Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.5.4.17 (adenosine deaminase)
 5,206 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine have been shown (Mitsuya, H., and Broder, S. (1987) Nature 325, 773-778) to have in vitro activity against the human immunodeficiency virus-1 (HIV). However, these dideoxynucleosides may be catabolized by human T cells, even when adenosine deaminase is inhibited by deoxycoformycin. To overcome this problem, we have synthesized the 2-fluoro-, 2-chloro-, and 2-bromo-derivatives of 2',3'-dideoxyadenosine. The metabolism and anti-HIV activity of the 2-halo-2',3'-dideoxyadenosine derivatives and of 2',3'-dideoxyadenosine were compared. The 2-halo-2',3'-dideoxyadenosine derivatives were not deaminated significantly by cultured CEM T lymphoblasts. Experiments with 2-chloro-2',3'-dideoxyadenosine showed that the T cells converted the dideoxynucleoside to the 5'-monophosphate, 5'-diphosphate, and 5'-triphosphate metabolites. At concentrations lower than those producing cytotoxicity in uninfected cells (3-10 microM), the 2-halo-2',3-dideoxyadenosine derivatives inhibited the cytopathic effects of HIV toward MT-2 T lymphoblasts, and retarded viral replication in CEM T lymphoblasts. Experiments with a deoxycytidine kinase-deficient mutant CEM T cell line showed that this enzyme was necessary for the phosphorylation and anti-HIV activity of the 2-chloro-2',3'-dideoxyadenosine. In contrast, 2',3'-dideoxyadenosine was phosphorylated by the deoxycytidine kinase-deficient mutant and retained anti-HIV activity in this cell line. Thus, the 2-halo derivatives of 2',3'-dideoxyadenosine, in contrast to 2',3'-dideoxyadenosine itself, are not catabolized by T cells. Their anti-HIV and anti-proliferative activities are manifest only in cells expressing deoxycytidine kinase. The in vivo implications of these results for anti-HIV chemotherapy are discussed.
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PMID:Metabolism and anti-human immunodeficiency virus-1 activity of 2-halo-2',3'-dideoxyadenosine derivatives. 325 2

Synthesis of (Z)-(2,3-bis-hydroxymethyl)methylenecyclopropane analogues of nucleosides adenosine 10a, 10b, 10c and 17 is described. Epimerization of Feist's acid (11) using acetic anhydride gave cyclic anhydride 12 which was reduced in situ to give diol 13. Acetylation (compound 14) followed by addition of bromine led to dibromo derivative 15. Alkylation-elimination of adenine with 15 afforded, after deacetylation, analogue 10a. Similar treatment of 2-amino-6-chloropurine and 2,6-diaminopurine led to diacetates 16 and 18. Deprotection then gave compounds 17 and 10c. Hydrolysis of 17 furnished guanine analogue 10b. Compounds 10a, 10b or 10c were inactive against HCMV, HSV-1, HSV-2, EBV VZV and HBV. Analogues 10a and 10b were also assayed for anti-HIV activity. Compound 10a was effective in HIV-1/MT-2 culture with EC50/CC50 33/> 100 microM but 10b was inactive. Analogue 10a was not a substrate for adenosine deaminase.
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PMID:Synthesis of (Z)-(2,3-bis-hydroxymethyl)methylenecyclopropane analogues of purine nucleosides. 1281 85

The Z- and E-isomers of fluoromethylenecyclopropane analogues 11a-d and 12a-d were synthesized, and their antiviral activities were evaluated. The purine (Z,E)-methylenecyclopropane carboxylates 13 and 24 were selectively fluorinated using lithium diisopropylamide, LiCl, and N-fluorobenzenesulfonimide to give (Z,E)-fluoroesters 22 and 25. Reduction with LiBH(4) or diisobutylaluminum hydride gave after chromatographic separation Z-isomers 11a and 11e and E-isomers 12a and 12e. The O-demethylation of 11e and 12e afforded guanine analogues 11b and 12b. Fluorination of (Z,E)-cytosine and thymine esters 15 and 16 afforded (Z,E)-fluoroesters 26 and 27, which were resolved before the reduction to analogues 11c and 11d and 12c and 12d. Adenine Z-isomer 11a was the most effective against Towne and AD169 strains of human cytomegalovirus (HCMV, EC(50) 3.6 and 6.0 microM, respectively), but it was less effective against murine virus (MCMV, EC(50) 69 microM). Thymine Z-isomer 11d was effective against HSV-1 in BSC-1 cells (ELISA, EC(50) 2.5 microM) but inactive against HSV-1 or HSV-2 in Vero or HFF cells. All of the analogues with the exception of 12d were effective at least in one of the assays against Epstein-Barr virus (EBV) in Daudi or H-1 cells in a micromolar or submicromolar range. Cytosine and thymine Z-isomers 11c and 11d were active against varicella zoster virus (VZV) with EC(50) 0.62 microM. Adenine Z- and E-isomers 11a and 12a were effective against HIV-1 in MT-2 or MT-4 cells with EC(50) 12-22 and 2.3-7.6 microM, respectively, whereas only 12a was effective against hepatitis B virus (HBV) with EC(50) 15 microM. Analogues 11a and 12a were weak substrates for adenosine deaminase.
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PMID:(Z)- and (E)-[2-Fluoro-2-(hydroxymethyl)cyclopropylidene]methylpurines and -pyrimidines, a new class of methylenecyclopropane analogues of nucleosides: synthesis and antiviral activity. 1561 45