Tight-binding inhibitors—IV. Inhibition of adenosine deaminases by various inhibitors

Agarwal, Rekha; Spector, Thomas; Parks, Robert E.

doi:10.1016/0006-2952(77)90192-7

Cited by 374 publications

(163 citation statements)

References 12 publications

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“…It is important to determine whether a selective sparing of γδ T cells also occurs in ADA-deficient humans. Because the use of Ada m1/m1 fetuses in FTOC was cumbersome, we evaluated the ability of the specific and potent ADA inhibitor dCF (8) to mimic the genetically ADA-deficient state. 2′-deoxycoformycin at 5 µM inhibited the production of thymocytes by 85% in FTOCs initiated on day 15 of gestation with C57BL/6 fetuses and harvested 5 days later (Table 1).…”

Section: Catctgcaggcagag-3′)mentioning

confidence: 99%

“…In vitro culture models require the addition of exogenous ADA substrates, making it impossible to draw conclusions about the relative contribution of Ado and dAdo in vivo. Conventional ADA-deficient mice die of liver failure in the immediate perinatal period (6,7), and normal mice treated with the specific and potent ADA inhibitor 2′-deoxycoformycin (dCF) (8) show signs of hepatic and adrenal toxicity (9). The problem of liver toxicity in ADA-deficient mice has been solved by the introduction of an Ada minigene expressed in the placenta (10).…”

Section: Introductionmentioning

confidence: 99%

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Metabolites from apoptotic thymocytes inhibit thymopoiesis in adenosine deaminase–deficient fetal thymic organ cultures

Thompson¹,

Wiele²,

Laurent³

et al. 2000

J. Clin. Invest.

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Murine fetal thymic organ culture was used to investigate the mechanism by which adenosine deaminase (ADA) deficiency causes T-cell immunodeficiency. C57BL/6 fetal thymuses treated with the specific ADA inhibitor 2′-deoxycoformycin exhibited features of the human disease, including accumulation of dATP and inhibition of S-adenosylhomocysteine hydrolase enzyme activity. Although T-cell receptor (TCR) Vβ gene rearrangements and pre-TCR-α expression were normal in ADA-deficient cultures, the production of αβ TCR + thymocytes was inhibited by 95%, and differentiation was blocked beginning at the time of β selection. In contrast, the production of γδ TCR + thymocytes was unaffected. Similar results were obtained using fetal thymuses from ADA gene-targeted mice. Differentiation and proliferation were preserved by the introduction of a bcl-2 transgene or disruption of the gene encoding apoptotic protease activating factor-1. The pan-caspase inhibitor carbobenzoxy-Val-Ala-Asp-fluoromethyl ketone also significantly lessened the effects of ADA deficiency and prevented the accumulation of dATP. Thus, ADA substrates accumulate and disrupt thymocyte development in ADA deficiency. These substrates derive from thymocytes that undergo apoptosis as a consequence of failing to pass developmental checkpoints, such as β selection.

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Section: Catctgcaggcagag-3′)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Metabolites from apoptotic thymocytes inhibit thymopoiesis in adenosine deaminase–deficient fetal thymic organ cultures

Thompson¹,

Wiele²,

Laurent³

et al. 2000

J. Clin. Invest.

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“…The specific ADA inhibitor, 2′-deoxycoformycin [8], dCF, was obtained from SuperGen (Dublin, CA). The adenosine kinase inhibitor, 5′-amino-5′-deoxyadenosine (5′A5′dAdo), and the nucleosides, 2′-deoxycytidine (dCyd) and dAdo were obtained from Sigma-Aldrich (St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Deoxynucleoside Kinases in Human Thymocytes Prevents dATP Accumulation and Induction of Apoptosis

Joachims

Marble

Knott‐Craig

et al. 2008

Nucleosides, Nucleotides and Nucleic Acids

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Thymocytes lacking adenosine deaminase (ADA) activity, a purine metabolism enzyme, accumulate intracellular dATP and consequently undergo apoptosis during development. We have analyzed the effect of ADA enzyme inhibition in human thymocyte suspension cultures with regard to accumulation of intracellular dATP and induction of apoptosis. We demonstrate that while inhibition of deoxycytidine kinase will prevent the accumulation of dATP and induction of apoptosis to a large degree, inhibition of both deoxycytidine kinase and adenosine kinase completely abrogates the accumulation of dATP and significantly reduces the induction of apoptosis. Thus, both deoxynucleoside kinases are involved in this model of ADA deficiency.

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“…1), the only clinically useful ADA inhibitor. 18,19) However, most of these compounds suffer from poor pharmacokinetics and they bind to the enzyme so tightly, that their activity is nearly irreversible, giving rise to toxic effects. In recent years research efforts have mainly focused on the investigation of ADA-ligand interactions aiming at the design of less toxic inhibitors of the enzyme.…”

Section: )mentioning

confidence: 99%

Synthesis of New Nebularine Analogues and Their Inhibitory Activity against Adenosine Deaminase

et al. 2015

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A number of new 2,6-disubstituted-1-deazanebularine analogues as well as two structurally related pyrazole-fused tricyclic nucleosides were prepared. Their synthesis was carried out by the conversion of 6-amino-2-picoline to a suitable 1-deazapurine, followed by a Vorbrüggen type glycosylation and subsequent elaboration of the condensed pyrazole ring. The synthesized nebularine analogues proved to be weak adenosine deaminase inhibitors.Key words 1-deazanebularine; tricyclic nucleoside; imidazo [4,5-b]pyridine; adenosine deaminase Nebularine (9-β-D-ribofuranosylpurine, Fig. 1), the simplest member of the purine nucleosides, was first isolated from the fungus Lepista nebularis 1) and has been found to exhibit interesting antibiotic, 2) antiviral, 3) antiamebal, 4) antiparasitic 5) and cytotoxic properties. 6,7) Since it can form a hydrogen bond with each of the four DNA heterocyclic bases, nebularine has the potential to serve as a universal base. 8) On the other hand, 2′-deoxynebularine has been used in oligonucleotide synthesis 9) and the analysis of DNA structural determinants, which are important for the recognition of damaged DNA by repair enzymes and for the formation of triple-helices at GC sequences. 10)Nebularine is also known as a competitive inhibitor of adenosine deaminase 11,12) and many purine metabolizing enzymes, including S-adenosylhomocysteine hydrolase, 13) herpes simplex DNA polymerase, 14) xanthine oxidase 15) and adenylyl cyclase. 16)As adenosine deaminase (ADA) regulates both intra-and extra-cellular adenosine concentrations, a decrease or increase in its levels triggers a number of pathological conditions and inhibitors of this enzyme demonstrate therapeutic potential for the treatment of several health disorders.17) Highly potent inhibitors have already been identified, including 2′-deoxycorfomycin (pentostatin, Fig. 1), the only clinically useful ADA inhibitor. 18,19) However, most of these compounds suffer from poor pharmacokinetics and they bind to the enzyme so tightly, that their activity is nearly irreversible, giving rise to toxic effects. In recent years research efforts have mainly focused on the investigation of ADA-ligand interactions aiming at the design of less toxic inhibitors of the enzyme. 20,21) Based on the interesting ADA inhibitory activity of several 2-substituted-adenosine and nebularine derivatives 21) and as a part of our ongoing research project directed towards the preparation of novel purine ribosides, [22][23][24][25][26] we were prompted to synthesize a number of new nebularine analogues and evaluate their potential ADA inhibitory activity. Thus, we present here the synthesis and biological evaluation of new 1-deazanebularine analogues, having in mind that the isosteric replacement of a heterocyclic nitrogen by a carbon unit is a well-established procedure for the study of the interactions of purines with their biological targets. 27-29) Results and DiscussionChemistry The new compounds were prepared from 6-amino-2-picoline (1, Chart 1), which was nitrated usi...

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Tight-binding inhibitors—IV. Inhibition of adenosine deaminases by various inhibitors

Cited by 374 publications

References 12 publications

Metabolites from apoptotic thymocytes inhibit thymopoiesis in adenosine deaminase–deficient fetal thymic organ cultures

Metabolites from apoptotic thymocytes inhibit thymopoiesis in adenosine deaminase–deficient fetal thymic organ cultures

Inhibition of Deoxynucleoside Kinases in Human Thymocytes Prevents dATP Accumulation and Induction of Apoptosis

Synthesis of New Nebularine Analogues and Their Inhibitory Activity against Adenosine Deaminase

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