Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.4.4 (adenosine deaminase)
 5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

9-beta-D-Arabinofuranosyl-2-fluoroadenine (2-F-ara-A), a derivative of 9-beta-D-arabinofuranosyladenine (ara-A) that is resistant to deamination, selectively inhibits DNA synthesis and has activity against mouse leukemia L1210 comparable to that of ara-A plus the adenosine deaminase inhibitor, 2'-deoxycoformycin. To determine if these two nucleosides have similar modes of action, comparisons were made of their effects and those of their triphosphates on enzymes known to be inhibited by ara-A or 9-beta-D-arabinofuranosyladenine 5'-triphosphate. 9-beta-D-Arabinofuranosyl-2-fluoroadenine 5'-triphosphate was more effective than 9-beta-D-arabinofuranosyladenine 5'-triphosphate in inhibiting the reduction of adenosine 5'-diphosphate and cytidine 5'-diphosphate by ribonucleotide reductase from HEp-2 cells or L1210 cells. DNA polymerase alpha from L1210 cells was equally sensitive to 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-triphosphate and 9-beta-D-arabinofuranosyladenine 5'-triphosphate, and DNA polymerase beta from L1210 cells was much less sensitive to both triphosphates. S-Adenosylhomocysteine hydrolase from L1210 cells was inactivated by 2-F-ara-A and ara-A, but higher concentrations of the fluoro derivative were required. These results are consistent with 2-F-ara-A and ara-A inhibition of DNA synthesis by inhibition of ribonucleotide reductase and DNA polymerase alpha.
 ...
PMID:Comparison of the actions of 9-beta-D-arabinofuranosyl-2-fluoroadenine and 9-beta-D-arabinofuranosyladenine on target enzymes from mouse tumor cells. 704 80

The inactivation of S-adenosylhomocysteine (AdoHcy) hydrolase (EC 3.3.1.1) in isolated rat hepatocytes by 9-beta-D-arabinofuranosyladenine (ara-A) was associated with tight binding of ara-A to the enzyme and showed an initial phase obeying first-order kinetics characterized by Ki (concentration of half-maximal rate of inactivation) of 12 microM for ara-A and a maximal rate of inactivation of 0.7 min-1. Two to 3% of the enzyme in rat hepatocytes was not available for inactivation. Similar results were obtained with some cultured cells, including mouse plasmacytoma cells (MPC-11), mouse fibroblasts (L-929), and human chronic myelogenic leukemia cells (K-562). In a cellular medium devoid of adenosine deaminase, inhibitors of this enzyme did not affect the inactivation process in rat hepatocytes and only slightly enhanced this process in the cultured cells (at low concentrations of ara-A). Inactivation of AdoHcy hydrolase in rat hepatocytes was associated with a massive build-up of AdoHcy (from 75 to 5200 pmol/10(6) cells after 3 hr of incubation) and a moderate increase in cellular S-adenosylmethionine. The accumulation of AdoHcy in the cultured cells exposed to ara-A was less pronounced and no increase in cellular S-adenosylmethionine was observed. There was a quantitatively important export of AdoHcy from the rat hepatocytes and the cultured cells into the extracellular medium, whereas no leakage of S-adenosylmethionine was detected. The inactivation of AdoHcy hydrolase by ara-A in rat hepatocytes was inhibited in the presence of adenosine or homocysteine in the cellular medium. This effect of homocysteine correlated with increased cellular level of AdoHcy induced by this agent but was also associated with reduction in cellular uptake of ara-A.
 ...
PMID:Inactivation of S-adenosylhomocysteine hydrolase by 9-beta-D-arabinofuranosyladenine in intact cells. 705 72

Single intraperitoneal and intravenous injections of isocoformycin at 1,200 mg/kg did not cause the death of mice. Isocoformycin which inhibited adenosine deaminase enhanced significantly the toxicity of formycin A and ara-A at various combination ratios. Isocoformycin potentiated antitumor activity of formycin A and ara-A against L1210 leukemia. Formycin A and ara-A disappeared rapidly from the blood and tissues and could not be found in any tissues even 0.5 hour after a single intraperitoneal injection. However, when used in combination with isocoformycin both were detected in the blood and tissues, especially at high concentration in liver and kidney. These indicate that the deamination of formycin A and ara-A is blocked by isocoformycin in vivo.
 ...
PMID:Effects of a new adenosine deaminase inhibitor, isocoformycin, on toxicity, antitumor activity and tissue distribution of formycin A and 9-beta-D-arabinofuranosyladenine. 738 Jul 42

A new acyclic nucleoside phosphonate (13) containing an adenine moiety was synthesized, which acted as an excellent inhibitor of calf mucosal adenosine deaminase. This inhibitory property allows it to exert great synergistic effect on certain antiviral agents (e.g., ara-A, 37). Phosphonate 13 was not phosphorylated by the bovine brain guanylate kinase nor by 5-phosphoribosyl 1-pyrophosphate synthetase. Syntheses of biologically active nucleotide phosphonate 40 and its phosphonoamidate derivative 42 were accomplished, which showed remarkable activity against herpes viruses and exhibited low host cell toxicity. 3'-Azido-nucleoside phosphonate 20 and 3'-fluoronucleoside phosphonate 32, as well as the corresponding dinucleotide analogs 47 and 48, and their respective phosphonoamidates 53-56 were also synthesized as new compounds, among which phosphonoamidates 53-56 showed potent activity against human immunodeficiency virus. Phosphonoamidates 55 and 56 bearing a methyl D-alaninate moiety exhibited less cellular toxicity than 53 and 54 bearing a methyl L-alaninate moiety. Nucleotide phosphonate 40 as well as dinucleotide phosphonates 47 and 48 were found susceptible to degradation by phosphodiesterases. Their respective phosphonoamidates 42 and 53-56, however, were completely resistant to snake venom and spleen enzymes.
 ...
PMID:Design, synthesis, and structure-activity relationship of novel dinucleotide analogs as agents against herpes and human immunodeficiency viruses. 747 92

Earlier studies have shown guanine arabinoside (ara-G) is an effective agent against growth of T-cell lines and freshly isolated human T-leukemic cells. However, poor water solubility of ara-G limits clinical use. 2-Amino-6-methoxypurine arabinoside (506U) is a water-soluble prodrug converted to ara-G by adenosine deaminase. 506U is not a substrate for deoxycytidine kinase, adenosine kinase, or purine nucleoside phosphorylase and is phosphorylated by mitochondrial deoxyguanosine kinase at a rate 4% that of ara-G phosphorylation. Mitochondrial DNA polymerase was the least sensitive to ara-GTP inhibition of the five human DNA polymerases tested. [3H]506U was anabolized to ara-G 5'-phosphates in CEM cells but not to phosphorylated metabolites of 506U. 506U was selective for transformed T over B cells and also inhibited growth in two of three monocytic lines tested. 506U given i.v. to cynomolgus monkeys was rapidly converted to ara-G; the ara-G had a half-life of approximately 2 h. 506U had in vivo dose-dependent efficacy against human T-cell tumors in immunodeficient mice. A Phase 1 trial of 506U against refractory hematological malignancies is now in progress at two study sites.
 ...
PMID:2-Amino-6-methoxypurine arabinoside: an agent for T-cell malignancies. 761 70

Antimetabolites are rational agents with specific S-phase and enzyme targets. Low levels of target enzymes in tumors are associated with innate drug sensitivity, and the general requirement for transport and metabolic activation of antimetabolites creates several loci of acquired drug resistance. Pharmacodynamic studies of TS inhibition after fluoropyrimidines clearly can predict for tumor sensitivity and response to fluoropyrimidine-based therapy or identify factors related to resistance, and ara-dCTP levels in leukemic cells can be useful for refined dosing of araC. Powerful new DHFR and TS directed agents are in advanced levels of clinical evaluation, and purine analogues directed against adenosine deaminase are newly available for treatment of indolent lymphomas. Progress in analysis of tumors, such as PCR techniques to study gene expression or immunostaining of target enzymes, offer increasing promise for individualization of patient selection. Increased experience with biochemical modulators, including biologic response modifiers, has opened the possibility for selective attack on specific mechanisms of drug resistance. Sophisticated pharmacokinetic modeling and pharmacogenetic testing of metabolic phenotypes can now be done to achieve optimal dosing with less risk of toxicity. Considerations of ultimate genetic mechanisms of antimetabolite effects, especially by programmed cell death, and relationships to mechanisms of cell cycle regulation offer exciting rationales for future drug development.
 ...
PMID:Clinical resistance to antimetabolites. 764 70

In an effort to improve the pharmacokinetic properties and tissue distribution of 2'-F-ara-ddI, two lipophilic prodrugs, 6-azido-2'-3'-dideoxy-2'-fluoro-beta-D- arabinofuranosylpurine (FAAddP, 4) and N6-methyl-2'-3'-dideoxy-2'-fluoro-beta-D-arabinofuranosyladenine (FMAddA, 5), were synthesized and their biotransformation was investigated in vitro and in vivo, in mice. Compounds 4 and 5 were synthesized via the intermediate 2. For the in vitro studies, FAAddP and FMAddA were incubated in mouse serum, liver homogenate, and brain homogenate. FAAddP was metabolized in liver homogenate by the reduction of the azido to the amino moiety followed by deamination, yielding 2'-F-ara-ddI. The conversion of FAAddP to 2'-F-ara-ddA was mediated by microsomal P-450 NADPH reductase system, as shown by the liver microsomal assay. FAAddP was also converted to 2'-F-ara-ddI at a slower rate in the brain than in the liver. FMAddA, however, was stable in brain homogenate and was slowly metabolized in the liver homogenate. Metabolic conversion of FMAddA in vitro was stimulated by the addition of adenosine deaminase. In the in vivo metabolism study, FAAddP underwent reduction to 2'-F-ara-ddA followed by deamination to 2'-F-ara-ddI. FMAddA did not result in increased brain delivery of 2'-F-ara-ddI in vivo, probably due to the slow conversion as observed in the in vitro studies. However, there was an increase in the half-life of 2'-F-ara-ddI produced from FMAddA. This report is the first example in the design of prodrugs using the azido group for adenine- and hypoxanthine-containing nucleosides. This interesting and novel approach can be extended to other antiviral and anticancer nucleosides.
 ...
PMID:In vitro and in vivo evaluation of 6-azido-2',3'-dideoxy-2'-fluoro-beta-D-arabinofuranosylpurine and N6-methyl-2',3'-dideoxy-2'-fluoro-beta-D-arabinofuranosyladenine as prodrugs of the anti-HIV nucleosides 2'-F-ara-ddA and 2'-F-ara-ddI. 891 56

As a part of our efforts to design prodrugs for antiviral nucleosides, 9-(beta-D-arabinofuranosyl)-6-azidopurine (6-AAP) was synthesized as a prodrug for ara-A that utilizes the azide reduction biotransformation pathway. 6-AAP was synthesized from ara-A via its 6-chloro analogue 4. The bioconversion of the prodrug was investigated in vitro and in vivo, and the pharmacokinetic parameters were determined. For in vitro studies, 6-AAP was incubated in mouse serum and liver and brain homogenates. The half-lives of 6-AAP in serum and liver and brain homogenates were 3.73, 4.90, and 7.29 h, respectively. 6-AAP was metabolized primarily in the liver homogenate microsomal fraction by the reduction of the azido moiety to the amine, yielding ara-A. However, 6-AAP was found to be stable to adenosine deaminase in a separate in vitro study. The in vivo metabolism and disposition of ara-A and 6-AAP were conducted in mice. When 6-AAP was administered by either oral or intravenous route,the half-life of ara-A was 7-14 times higher than for ara-A administered intravenously. Ara-A could not be found in the brain after the intravenous administration of ara-A. However, after 6-AAP administration (by either oral or intravenous route), significant levels of ara-A were found in the brain. The results of this study demonstrate that 6-AAP is converted to ara-A, potentially increasing the half-life and the brain delivery of ara-A. Further studies to utilize the azide reduction approach on other clinically useful agents containing an amino group are in progress in our laboratories.
 ...
PMID:Synthesis, biotransformation, and pharmacokinetic studies of 9-(beta-D-arabinofuranosyl)-6-azidopurine: a prodrug for ara-A designed to utilize the azide reduction pathway. 897 48

The deamination of cyclaradine corresponding to a carbocyclic analogue of ara-A having anti-HSV activity by adenosine deaminase was examined under various pressure. The deamination of (+)- and (+/-)-cyclaradine was remarkably facilitated by high pressure, and the rate was increased with increasing of pressure. However, (-)-cyclaradine was not deaminated even under high pressure.
 ...
PMID:Deamination of cyclaradine by adenosine deaminase under high pressure. 970 42

A novel strategy was developed for the synthesis of N(7)-purine acyclic nucleosides 9 and 14. The key step involved the reaction between [2-(p-methoxyphenyloxy)ethoxy]methyl chloride and N(9)-tritylated nucleobases 6 or 11 followed by concomitant self-detritylation. N(7)-Guanine acyclic nucleoside 9 exhibited antiviral activity, but was phosphorylated by both HSV and Vero cell thymidine kinases. Thus, it showed more potent cellular toxicity than acyclovir (2). N(7)-Adenine acyclic nucleoside 14 was found to be an excellent antiviral agent as well as a good inhibitor of calf mucosal adenosine deaminase. This inhibitory property allows for a greater expression of antiviral activity of antiviral agents, such as N(9)-adenine acyclic nucleoside 1 and ara-A (3). Compound 14 was phosphorylated neither by herpes simplex virus (HSV) thymidine kinase nor by Vero cell thymidine kinase, yet it enhanced the rate constant for the monophosphorylation of acyclovir (2) by HSV thymidine kinase. Consequently, the combination of acyclovir (2) and 14 exhibited greater antiviral activity than acyclovir alone. 7-[2-(Phosphonomethoxy)ethyl]adenine (20) was also synthesized. The key step involved the reaction of 9-(2-cyanoethyl)adenine (15) with methyl iodoacetate in the presence of lithium 2,2,6,6-tetramethylpiperidine in THF. Unlike 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA, 4), the N(7)-isomer 20 was not phosphorylated effectively by 5-phosphoribosyl 1-pyrophosphate synthetase (PRPP synthetase). Thus, it did not exhibit pronounced antiviral activity. Dinucleotide 5'-monophosphate 24 and its butenolide ester 25 were also synthesized. Compound 24 showed substrate activity toward PRPP synthetase and exhibited notable activity against DNA viruses. The antiviral activity of the ester derivative 25 was found to be higher than that of the parent molecule 24. Dinucleotide 5'-monophosphate 24 is susceptible to degradation by snake venom and spleen phosphodiesterases. However, its respective butenolide ester derivative 25 was completely resistant to snake venom and spleen enzymes. Butenolide ester derivatives 28 and 29 were also synthesized and exhibited notable anti-DNA virus and anti-retrovirus activity in vitro. Compounds 2, 4, 9, 14, 20, 24, 25, and 28 were also evaluated for their inhibitory effect on HSV-1-induced mortality in NMRI mice. N(7)-adenine acyclic nucleoside 14 [LD(50) (intraperitoneal, ip) 950 mg/kg], nucleotide-containing butenolide 25 [LD(50) (ip) 675 mg/kg], and butenolide 28 [LD(50) (ip) 710 mg/kg] were found to be potent anti-HSV-1 agents in vivo. In addition, butenolide 28 efficiently decreased tumor formation induced by Moloney murine sarcoma virus (MSV) in NMRI mice while significantly increasing the survival time of MSV-infected mice.
 ...
PMID:Design, synthesis, and biological evaluation of novel nucleoside and nucleotide analogues as agents against DNA viruses and/or retroviruses. 1160 36


<< Previous 1 2 3 4 5 6 7 Next >>