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)

A series of dialkyl esters of purine and pyrimidine N-[2-(phosphonomethoxy)ethyl] derivatives substituted at position 2, 6, or 8 of the purine base or position 2, 4, or 5 of the pyrimidine base were prepared by alkylation of the appropriate heterocyclic base with 2-chloroethoxymethylphosphonate diester in the presence of sodium hydride, cesium carbonate, or 1,8-diazabicyclo[5,4, 0]undec-7-ene (DBU) in dimethylformamide. Additional derivatives were obtained by the transformations of the bases in the suitably modified intermediates bearing reactive functions at the base moiety. The diesters were converted to the corresponding monoesters by sodium azide treatment, while the free acids were obtained from the diester by successive treatment with bromotrimethylsilane and hydrolysis. None of the PME derivatives in the pyrimidine series, their 6-aza or 3-deaza analogues, exhibited any activity against DNA viruses or retroviruses tested, except for the 5-bromocytosine derivative. Substitution of the adenine ring in PMEA at position 2 by Cl, F, or OH group decreased the activity against all DNA viruses tested. PMEDAP was highly active against HSV-1, HSV-2, and VZV in the concentration range (EC50) of 0.07-2 microg/mL. Also the 2-amino-6-chloropurine derivative was strongly active (EC50 = 0.1-0. 4 microg/mL) against herpes simplex viruses and (EC50 = 0.006-0.3 microg/mL) against CMV and VZV. PMEG was the most active compound of the whole series against DNA viruses (EC50 approximately 0.01-0.02 microg/mL), though it exhibited significant toxicity against the host cells. The base-modified compounds did not show any appreciable activity against DNA viruses except for 7-deazaPMEA (IC50 approximately 7.5 microg/mL) against HIV-1 and MSV. The neutral (diisopropyl, diisooctyl) diesters of PMEA were active against CMV and VZV, while the corresponding monoesters were inactive. The diisopropyl ester of the 2-chloroadenine analogue of PMEA showed substantially (10-100x) higher activity against CMV and VZV than the parent phosphonate. Also, the diisopropyl and diisooctyl ester of PMEDAP inhibited CMV and VZV, but esterification of the phosphonate residue did not improve the activity against either MSV or HIV.
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PMID:Structure-antiviral activity relationship in the series of pyrimidine and purine N-[2-(2-phosphonomethoxy)ethyl] nucleotide analogues. 1. Derivatives substituted at the carbon atoms of the base. 1037 14

Some new tetrahydrobenzoquinazolinediones 2a-4a, tetrahydrobenzocycloheptenuracils 5a, 6a and their thioxo analogues 2b-6b were synthesized within a project aimed at obtaining new HIV-1 tricyclic inhibitors whose scaffold includes a pyrimidine and a phenyl ring, which are present in various HIV-1 non-nucleoside inhibitors. Among the tetrahydrobenzoquinazolinediones 2a-4a, compounds 3a and 4a, in which the tricyclic system is respectively in an angular or linear arrangement, proved to possess a HIV-1 inhibitory activity which was in the micromolar range, while compound 2a, in which the tricyclic system is in the angular arrangement opposite to that of 3a, was found to be completely inactive. As regards the tetrahydrobenzocycloheptenuracil derivatives (5a and 6a), only 5a showed an inhibitory activity similar to that of 3a and 4a. Furthermore, all thioxo analogues 2b-6b were found to be devoid of any activity.
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PMID:Synthesis and HIV-1 inhibitory properties of new tetrahydrobenzoquinazolinedione and tetrahydrobenzocycloheptenuracil derivatives and of their thioxo analogues. 1038 18

A series of 4'alpha-C-branched-chain pyrimidine nucleosides was synthesized from 2'-deoxycytidine or uridine. In the 2'-deoxycytidine series, the substituent at the 4'alpha-position affected cytotoxicity against L1210 mouse leukemic cells in vitro in the order Me (23) > CN (22) > C(symbol)CH (21) > CH=CH(2) (19) > Et (24) > CH=CHCl (20). However, uridine and cytidine derivatives with ethynyl and cyano groups at the 4'alpha-position did not show any cytotoxicity. The antiviral activities of these nucleosides against HSV-1, HSV-2, and HIV-1 in vitro were also examined. Compounds 22 and 23 showed antiviral activities against HSV-1 and HSV-2 without showing significant toxicity to the host cells (MRC-5 cells). Although almost all of the nucleosides showed anti-HIV-1 activities, they were also cytotoxic to the host cells (MT-4).
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PMID:Nucleosides and nucleotides. 185. Synthesis and biological activities of 4'alpha-C-branched-chain sugar pyrimidine nucleosides. 1042 99

We investigated the interaction of a highly potent acridine-based tat-antagonist with the TAR RNA of HIV-1. The wild type TAR RNA and three mutants with U-->C23, G x C-->C x G26-39 or G x C-->A x U26-39 substitutions were used as substrates to study the molecular basis of drug-TAR RNA complex formation. Melting temperature and RNase protection experiments reveal that the G x C26-39 pair is a critical element for specific major groove recognition of TAR at the pyrimidine bulge. The results provide a rational basis for future design of optimized tat/TAR inhibitors.
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PMID:Molecular basis of HIV-1 TAR RNA specific recognition by an acridine tat-antagonist. 1042 76

A series of four biscationic diphenylfuran derivatives was used to investigate drug binding to the transactivation response element (TAR) RNA. The drugs, which are active against the Pneumocystis carinii pathogen (PCP), differ by the nature of the terminal basic side chains. Furimidazoline (DB60) is more potent at inhibiting binding of the Tat protein to TAR than furamidine (DB75) and the amidine-substituted analogues DB244 and DB226. In vivo studies using the fusion-induced gene stimulation (FIGS) assay entirely agree with the in vitro gel mobility shift data. The capacity of the drugs to antagonize Tat binding correlates with their RNA binding properties determined by melting temperature and RNase protection experiments. Footprinting studies indicate that the bulge region of TAR provides the identity element for the diphenylfurans. Access of the drugs to the major groove cavity at the pyrimidine bulge depends on the bulk of the alkylamine substituents. Experiments using TAR mutants show that the bulge of TAR is critical for drug binding but also reveal that the fit of the drugs into the major groove cavity of TAR does not involve specific contacts with the highly conserved residue U23 or the C x G26-39 base pair. The binding essentially involves shape recognition. The results are also discussed with respect to the known activity of the drug against PCP which is the major cause of mortality in AIDS patients. This study provides guidelines for future development of TAR-targeted anti-HIV-1 drugs.
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PMID:Inhibition of HIV-1 Tat-TAR interaction by diphenylfuran derivatives: effects of the terminal basic side chains. 1042 78

Novel 1,3-oxathiolanyl pyrimidine nucleosides with 5-hydroxymethyl substituent were synthesized starting from D-mannose and evaluated for antiviral activities against HIV-1, HSV type 1,2 and HCMV.
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PMID:Synthesis and antiviral activities of 1,3-oxathiolanyl nucleosides with 5-hydroxymethyl substituent. 1043 54

This investigation is devoted to design of short "switch" oligonucleotides mono- or bi-functionnalized with intercalating agents capable to form a stable triplex with HIV integrase-cognate sequences and inhibit selectively HIV integration. Methods of intercalator incorporation at 5'- and/or 3'-terminal positions or one of the pyrimidine heterocyclic bases are developed.
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PMID:Synthesis of oligonucleotide-intercalator conjugates capable to inhibit HIV-1 DNA integration. 1047 39

The regulatory protein Tat is essential for viral gene expression and replication of the human immunodeficiency virus type 1 (HIV-1). Tat transactivates the HIV-1 long terminal repeat (LTR) via its binding to the transactivation responsive element (TAR) and increases the viral transcription. Studies have shown that the binding of arginine and arginine derivatives induces a conformational change of the TAR RNA at the Tat-binding site. The unpaired A17 residue delimits a small cavity which constitutes a receptor site for small molecules, especially for ethidium bromide. These binding characteristics have prompted us to design a series of ethidium-arginine conjugates capable of interacting with the TAR RNA. Here we report the synthesis of six ethidium derivatives equipped with arginine side chains. These molecules were biologically evaluated, and two compounds (17 and 20) exhibited in vitro anti-HIV-1 activity at micromolar concentration, without toxicity (up to 100 microM concentration). Melting temperature studies indicated that the most active molecule (20) bound strongly to TAR in vitro. RNase protection experiments agreed with the molecular modeling studies which suggested that the ethidium moiety of 20 was inserted next to the A17 residue while the arginine side chain occupied the pyrimidine bulge.
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PMID:Synthesis and antiviral activity of ethidium-arginine conjugates directed against the TAR RNA of HIV-1. 1051 74

A computer model of reverse transcriptase (RT) from human immunodeficiency virus type 1 (HIV-1) was used to design thiourea compounds that were predicted to inhibit RT. The RT model was used to approximate how changes in binding pocket shape, volume and chemical properties resulting from residue mutations would affect inhibitor binding. Our lead compound, N-[2-(2,5-dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thi ourea (HI-236) was tested against clinically observed non-nucleoside inhibitor (NNI)-resistant mutated strains of HIV. HI-236 was more potent than trovirdine, MKC-442 and zidovudine against the drug-sensitive HIV-1 strain IIIB, 50-100 times more effective than delavirdine or nevirapine and twice as effective as our recently reported lead compound N-[2-(2-fluorophenethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-240) against the NNI-resistant Y181C mutant HIV-1 strain A17. HI-236 was highly effective against the multidrug-resistant HIV-1 strain RT-MDR containing multiple mutations involving the RT residues 74V, 41L, 106A and 215Y. In general, thiourea compounds such as HI-236 and HI-240 showed better inhibition of drug-resistant strains of HIV-1 than thioalkylbenzyl-pyrimidine compounds such as HI-280 and HI-281. The improved activity of thioureas against RT mutants is consistent with a structural analysis of the NNI binding pocket model of RT. The activity of HI-236 against RT-MDR was superior to that of other anti-HIV agents tested, in the following order, from high to low activity; HI-236 (IC50 5 nM), HI-240 (IC50 6 nM), trovirdine (IC50 20 nM), zidovudine (IC50 150 nM), MKC-442 (IC50 300 nM), delavirdine (IC50 400 nM) and nevirapine (IC50 5 microM).
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PMID:Structure-based design of non-nucleoside reverse transcriptase inhibitors of drug-resistant human immunodeficiency virus. 1057 78

In the central nervous system, HIV-1 has a defined tropism for brain macrophages and microglia. Nucleoside analog drugs such as zidovudine improve the clinical and neuropsychological functions in HIV-demented patients. Multiple carrier-mediated transport systems can play an important role in the membrane permeation of nucleosides and nucleoside analog drugs in a number of cells. The purpose of this project was to characterize the uptake properties of the pyrimidine nucleoside probe thymidine by a continuous rat microglia cell line (MLS-9) grown as a monolayer on an impermeable substratum. Approximately 50% of thymidine (10 microM) uptake by the monolayer cells was found to be Na(+) dependent. Kinetics of specific thymidine uptake showed a single saturation system (K(m) = 44 microM at 37 degrees C) and a Na(+)/thymidine stoichiometry of 2:1. Pyrimidine and purine nucleoside probes (50 microM) exerted a competitive inhibitory effect on specific thymidine uptake with K(i) values of 40, 38, 45, and 39 microM for adenosine, uridine, guanosine, and cytidine, respectively. In addition, nucleoside analog drugs significantly decreased specific thymidine uptake, with IC(50) values of 135.1 microM for abacavir and 0.6 microM for zidovudine, which inhibited in a noncompetitive manner. These results suggest that a Na(+)-dependent nucleoside transport system is present in rat microglia and that long-range interactions between antiretroviral nucleoside analog drugs and the nucleoside substrates may occur at the transporter sites.
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PMID:A Na(+)-dependent nucleoside transporter in microglia. 1060 72


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