Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Synthesis of optically pure (-)- and (+)-adenallene 2 and 3 is described. Racemic adenallene (1a) was subjected to deamination with adenosine deaminase monitored by HPLC using a Chiralcel CA-1 column to give (-)-adenallene (2) and (+)-hypoxallene (4). The latter compound was converted to acetate 5. The reaction of 5 with trifluoromethanesulfonic anhydride and pyridine followed by ammonolysis furnished acetate 6 or (+)-adenallene (3) depending on the solvent used in the last step. Acetate 5 was smoothly transformed to the 6-chloro derivative 7, but an attempted ammonolysis led only to racemization and decomposition. Single crystal X-ray diffraction established the R-configuration of (-)-enantiomer 2. The latter forms a pseudosymmetric dimer in the lattice with the adenine moiety in an anti-like conformation. The torsional angles of the allenic bonds show departures from 90 degrees (91 and 97 degrees, respectively) and rotameric preference of the hydroxymethyl groups is different in both molecules of the dimer. The R-enantiomer 2 inhibited the replication and cytopathic effect of human immunodeficiency virus (HIV-1) in ATH8 cell culture with an IC50 of 5.8 microM, whereas the S-enantiomer 3 was less active (IC50 > 200 microM). The enantioselectivity of the anti-HIV effect is significantly lower than that of 2',3'-dideoxyadenosine. Kinetics of deamination of R- and S-enantiomers 2 and 3 catalyzed by adenosine deaminase gave the following parameters: Km values of S-form 3 and R-form 2 were 0.41 and 0.52 mM with Vmax being 530 and 18.5 mumol/min, respectively [corrected]. Again,, a much lower level of enantioselectivity of deamination was observed than that of D- and L-adenosine. These results indicate (i) different enantioselectivity of enantiomers 2 and 3 as HIV inhibitors and adenosine deaminase substrates and (ii) both R- and S-enantiomers 2 and 3 can function as nucleoside analogues with varied enantioselectivity for different enzymes or receptors.
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PMID:(R)-(-)- and (S)-(+)-adenallene: synthesis, absolute configuration, enantioselectivity of antiretroviral effect, and enzymic deamination. 130 69

The synthesis of a series of novel thiosemicarbazones (TSC's) derived from various alkyl diazinyl (3-pyridazinyl, 4-pyrimidinyl, 2-pyrazinyl) ketones and 3-pyridazinecarbaldehyde and their evaluation against herpes simplex virus (HSV) and human immunodeficiency virus (HIV) as well as the determination of their cytotoxicity are described. In addition, the effects of combination of such TSC's with the well-known antiviral drugs acyclovir (ACV) and 3'-azido-3'-deoxythymidine (AZT) were studied. Under our experimental conditions, i.e. determination of virus-induced cytopathic effect upon infection of HUT78 cells with HSV-1 and upon infection of MT4 cells with HIV-1, no antiviral activity could be detected with any of the TSC's. However, pronounced effects on proliferation of these rapidly growing T4 lymphocyte cell lines were observed. Clear structure-activity relationships with regard to these cytotoxic effects could be established: compared to pyridine, pyrazine, or pyrimidine-derived TSC's most of the 3-pyridazinyl congeners investigated are less cytotoxic; introduction of a methyl group into C-6 of the pyridazine system or prolongation of the acyl moiety in these compounds has essentially no influence; all compounds bearing an N,N-dimethylamino or a cycloamino substituent are much more toxic than those with an NH2 or NHR substituent; the nature of R in the latter type of compounds has only moderate influence. It has been reported that combination of TSC's with the antiviral agent acyclovir (ACV) results in potentiation of this well-known drug. We evaluated the potential of our series of novel TSC's in combination with ACV for inhibition of HSV-1-induced cytopathic effect in HUT78 cells and in combination with 3'-azido-3'-deoxythymidine (AZT) for inhibition of HIV-1-induced cytopathic effect in MT4 cells. Only four compounds out of this series, all characterized by an unsubstituted NH2 group, exhibited moderate synergism with the above mentioned antiviral drugs. Our results do not support the previously expressed opinion that TSC's are selective antiviral agents. In our test systems no evidence for inhibition of virus-induced cytopathic effect was obtained. The TSC derivatives exhibited a broad range of cytotoxic effects, some at concentrations considerably below those reported to have antiviral efficacy. Several of our novel diazine-derived compounds proved advantageous over the previously described pyridine analogues with regard to cytotoxicity. Moderate synergism could be detected for relatively noncytotoxic TSC's with the antiviral drugs ACV (antiherpes) and AZT (anti-HIV).
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PMID:Novel thiosemicarbazones derived from formyl- and acyldiazines: synthesis, effects on cell proliferation, and synergism with antiviral agents. 135 51

The 5'-azidonucleosides 3 and 4 were obtained by treating thymidine and 2'-deoxyuridine with TPP/DEAD/HN3. The 3'-O-silylated 5'-azido-5'-deoxythymidine 5 and the corresponding 2'-deoxyuridine derivative 6 were transformed to the formamides (7 and 8, respectively) and dehydrated to the protected 5'-isocyano derivatives 9 and 10; deblocking gave 5'-isocyano-5'-deoxythymidine (11) and 5'-isocyano-2',5'-dideoxyuridine (12). 2,3'-Anhydro-5'-formamido derivatives of thymidine and 2'-deoxyuridine (19 and 20, respectively) were prepared by three different ways. In the most direct synthesis 3 and 4 were transformed to the 2,3'-anhydro-5'- azidonucleosides 17 and 18 by using TPP/DEAD; following the reaction with TPP/HCO2COCH3 gave 19 and 20. Nucleophilic opening reaction with LiN3 yielded the 3'-azido-5'-formylamino derivatives 21 and 22. Dehydration to 3'-azido-5'-isocyano-3',5'-dideoxythymidine (23) and 3'-azido-5'-isocyano-2',3',5'-trideoxyuridine (24) was achieved with tosyl chloride/pyridine. In contrast with 3'-azido-3'-deoxythymidine, compounds 11, 12, 23, and 24 were devoid of any marked inhibitory effect against DNA and RNA viruses including human immunodeficiency virus type I (HIV).
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PMID:Synthesis and antiretrovirus properties of 5'-isocyano-5'-deoxythymidine, 5'-isocyano-2',5'-dideoxyuridine, 3'-azido-5'-isocyano-3',5'-dideoxythymidine, and 3'-azido-5'-isocyano-2',3',5'-trideoxyuridine. 201 18

A series of 1-deazaadenine nucleosides with the N6 nitrogen unsubstituted or bearing methyl or cycloalkyl substituents, with or without a chloro group in the 2-position, and with the glycosylic moiety being ribose (1-16), 2'-deoxyribose (17-32), or 2', 3'-dideoxyribose (33-48) were designed and synthesized starting from 5,7-dichloro-3H-imidazo[4,5-b] pyridine (50). These compounds were evaluated for their in vitro activity against human immunodeficiency virus type-1 (HIV-1) and herpes simplex virus type-1 (HSV-1). In addition they were tested for their ability to inhibit adenosine deaminase (ADA) from calf intestine. While the parent compounds 1-deazaadenosine (9), 2'-deoxy-1-deazaadenosine (25), and 2',3'-dideoxy-1- deazaadenosine (41) and the corresponding 2-chloro derivatives were inactive, nucleosides bearing cycloalkyl substituents on N6 exhibited moderate to good anti-HIV-1 activity, compared to 2',3'-dideoxyadenosine, with the degree and pattern of improvement depending on the structure of the sugar moiety. In general, 2'-deoxy- and 2',3'-dideoxy derivatives were more potent compounds than the corresponding ribose nucleosides. Compounds bearing a 6-cycloheptyl or cyclooctylamine were the most active in every series. The presence of a chloro group in the 2-position improved both activity and therapeutic index in every series, the most active compound being 2'-deoxy-2-chloro-N6-cycloheptyl-1-deazaadenosine (23; ED50 = 0.2 microM). On the other hand, most of these derivatives were inactive as anti-HSV-1 agents, showing a high degree of virus selectivity. The 1-deazaadenine derivatives were not substrates of adenosine deaminase, and some of them proved to be good inhibitors of the enzyme. However, the ADA inhibitory activity does not account for the antiviral potency since increased lipophilicity and steric hindrance of substituents resulted in derivatives much less active than the parent compounds.
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PMID:Synthesis and biological evaluation of N6-cycloalkyl derivatives of 1-deazaadenine nucleosides: a new class of anti-human immunodeficiency virus agents. 756 37

L-735,524 is a potent, orally bioavailable inhibitor of human immunodeficiency virus (HIV) protease currently in a Phase II clinical trial. We report here the three-dimensional structure of L-735,524 complexed to HIV-2 protease at 1.9-A resolution, as well as the structure of the native HIV-2 protease at 2.5-A resolution. The structure of HIV-2 protease is found to be essentially identical to that of HIV-1 protease. In the crystal lattice of the HIV-2 protease complexed with L-735,524, the inhibitor is chelated to the active site of the homodimeric enzyme in one orientation. This feature allows an unambiguous assignment of protein-ligand interactions from the electron density map. Both Fourier and difference Fourier maps reveal clearly the closure of the flap domains of the protease upon L-735,524 binding. Specific interactions between the enzyme and the inhibitor include the hydroxy group of the hydroxyaminopentane amide moiety of L-735,524 ligating to the carboxyl groups of the essential Asp-25 and Asp-25' enzymic residues and the amide oxygens of the inhibitor hydrogen bonding to the backbone amide nitrogen of Ile-50 and Ile-50' via an intervening water molecule. A second bridging water molecule is found between the amide nitrogen N2 of L-735,524 and the carboxyl oxygen of Asp-29'. Although other hydrogen bonds also add to binding, an equally significant contribution to affinity arises from hydrophobic interactions between the protease and the inhibitor throughout the pseudo-symmetric S1/S1', S2/S2', and S3/S3' regions of the enzyme. Except for its pyridine ring, all lipophilic moieties (t-butyl, indanyl, benzyl, and piperidyl) of L-735,524 are rigidly defined in the active site.
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PMID:Crystal structure at 1.9-A resolution of human immunodeficiency virus (HIV) II protease complexed with L-735,524, an orally bioavailable inhibitor of the HIV proteases. 792 52

Reaction of 9-[3,5-di-O-(tetrahydropyran-2-yl)-beta-D-arabinofuranosyl]uracil (2) with diethylaminosulfur trifluoride in the presence of pyridine afforded 2'-deoxy-2'-fluororiboside 3a, from which 2'-deoxy-2'-fluorocytidine (4b) has been synthesized in good yield. Compound 3a was deprotected and subsequently treated with various benzyl halides or 2-chloro-4-fluoroacetophenone to give corresponding N3-substituted 2'-deoxy-2'-fluorouridines 5a-c and 6. Compounds 5a-c, as well as 6, showed weak hypnotic activity in mice. Compound 4b showed moderate antiviral activity against human immunodeficiency virus-1 but 3b, 5a-c, and 6 were virtually inactive.
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PMID:Synthesis and hypnotic and anti-human immunodeficiency virus-1 activities of N3-substituted 2'-deoxy-2'-fluorouridines. 800 6

Phospholipid conjugates of 3'-azido-3'-deoxythymidine (AZT) show activity against the human immunodeficiency virus (HIV) in vitro. In a previous report (K.Y. Hostetler, L.M. Stuhmiller, B.H.M. Lenting, H. van den Bosch and D.D. Richman (1991), J. Biol. Chem. 265, 6112-6117) the syntheses and anti-HIV activities of AZT mono- and diphosphate diglyceride have been described. We now report on the synthesis, characterization and biological activity of 3'-azido-3'-deoxythymidine triphosphate distearoylglycerol (AZTTP-DSG). The compound was prepared by the condensation of AZT diphosphate with distearoylphosphatidic acid morpholidate in anhydrous pyridine at room temperature and purified by means of high-performance liquid chromatography using a silica column. Characterization was performed with 31P-NMR and IR analyses and determination of the fatty acid, phosphorus and nucleoside content of the product. AZTTP-DSG inhibited HIV-1 replication in both CEM and HT4-6C cells at a level intermediate in potency between its mono- and diphosphate analogs. The IC50 values of AZTTP-DSG were 0.33 and 0.79 microM in these two cell lines, respectively. In addition, AZTTP-DSG was less toxic to CEM cells in vitro than the other AZT liponucleotides and reduced viable cell numbers in this cell type by 50% at 1000 microM. Initial studies on the metabolism of AZTTP-DSG revealed that both AZT and AZT monophosphate were liberated from the lipid pro-drug by a rat liver mitochondrial enzyme preparation. These phospholipid derivatives of AZT nucleotides represent pro-drugs for the intracellular delivery of phosphorylated antiviral nucleoside analogs.
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PMID:Synthesis and antiviral activity of 3'-azido-3'-deoxythymidine triphosphate distearoylglycerol: a novel phospholipid conjugate of the anti-HIV agent AZT. 803 92

The one-pot synthesis of 1H,3H-thiazolo[3,4-a]imidazo[4,5-b]pyridines is described. The antiviral activity against human immunodeficiency virus (HIV) of the compounds obtained was explored: 1-(2',6'-dichlorophenyl) (5g) and 1-(2',6'-difluorophenyl)-1H,3H-thiazolo- [3,4-a]imidazo[4,5-b]pyridine (5h) exhibit reproducible in vitro anti-HIV activity.
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PMID:Anti-HIV agents. III. Synthesis and in vitro anti-HIV activity of novel 1H,3H-thiazolo[3,4-a]imidazo[4,5-b]pyridines. 808 Jun 17

2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are two members of a family of carcinogenic heterocyclic amines (HAs) found in cooked meats that form DNA adducts after activation to N-acetoxy derivatives. The ability of IQ- and PhIP-DNA adducts to inhibit gene expression was investigated using a human growth hormone (hGH) reporter gene in a pUC12-based mammalian expression vector under the control of either the herpes simplex virus-1 thymidine kinase promoter or the human immunodeficiency virus-1 long terminal repeat. The plasmids were treated in vitro with 0, 5, 10, or 40 microM N-hydroxy-IQ or N-hydroxy-PhIP in the presence of a 10-fold molar excess of acetic anhydride to generate the N-acetoxy derivatives in situ. The adduct levels in the plasmids were quantitated by the 32P-postlabeling method. The adducted (and control) plasmids were each transfected into repair-deficient or -proficient Chinese hamster ovary cells, and expression of hGH was measured by immunoassay of growth hormone secreted into the cell medium. The results showed that IQ- and PhIP-DNA adducts inhibited gene expression in both plasmids and that the degree of inhibition of hGH production was proportional to the levels of IQ- and PhIP-DNA adducts. The degree of inhibition, however, was independent of the promoter, despite the differences in the strengths of the two promoters to drive hGH production. Repair capacity influenced the extent of inhibition of gene expression by HA adducts since, in general, fewer adducts were needed to inhibit reporter gene expression in repair-deficient cells than in repair-proficient cells. In both cell lines, DNA adducts of PhIP appeared to be more potent in inhibiting hGH expression than adducts of IQ. Whether alteration of gene expression by HA adducts plays a role in the carcinogenicity of these compounds deserves further study.
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PMID:Inhibition of plasmid reporter gene expression in CHO cells by DNA adducts of 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. 818 27

Incubation of highly enriched neurons from rat cerebral cortex with the human immunodeficiency virus type 1 (HIV-1) coat protein gp120 for 18 h results in fragmentation of DNA at internucleosomal linkers, a feature of apoptosis. We report that neurons respond to exposure to gp120 with an increased release of arachidonic acid via activation of phospholipase A2. This process is not inhibited by antagonists of the N-methyl-D-aspartate (NMDA) receptor channels. To investigate the influence of arachidonic acid on the sensitivity of NMDA receptor towards its against, low concentrations of NMDA were coadministered with arachidonic acid. Under these conditions the NMDA-mediated cytotoxicity was enhanced. We conclude that gp120 causes an activation of phospholipase A2, resulting in an increased release of arachidonic acid which in turn sensitizes the NMDA receptor. Two compounds were found to act cytoprotectively against the deleterious effect caused by gp120 on neurons: Memantine [1-amino-3,5-dimethyladamantane] and Flupirtine [2-amino-3-ethoxycarbonylamino-6-(4-fluoro-benzyl-amino)-pyridine maleate]. Both compounds have been found to display a potent cytoprotective effect on neurons treated with the excitatory amino acid NMDA or with the human immunodeficiency virus type 1 (HIV-1) coat protein gp120. The NMDA antagonist Memantine, a drug currently used in the therapy of spasticity and Parkinson's disease, prevented the effects of gp120 at micromolar concentrations. Flupirtine was previously found to be a centrally acting, nonopiate analgesic agent which additionally possesses anticonvulsant and muscle-relaxant activity at doses similar to those producing analgesia. The cytoprotective effect of Flupirtine in vitro was significant (above 10 microM). Considering the fact that both Memantine and Flupirtine display almost no clinical side effects, these drugs may prove useful both in preventing primary infection of brain cells with the HIV virus, as well as in treating the neurological disorders often associated with the immunodeficiency syndrome such as AIDS-related dementia.
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PMID:Neurotoxicity in rat cortical cells caused by N-methyl-D-aspartate (NMDA) and gp120 of HIV-1: induction and pharmacological intervention. 882 91


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