA, guanine nucleotides, or guanosine or guanine per se can undergo nitration (for example, by peroxynitrite) or hydroxylation (for example, by superoxide anion) on position 8 of the purine ring. Subsequent catabolism of these modified biomolecules leads to the production of a diverse group of 8-nitro, 8-amino, and 8-hydroxy guanosine and guanine compounds. Indeed, studies suggest the in vivo existence of 8-nitroguanosine, 8-nitroguanine, 8-aminoguanosine, 8-aminoguanine, 8-hydroxyguanosine, 8-hydroxy-2'-deoxyguanosine, and 8-hydroxyguanine. Since a multitude of these compounds exist in vivo, and since the renal effects of 8-substituted guanosine and guanine compounds are entirely unknown, we examined the effects of guanosine, guanine, 8-nitroguanosine, 8-nitroguanine, 8-hydroxyguanosine, 8-hydroxyguanine, 8-hydroxy-2'-deoxyguanosine, 8-aminoguanosine, and 8-aminoguanine (33.5 µmol/kg/min; intravenous infusion for 115 minutes) on excretion of sodium, potassium, and glucose in rats. Guanosine, 8-nitroguanosine, and 8-hydroxy-2'-deoxyguanosine had minimal natriuretic activity. Guanine, 8-nitroguanine, 8-hydroxyguanosine, and 8-hydroxyguanine had moderate natriuretic activity (increased sodium excretion by 9.4-, 7.8-, 7.1-, and 8.6-fold, respectively). In comparison with all other compounds, 8-aminoguanosine and 8-aminoguanine were highly efficacious and increased sodium excretion by 26.6- and 17.2-fold, respectively, exceeding that of a matched dose of amiloride (13.6-fold increase). 8-Aminoguanosine and 8-aminoguanine also increased glucose excretion by 12.1- and 12.2-fold, respectively, and decreased potassium excretion by 69.1 and 71.0%, respectively. Long-term radiotelemetry studies demonstrated that oral 8-aminoguanosine and 8-aminoguanine (5 mg/kg/day) suppressed deoxycorticosterone/salt-induced hypertension. These experiments demonstrate that some naturally occurring 8-substitued guanosine and guanine compounds, particularly 8-aminoguanosine and 8-aminoguanine, are potent and efficacious potassium-sparing diuretics/natriuretics that may represent a novel class of antihypertensive diuretics.

Topics: Animals; Antihypertensive Agents; Diuretics; Glycosuria; Guanine; Guanosine; Male; Natriuresis; Rats; Rats, Sprague-Dawley

In an effort to develop potent human purine nucleoside phosphorylase (PNP) inhibitors as immunosuppressive and chemotherapeutic agents, several 8-aminoguanine derivatives were synthesized and evaluated as potential PNP inhibitors. These studies were designed to investigate the hydrophobic effect of a substituent on the N-9 of the purine heterocycle and/or the C-5' positions. Compounds such as 8-aminoguanosine, guanosine, formycin B, and 8-aminoacyclovir containing a p-(fluorosulfonyl)benzoyl moiety were synthesized. The affinity of these compounds to erythrocytic PNP was determined and none of these compounds showed a better affinity than those of the parent compounds. However, we found that the effect of hydrophobicity at the N-9 and the C-5' positions might play an important role in binding to the active site of PNP. Thus, 8-amino-5'-deoxy-5'-(phenylthio)guanosine (19) was found to be the best inhibitor in this series of compounds with a Ki = 0.45 microM.

Topics: Binding Sites; Formycins; Guanine; Humans; Kinetics; Purine-Nucleoside Phosphorylase; Structure-Activity Relationship

8-Aminoguanine is a potent inhibitor of purine nucleoside phosphorylase (PNP) and also a substrate of PNP. Two thio isosteres of 8-aminoguanine, 2,5-diaminothiazolo[5,4-d]pyrimidin-7(6H)-one (2) and 2,4-diaminothiazolo[4,5-d]pyrimidin-7(6H)-one (3), which cannot be substrates of PNP, were synthesized and evaluated for their inhibitory activity against PNP. They were found to be weak inhibitors of PNP and to be noncytotoxic for MOLT-4 T-cells in culture.

Topics: Cell Division; Cells, Cultured; Chemical Phenomena; Chemistry; Guanine; Humans; Pentosyltransferases; Purine-Nucleoside Phosphorylase; Structure-Activity Relationship; T-Lymphocytes

8-Amino-3-deazaguanine (15), an analogue of both 3-deazaguanine (1) and 8-aminoguanine (6), an antitumor agent and a purine nucleoside phosphorylase (PNP) inhibitor, respectively, was synthesized from the ammonolysis of an imidazole precursor, methyl 2-(benzoylamino)-5-(cyanomethyl)-1H-imidazole-4-carboxylate (13). The requisite imidazole, methyl 2-(benzoylamino)-4-(methoxycarbonyl)-1H-imidazole-5-acetate (11), was prepared from the monoheterocyclic rearrangement of dimethyl 3-[(5-phenyl-1,2,4-oxadiazol-3-yl)amino]-2-pentenedioate (10) by NaH/DMF. Ammonolysis and subsequent dehydration of 11 provided the penultimate imidazole intermediate 13. Its deprotected (NaOMe/100 degrees C) product, methyl 2-amino-5-(cyanomethyl)-1H-imidazole-4-carboxylate (14), was also converted to 15. 8-Amino-3-deazaguanine, as its methanesulfonic acid (mesylate 7), exhibited an inhibition constant (IC50) of 9.9 microM against isolated mammalian PNP. It was a very weak inhibitor of T and B cell growth and did not enhance 2'-deoxyguanosine toxicity in the same cells. 8-Amino-3-deazaguanine mesylate was not significantly active in L1210 cells in vitro or L1210 leukemic mice. Thus, the amino group introduced in the 8-position of 3-deazaguanine enhances its PNP activity but diminishes its antitumor activity.

Topics: Animals; Antineoplastic Agents; Guanine; Humans; Leukemia L1210; Lymphocytes; Pentosyltransferases; Purine-Nucleoside Phosphorylase; Structure-Activity Relationship

Topics: Animals; Cells, Cultured; Chromatography, High Pressure Liquid; Erythrocytes; Guanine; Guanosine; Humans; In Vitro Techniques; Inosine; Kinetics; Pentosyltransferases; Purine-Nucleoside Phosphorylase; Sarcoma 180; Structure-Activity Relationship; Substrate Specificity