Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 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 structural requirements for the immunopotentiating (adjuvant) effect of endotoxin (ET) were investigated. Mild hydrolysis (0.2 N acetic acid at 95 degrees C) was applied to various ET preparations and the lipid rich (Lipid A) and polysaccharide-rich (PS) preparations obtained were tested as adjuvants on three immunogens: sheep red blood cells (SRBC), L-glutamine: L-lysine: L-alanine containing random synthetic polypeptide (GLA-40), and recombinant HIV viral envelope polypeptide (CBre3). It was found that not only the Lipid A precipitates, but under certain hydrolytic conditions the non-toxic PS preparations were also potent adjuvants. The exact conditions of hydrolysis which led to the isolation of immune adjuvant bacterial products were established. These materials were also tested for endotoxicity (Limulus lysate clotting, chick embryo lethality and local Shwartzman skin reactivity), as well as for TNF generating activities. It was found that TNF generation runs parallel with toxicity of the samples, but it does not follow the adjuvant activity of the isolates. Chemical analysis of the preparations indicated that they did not contain residual ET or Lipid A, however, they did not exclude that deacylated and dephosphorylated skeletal remains of ET are among those components in these preparations which have immunomodulatory activity.
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PMID:Potentiation of HIV envelope glycoprotein and other immunogens by endotoxin (ET) and its molecular fragments. 152 25

Various non-invasive investigations were carried out in patients infected with HIV who had respiratory symptoms with and without pneumocystis pneumonia (with pneumonia, n = 13 (five smokers); without pneumonia, n = 22 (13 smokers]. These included chest radiography; lung function tests (forced expiratory volume in one second, forced vital capacity; transfer factor and coefficient for carbon monoxide); arterial blood gas tensions; arterial oxygen saturation at rest and on exercise; and lung clearance of diethylenetriaminepenta-acetic acid labelled with technetium-99m (99mTc DTPA). The effect of scan time (seven v 45 minutes from peak counts) and subtraction of background counts were examined. There were no significant differences between the two groups in lung function tests or arterial blood gas tensions at rest. The median clearance half time of inhaled 99mTc DTPA for the first seven minutes from peak counts was 7.2 minutes for patients with pneumocystis pneumonia and 22 minutes for those without. The median arterial oxygen desaturation on exercise was 5% in patients with pneumocystis pneumonia and 2% in those without. 99mTc DTPA lung clearance was better than the other non-invasive tests in discriminating pneumocystis pneumonia from other pulmonary disorders in patients positive for HIV. A short scan time of seven minutes was as sensitive and specific as the longer scan time of 45 minutes, and this allows the clearance of 99mTc DTPA to become a rapid screening test.
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PMID:Diagnostic value of lung clearance of 99mTc DTPA compared with other non-invasive investigations in Pneumocystis carinii pneumonia in AIDS. 154 24

Thirty-nine HIV-negative men, without apparent genital warts, were evaluated for evidence of subclinical genital condylomata by visual examination of the genitalia with colposcopy after the application of 5% acetic acid. 24 patients (group I) had a history of recurrent genital condylomata; 8 (group II) were sexual partners of women with HPV-related lesions and 7 (group III) presented another sexually transmitted disease. Under colposcopic magnification, acetowhite areas were biopsied for conventional histology and in situ hybridization using 6/11, 16/18 and 31/35/51 HPV-DNA probes. Colposcopy and histologic features were positive for condylomata acuminata in 16 patients of group III (14%). HPV 16/18 - whose oncogenic potentiality is well known - was detected in 3 patients: of these, one patient of group I presented a histologic picture suggestive of bowenoid papulosis.
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PMID:[HPV-induced subclinical lesions of the male genitalia. Use of a colposcope]. 225 48

(+-)-cis-[4-[(2,5-Diamino-6-chloropyrimidinyl)amino]-2- cyclopentenyl]carbinol (5a) was synthesized from 2-amino-4,6-dichloropyrimidine and cis-4-(hydroxymethyl)cyclopentenylamine (2a) by subsequent preparation of the 5-[(4-chlorophenyl)azo] derivative of the resulting pyrimidine (3a) and reduction of the azo moiety with zinc and acetic acid. The carbocyclic analogue of 2',3'-didehydro-2',3'-dideoxy 2-amino-6-chloropurine (6a) and the corresponding 8-azapurine (9a) were prepared from 5a. The carbocyclic 2',3'-didehydro-2',3'-dideoxy analogues of guanine (7a) and 2,6-diaminopurine (8a), and 8-azaguanine (10a) and 8-aza-2,6-diaminopurine (11a) were prepared from 6a and 9a, respectively. The corresponding 2',3'-saturated series of 2-amino-6-substituted-purine carbocyclic nucleosides was prepared following the same scheme starting with cis-4-(hydroxymethyl)cyclopentylamine (2b). Carbocyclic 2',3'-didehydro-2',3'-dideoxyguanosine (carbovir, 7a) emerged as a potent and selective anti-HIV agent. Its hydrolytic stability and its ability to inhibit the infectivity and replication of HIV in T-cells at concentrations of approximately 200-400-fold below toxic concentrations make carbovir an excellent candidate for development as a potential antiretroviral agent.
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PMID:Synthesis and anti-HIV activity of carbocyclic 2',3'-didehydro-2',3'-dideoxy 2,6-disubstituted purine nucleosides. 229 18

A series of prodrugs of zidovudine (AZT) has been synthesized in an effort to enhance the uptake of the prodrugs by the HIV-1 infected cells and to increase the plasma half-life of AZT. The 5'-OH function of AZT was esterified with various acids in the presence of DCC and 4-(dimethylamino)pyridine (DMAP). The prodrug moieties included (a) morpholine and N-phenylpiperazine-1-acetic acid, (b) 1,4-dihydro-1-methyl-3-nicotinic acid, (c) retinoic acid, and (d) certain amino acids. The anti-HIV-1 activity of the esters was determined in peripheral blood lymphocytes. The IC50 for AZT in this system was 0.12 microM whereas for prodrugs it ranged from 0.05 to 0.2 microM. The prodrugs were generally less cytotoxic than AZT except the retinoic acid ester. In vitro hydrolysis of the various esters in human plasma indicated that these agents were relatively stable toward plasma esterases with t1/2 ranging from 10 to 240 min. Drug uptake studies in H9 cells with radiolabeled analogues demonstrated that the retinoic acid ester achieved approximately 4-fold higher intracellular concentration than [3H]AZT. However, 1,4-dihydro-1-methyl-3-[(pyridylcarbonyl)oxy] ester (5) was the most active agent of this series and had a higher therapeutic index than AZT.
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PMID:Synthesis and biological evaluation of prodrugs of zidovudine. 232 72

Short peptides often do not bind well to the plastic surface of microtitre wells in solid-phase immunoassays. To improve the reactivity of synthetic peptides coated on the solid phase, we have developed a highly sensitive, rapid and simple ELISA. This ELISA is based on the treatment of microtitre plates with Alcian blue prepared in acetic acid prior to coating the target peptide. With hyperimmune serum, this treatment increases the specific signal in such a manner that the detection of antibodies needs less antigen than with conventional ELISA. Moreover, the Alcian blue treatment was shown to be particularly effective for the detection of monoclonal antibodies against a synthetic peptide derived from the human immunodeficiency type 1 (HIV-1) vpu protein. These monoclonal antibodies that were not detected in conventional ELISA gave a positive signal up to a 1 in 1000 dilution after Alcian blue treatment of microtitre wells. This assay should be applicable to a variety of synthetic peptides and other types of molecules posing problems in assays requiring their immobilization on solid phases.
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PMID:Alcian blue-treated polystyrene microtitre plates for use in an ELISA to measure antibodies against synthetic peptides. 793 Jun 36

The reaction of bicyclo[3.1.0]hexane 1, possessing a doubly activated cyclopropane ring, with acetic acid and potassium acetate in DMSO proceeded smoothly to give the adduct 2 in good yield. A formal total synthesis of the potent anti-HIV agent (+/-)-carbovir (9) was done by converting 2 into a known precursor 8 in 8 steps via allyl alcohol 7 including the regioselective introduction of a double bond (4 to 5) and attachment of the nucleobase using the Mitsunobu reaction (7 to 8).
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PMID:A new nucleophilic ring opening of an activated cyclopropane and a formal synthesis of (+/-)-carbovir. 854 48

The synthesis and the evaluation of cytotoxicity and anti-HIV-1 activity of new aryl pyrrolyl (8) and aryl indolyl (9) sulfones are reported. Preparation of above sulfones was achieved by reacting arylsulfonyl chlorides with substituted pyrroles and indoles or by condensing sulfonamides with 2,5-dimethoxytetrahydrofuran in glacial acetic acid according to the Clauson-Kaas method. Chemical requisites relevant to the anti-HIV-1 activity of these compounds are both a 2-sulfonyl-4-chloroanilino moiety and an alkoxycarbonyl group at position 2 of the pyrrole ring. The best activity and selectivity were obtained with ethoxycarbonyl and isopropoxycarbonyl substituents. Substitutions at the amino group of the pharmacophore moiety led to inactive products (alkylation) or weakened (acylation) anti-HIV-1 activity. Among test derivatives, 16 compounds showed EC50 values ranging between 10 and 1 microM, and five (8b',d',f',h'j') showed EC50S in the sub-micromolar range. The compounds were active against HIV-1, both wild type and AZT-resistant strains, but not against HIV-2. Moreover, in enzyme assays they potently inhibited the HIV-1 recombinant reverse transcriptase, were 10 times less active against enzymes from nevirapine- and TIBO-resistant strains, and were totally inactive against the HIV-2 recombinant enzyme. Interestingly, some compounds (8r'-y') were inactive against the recombinant reverse transcriptase while being active in tissue culture.
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PMID:2-Sulfonyl-4-chloroanilino moiety: a potent pharmacophore for the anti-human immunodeficiency virus type 1 activity of pyrrolyl aryl sulfones. 855 22

Epidemiological hypotheses on disease etiology, generated by the observation of geographic distribution and time trends, can be confirmed or refuted by analytical investigations on specific risk factors. In the case of leukemias, lymphomas and myelomas, however, hypothesis generation is limited by the use of the ICD classification in mortality and incidence statistics. We compared recent incidence data in different parts of the world and at different times for leukemias, lymphomas and myelomas. The incidence rate of non-Hodgkin's lymphomas (NHL) is increasing in most Western countries, while trends for the other hematolymphopoietic malignancies are strikingly stable. To formulate hypotheses on the causes of this pattern would require a more appropriate classification of descriptive data. Excesses of non-Hodgkin's lymphomas have been observed in populations exposed to phenoxy-acetic acid herbicides, to insecticides and to organic solvents. Some of these exposures, in particular TCDD, which is a contaminant of phenoxy herbicides, DDT and chlorinated solvents, have been reported to alter cell-mediated immunity. The incidence of NHL is also increased among subjects with HIV infection and subjects undergoing heart or kidney transplantation, all of whom experience immunodeficiency. A hypothesis that has been put forward recently is that the NHL increase is related to increased exposure to sunlight, which has immunosuppressive effects. From a mechanistic point of view, one can hypothesize that NHL is caused by exposures that induce proliferation and immortalization of B-cells, followed by T-cell impairment entailing cell-mediated immune deficiency.
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PMID:Incidence and time trends for lymphomas, leukemias and myelomas: hypothesis generation. Working Group on the Epidemiology of Hematolymphopoietic Malignancies in Italy. 864 39


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