AMP deaminase inhibitors

JMC3596>, an imidazo[4,5-d][l,3]diazepin-8-ol as an AMP deaminase inhibitor <00JMC1508>, the antimaiarial mode of action of artemisinin <00FEBSL238>, and finally dithiepin-l,l,4,4-tetroxides as non-peptidic human galanin receptor antagonists <00BMC1383>. 

Bookser, B. C., Kasibhatla, S. R., Erion, M. D. AMP deaminase inhibitors. 4. Further N3-substituted coformycin aglycon analogues N3-alkylmalonates as ribose 5 -monophosphate mimetics. J. Med. Chem. 2000, 45(8), 1519-1524. 

M. D. Erion and M. R. Reddy, in Rational Drug Design Novel Methodology and Practical Applications, ACS Symposium Series 719, A. L. Parrill and M. R. Reddy, Eds., Oxford University Press, Washington, DC, 1999, pp. 107-120. Calculation of Relative Hydration Free Energy Differences for Heteroaromatic Compounds Use in the Design of AMP Deaminase Inhibitors. 

Nucleoside antibiotic. Isol. from Nocardia interforma, Streptomyces lavendulae and Streptomyces kaniharaensis. Shows antibiotic props. AMP deaminase inhibitor. Sol. H2O, MeOH, DMSO poorly sol. EtOH, hexane. 

DiaZepin Nucleosides. Four naturally occurring dia2epin nucleosides, coformycin (58), 2 -deoxycoformycin (59), adechlorin or 2 -chloro-2 -deoxycoformycin (60), and adecypenol (61), have been isolated (1—4,174,175). The biosynthesis of (59) and (60) have been reported to proceed from adenosine and C-1 of D-ribose (30,176,177). They are strong inhibitors of adenosine deaminase and AMP deaminase (178). Compound (58) protects adenosine and formycin (12) from deamination by adenosine deaminase. Advanced hairy cell leukemia has shown rapid response to (59) with or without a-or P-interferon treatment (179—187). In addition, (59) affects interleukin-2 production, receptor expression on human T-ceUs, DNA repair synthesis, immunosuppression, natural killer cell activity, and cytokine production (188—194). 

By reactions of different 13,4-triazine derivatives, C-ribosyl imidazo[2,l-/][13,4]triazines <99JCS(P1)2929> and C-ribosyl 13.4-triazolo[3,4-/ [13,4]triazines <99JCS(P1)2937> have been synthesized as inhibitors of adenosine and AMP deaminases. Catalytic asymmetric aminohydroxylation with amino substituted 13,4-triazine and 133-tiiazine derivatives, as nitrogen sources, has been described <99AG(E)1080>. 

SCHEME 4.12 Coformycin (4.11), a transition state inhibitor of AMP deaminase... 

Fig. 2 depicts an experiment in which the hepatic adenine nucleotides were labelled with [ C]adenine, prior to the isolation of the liver for perfusion. Coformycin was added to the recirculating medium at the beginning of the perfusion. This resulted in a tissue concentration of the inhibitor, measured after 30 min, equal to 2.5 x lo M. This concentration was previously shown to inhibit maximally hepatic adenosine deaminase, without influencing AMP deaminase (Van den Berghe et al., 1980). A release of radioactive uric acid and allantoin was measured in the... 

The limited degradation of increased concentrations of AMP by AMP deaminase in anoxic conditions, may thus be explained by the decrease in its stimulator ATP and the increase in P, one of its physiological inhibitors. The better preservation of AMP in fasted hepatocytes can be accounted for by the fact that the variation of both effectors occurs more promptly in the fasting state. 

Evaluation of the stimulatory effect of ATP on the activity of partially purified AMP deaminase, in the presence of physiological concentrations of its substrate and inhibitors, GTP and P. (Van den Berghe et al., 1977a), revealed that this activity was increased about 2-fold when ATP was raised from its concentration in the control situation (approx. 2.5 mM), to the concentration prevailing after the administration of adenosine... 

Figure 4.4 The HPLC analysis of a reaction mixture containing AMP and alkaline phosphatase. Separations were carried out on a reversed-phase column with a mobile phase of potassium phosphate (pH 5.5) and 10% methanol. The column was eluted isocratically, and the detection was at 254 nm. Two sets of tracings were obtained, according to the following schedules. For the original reaction mixture (A) immediately after the addition of enzyme, (B) after 10 minutes, and (C) after 15 minutes. For the reaction mixture to which had been added EHNA (5 /xAf), an inhibitor of adenosine deaminase, the suspected contaminant (D ) after 2 minutes, ( ) after 10 minutes, and (F) after 40 minutes. (From Rossomando et al., 1981.)...

To follow up the observation, a second reaction mixture was prepared that was similar in composition to the first but also contained an inhibitor of adenosine deaminase. After the start of the reaction, samples were removed and analyzed, and the chromatograms obtained (Fig. AAD-F) illustrated the loss of AMP and quantitative recovery of the adenosine. 

Evidence that purine metabolism is important in the immune response has been obtained from the observation that markedly reduced or absent adenosine deaminase (ADA) activity in man has been casually associated with an autosomal recessive form of severe combined immunodeficiency disease (3). Recently, ADA levels in lymphocytes from patients with untreated chronic lymphatic leukemia have been found to be consistently lower than in lymphocytes from normal subjects (4). Children with ADA deficiency and immunodeficiency have been shown to have increased levels in plasma, urine, lymphocytes and erythrocytes of adenosine, adenine, deoxy-adenosine, adenine nucleotides, and deoxyadenine (5, 6). Although the exact biochemical mechanism(s) is unknown, elevated levels of adenosine, and/or deoxyadenosine and their metabolites are thought to be selective inhibitors of both differentiation and effector function of lymphocytes (7, 8). Adenosine was known to inhibit the PHA-induced blastogenesis of human peripheral blood lymphocytes (9) even before the discovery of the first ADA-deficient child. In addition, elevated levels of cyclic AMP (cAMP) were known to be inhibitory for lymphocyte-mediated cytotoxicity (7). Since... 

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