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

A series of unsaturated analogues of nucleosides were prepared and their cytotoxic, antitumor, and antiviral activities were investigated. Alkylation of cytosine with (E)-1,4-dichloro-2-butene gave chloro derivative 2f, which was hydrolyzed to alcohol 2h. Cytosine, adenine, 2-amino-6-chloropurine, thymine, and (Z)-1,4-chloro-2-butene gave compounds 4c-f, which, after hydrolysis, afforded alcohols 4a, 4b, 4g, and 4h. Alkenes 4d and 4e were cyclized to heterocycles 12 and 13. Alkylation of 2,6-diaminopurine with 1,4-dichloro-2-butyne led to chloro derivative 6a, which was hydrolyzed to alcohol 6b. Allenic isomerization of 6b gave compound 5c. Chloro derivatives 2e-g, 4c-f, 5d, and 6c-e as well as pyrimidine oxacyclopentenes 9c and 9d are slow-acting inhibitors of murine leukemia L1210 of IC50 10-100 microM. The most active were analogues 4c, 4d, 4e, and 6e (IC50 10-20 microM). The corresponding hydroxy derivatives were less active of inactive. Inhibition of macromolecular synthesis with compounds 4c, 4d, 6e, 9c, and 9d follows the order: DNA greater than RNA greater than or equal to protein. Cytotoxic effects of 4c, 6e, and 9d are not reversed with any of the four basic ribonucleosides or 2'-deoxyribonucleosides. Inhibitory activity of cytosine derivative 9c is reversed with uridine and 2'-deoxyuridine but not with the corresponding cytosine nucleosides. Zone assays in several tumor cell lines show that active compounds are cytotoxic agents with little selectivity for tumor cells. Analogue 6c showed 16.7% ILS in leukemia P388/o implanted ip in mice at 510 and 1020 mg/kg, respectively. Cytallene (5b) and 6'beta-hydroxyaristeromycin (10) exhibited significant activity against Friend and Rauscher murine leukemia viruses. The rest of the hydroxy derivatives, with the exception of 4a, were moderately effective or inactive as antiviral agents. None of the chloro derivatives or oxacyclopentenes exhibited an antiviral effect at noncytotoxic concentrations. Z-Olefin 4b and 2-aminoadenallene (5c) are substrates for adenosine deaminase.
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PMID:Unsaturated and carbocyclic nucleoside analogues: synthesis, antitumor, and antiviral activity. 199 43

Cytosine deaminase (CD) catalyzes the deamination of cytosine, producing uracil. This enzyme is present in prokaryotes and fungi (but not multicellular eukaryotes) and is an important member of the pyrimidine salvage pathway in those organisms. The same enzyme also catalyzes the conversion of 5-fluorocytosine to 5-fluorouracil; this activity allows the formation of a cytotoxic chemotherapeutic agent from a non-cytotoxic precursor. The enzyme is of widespread interest both for antimicrobial drug design and for gene therapy applications against tumors. The structure of Escherichia coli CD has been determined in the presence and absence of a bound mechanism-based inhibitor. The enzyme forms an (alphabeta)(8) barrel structure with structural similarity to adenosine deaminase, a relationship that is undetectable at the sequence level, and no similarity to bacterial cytidine deaminase. The enzyme is packed into a hexameric assembly stabilized by a unique domain-swapping interaction between enzyme subunits. The active site is located in the mouth of the enzyme barrel and contains a bound iron ion that coordinates a hydroxyl nucleophile. Substrate binding involves a significant conformational change that sequesters the reaction complex from solvent.
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PMID:The structure of Escherichia coli cytosine deaminase. 1181 40

Cytosine deaminase (CD) catalyzes the deamination of cytosine and is only present in prokaryotes and fungi, where it is a member of the pyrimidine salvage pathway. The enzyme is of interest both for antimicrobial drug design and gene therapy applications against tumors. The structure of Saccharomyces cerevisiae CD has been determined in the presence and absence of a mechanism-based inhibitor, at 1.14 and 1.43 A resolution, respectively. The enzyme forms an alpha/beta fold similar to bacterial cytidine deaminase, but with no similarity to the alpha/beta barrel fold used by bacterial cytosine deaminase or mammalian adenosine deaminase. The structures observed for bacterial, fungal, and mammalian nucleic acid deaminases represent an example of the parallel evolution of two unique protein folds to carry out the same reaction on a diverse array of substrates.
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PMID:The 1.14 A crystal structure of yeast cytosine deaminase: evolution of nucleotide salvage enzymes and implications for genetic chemotherapy. 1290 27

The second generation of methylenecyclopropane analogues of nucleosides 5a-5i and 6a-6i was synthesized and evaluated for antiviral activity. The 2,2-bis(hydroxymethyl)methylenecyclopropane (11) was converted to dibromo derivative 7 via acetate 12. Alkylation-elimination of adenine (16) with 7 afforded the Z/E mixture of acetates 17 + 18, which was deacetylated to give analogues 5a and 6a separated by chromatography. A similar reaction with 2-amino-6-chloropurine (19) afforded acetates 20 + 21 and, after deprotection and separation, isomers 5f and 6f. The latter served as starting materials for synthesis of analogues 5b, 5e, 5g-5i and 6b, 6e, 6g-6i. Alkylation-elimination of N(4)-acetylcytosine (22) with 7 afforded a mixture of isomers 5c + 6c which were separated via N(4)-benzoyl derivatives 23 and 24. Deprotection furnished analogues 5c and 6c. Alkylation of 2,4-bis(trimethylsilyloxy)-5-methylpyrimidine (25) with 7 led to bromo derivative 26. Elimination of HBr followed by deacetylation and separation gave thymine analogues 5d and 6d. The guanine Z-isomer 5b was the most effective against human and murine cytomegalovirus (HCMV and MCMV) with EC(50) = 0.27-0.49 microM and no cytotoxicity. The 6-methoxy analogue 5g was also active (EC(50) = 2.0-3.5 microM) whereas adenine Z-isomer 5a was less potent (EC(50) = 3.6-11.7 microM). Cytosine analogue 5c was moderately effective, but 2-amino-6-cyclopropylamino derivative 5e was inactive. All E-isomers were devoid of anti-CMV activity, and none of the analogues was significantly active against herpes simplex viruses (HSV-1 or HSV-2). The potency against Epstein-Barr virus (EBV) was assay-dependent. In Daudi cells, the E-isomers of 2-amino-6-cyclopropylamino- and 2,6-diaminopurine derivatives 6e and 6h were the most potent (EC(50) approximately 0.3 microM), whereas only the thymine Z-isomer 5d was active (EC(50) = 4.6 microM). Guanine Z-derivative 5b was the most effective compound in H-1 cells (EC(50) = 7 microM). In the Z-series, the 2-amino-6-methoxypurine analogue 5g was the most effective against varicella zoster virus (VZV, EC(50) = 3.3 microM) and 2,6-diaminopurine 5h against hepatitis B virus (HBV, EC(50) = 4 microM). Adenine analogues 5a and 6a were moderately active as substrates for adenosine deaminase.
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PMID:Synthesis and antiviral activity of (Z)- and (E)-2,2-[bis(hydroxymethyl)cyclopropylidene]methylpurines and -pyrimidines: second-generation methylenecyclopropane analogues of nucleosides. 1473 38

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