Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

3'-Fluoro-2',3'-dideoxythymidine 5'-(alpha-methylphosphonyl)-beta,gamma- diphosphate and 2'-deoxythymidine-5'-(alpha-methylphosphonyl)-beta, gamma- diphosphate have been synthesized. Both compounds are incorporated into DNA chains during catalysis by reverse transcriptases of human immunodeficiency (HIV) and avian myeloblastosis (AMV) viruses, DNA polymerase beta from rat liver, terminal deoxynucleotidyl transferase from calf thymus and (at a very low rate) is by E. coli DNA polymerase I, Klenow fragment. The first compound is a termination substrate while the second is capable of multiple incorporation into the DNA chains. For instance, reverse transcriptase catalysis resulted in the appearance of 8 residues of second compound. DNA polymerases alpha and epsilon from human placenta incorporated none of the above compounds into DNA chains, although an inhibition of DNA synthesis by both compounds was observed with all enzymes mentioned. The 3'----5'-exonuclease activity of DNA polymerase I, Klenow fragment, hydrolyzed DNA fragments containing phosphonomethyl internucleoside groups, while such DNA fragments were resistant to the E. coli exonuclease III.
 ...
PMID:Formation of phosphonester bonds catalyzed by DNA polymerase. 137 65

3'-Fluoro-3'-deoxythymidine (FLT), a candidate anti-AIDS compound in clinical trials, showed anti-human immunodeficiency virus type 1 (HIV-1) potency (50% effective concentration, 0.0052 microM) slightly better than or equal to that of 3'-azido-3'-deoxythymidine (AZT) in MT4 cells and was threefold more potent in H9 cells. There was no FLT resistance demonstrable in the AZT-resistant HIV-1 strains. Both FLT and AZT showed low cytotoxicity for MT4 cells, with selectivity indices (efficacy/toxicity ratio) of greater than 47,000 and greater than 33,000, respectively. Cellular permeation of FLT and thymidine (dThd) was greater than that of AZT, and FLT and dThd permeated the cell membranes by a carrier-mediated mechanism as well as by simple diffusion, as indicated by the existence of nitrobenzylthioinosine-5'-monophosphate-sensitive and -insensitive components. By contrast, transport of AZT into cells was by simple diffusion. The intracellular level of the triphosphate of FLT (FLTTP) in MT4 cells was two- to threefold higher than that of AZT (AZTTP) after exposure to 1.8 microM each compound for 12 h. The elimination kinetics of FLTTP and AZTTP in HIV-1-infected MT4 cells in fresh medium showed biphasic patterns, with initial half-lives of 1.03 and 1.09 h, respectively. In phytohemagglutinin-stimulated human peripheral blood lymphocytes, the FLTTP level was increased 59-fold compared with that in unstimulated cells at 12 h, was four- to sixfold higher than the level of AZTTP in stimulated cells at 12 h, and remained four- to fivefold higher during a 4-h elimination period in fresh medium and twofold higher at the end of a 12-h elimination period. Two- to eightfold more [3H]AZT than [3H]FLT was incorporated into the host cell DNA, and both [3H]AZT and [3H]FLT remained persistently incorporated for over 24 h. The incorporated [3H]AZT and [3H]FLT were alkali labile, whereas incorporated [3H]dThd was alkali stable. Pharmacokinetics of FLT in plasma of monkeys after intravenous (i.v.) administration showed that the FLT concentration in plasma declined, with a half-life of 1.19 +/- 0.1 h; the steady-state volume of distribution was 0.93 +/- 0.2 liter/kg of body weight, and total clearance was 0.56 +/- 0.15 liter/kg. Oral bioavailability of FLT was excellent and comparable to i.v. bioavailability in terms of areas under the concentration-time curves for three monkeys. Of the total dose, 41 to 61% was excreted in urine as unchanged FLT, and only 3.2 to 7.4% of the total dose was identified as glucuronide-conjugated FLT in urine 48 h after i.v. administration to monkeys. We conclude that FLT exhibits an anti-HIV-1 potency similar to that of AZT but with slightly better selectivity of effects and with higher intracellular active metabolite levels.
 ...
PMID:Comparisons of anti-human immunodeficiency virus activities, cellular transport, and plasma and intracellular pharmacokinetics of 3'-fluoro-3'-deoxythymidine and 3'-azido-3'-deoxythymidine. 150 43

3'-Fluoro-3'-deoxythymidine and 3'-deoxy-2',3'-didehydrothymidine are nucleoside analogs which inhibit human and simian immunodeficiency virus in vitro. The pharmacokinetic properties of these compounds in rhesus monkeys after intravenous, oral, and subcutaneous administration of the drug were compared. Half-lives, total clearances, and steady-state volumes of distribution of the two drugs were determined. The half-lives for the drugs by the different routes were between 0.58 and 1.4 h. Oral bioavailability of 3'-deoxy-2',3'-didehydrothymidine was incomplete, with an average of 42% +/- 15% of the dose reaching the systemic circulation. Absorption of 3'-fluoro-3'-deoxythymidine after oral administration was variable, with bioavailability ranging from 21 to 95%. Bioavailability after subcutaneous administration ranged from 59 to 77% for 3'-deoxy-2',3'-didehydrothymidine and from 52 to 59% for 3'-fluoro-3'-deoxythymidine. The ratio of concentrations in cerebrospinal fluid and serum for the drugs was about 0.15 at 1 h after drug administration and was independent of the route of administration, suggesting that a nucleoside carrier-mediated process is involved in the transport of these compounds to the central nervous system. Because of the similar metabolism of nucleoside analogs in monkeys and humans, the potential glucuronide formation was assessed. Whereas the glucuronide of 3'-fluoro-3'-deoxythymidine was readily detected in urine, the amount of 3'-deoxy-2',3'-didehydrothymidine glucuronidated was small or not detectable in one-half of the urine samples. Pharmacokinetic parameters for the two drugs were similar to each other and analogous to those for 3'-azido-3'-deoxythymidine in monkeys, suggesting that the same dose and scheduling of the drug can be used for all three compounds in prophylactic and therapeutic efficacy drug studies in rhesus monkeys.
 ...
PMID:Pharmacokinetics of 3'-fluoro-3'-deoxythymidine and 3'-deoxy-2',3'-didehydrothymidine in rhesus monkeys. 216 44

One hundred nucleoside analogs with fluorine substitutions at various positions on the pentose ring were evaluated for inhibitory activity against human immunodeficiency virus type 1 (HIV-1). Nine compounds emerged as inhibitors of HIV-1 replication, with various degrees of selectivity; the most active of these was 3'-fluoro-3'-deoxythymidine, followed by 5'-amino-3'-fluoro-3'-deoxyadenosine. Substitution of fluorine at the 2'-deoxy or 3'-deoxy position resulted in increased antiviral activity of the thymidine analogs, whereas the activity of adenosine or cytidine analogs was not increased by fluorination at either position. The most potent inhibitor, 3'-fluoro-3'-deoxythymidine, was shown to give synergistic inhibition of HIV-1 replication in combination with the PPi analog phosphonoformate.
 ...
PMID:Structure-activity relationships of fluorinated nucleoside analogs and their synergistic effect in combination with phosphonoformate against human immunodeficiency virus type 1. 253 74

A series of 2'- and 3'-fluorinated 2',3'-dideoxynucleosides and 3'-azido-2',3'-dideoxynucleosides were synthesized and evaluated for their inhibitory activity against human immunodeficiency virus-1 (HIV-1) replication in MT-4 cells. Neither conversion of 3'-fluoro- or 3'-azido-2',3'-dideoxyadenosine to the corresponding inosine derivatives nor 8-bromination of 2',3'-dideoxyadenosine resulted in increased anti-HIV-1 activity. Nor did introduction of a 2'-fluorine in the erythro or threo configuration lead to improved anti-HIV-1 activity of the parent 2',3'-dideoxynucleosides. 1-(2-Fluoro-2,3-dideoxy-beta-D-threo-pentofuranosyl)cytosine and 1-(2-fluoro-2,3-dideoxy-beta-D-erythropentofuranosyl)thymine were only marginally active. However, 3'-fluoro-2',3'-dideoxyuridine (FddUrd) proved to be potent and a relatively nontoxic inhibitor of HIV-1. 5-Halogenated derivatives of FddUrd were prepared in attempts to further increase its anti-HIV potency and selectivity. Of these 5-halogenated derivatives, 3'-fluoro-2',3'-dideoxy-5-chlorouridine emerged as the most selective inhibitor of HIV-1 replication. Its selectivity index was comparable to that of azidothymidine when evaluated under the same conditions.
 ...
PMID:3'-Fluoro-2',3'-dideoxy-5-chlorouridine: most selective anti-HIV-1 agent among a series of new 2'- and 3'-fluorinated 2',3'-dideoxynucleoside analogues. 275

A systematic synthesis was undertaken of 2',3'-dideoxyadenosine analogues with either an azido, fluorine, or hydroxyl group substituted in the "up" or "down" position of C-2 or C-3 of the sugar moiety. The compounds were evaluated against the cytopathogenicity of human immunodeficiency virus (HIV) for MT-4 cells. The four azido derivatives 6, 7, 8, and 9 were synthesized by a nucleophilic displacement reaction with lithium azide on the mesylates 3, 2, 5, and 4. (Diethylamido)sulfur trifluoride was used for the synthesis of 10-12. The compound 13 was obtained by 2'-deoxygenation of 9-(3-fluoro-3-deoxy-beta-D-xylofuranosyl)adenine. Among the azido derivatives, compound 8 with the 3'-azido "down" was slightly more active than 2',3'-dideoxyadenosine (1) but considerably more toxic, and, of the fluorine series, compound 11, with the 2'-fluoro "up", was the most selective inhibitor of HIV, although it was less active than 1. Hence, none of the newly synthesized compounds proved more selective in their anti-HIV activity than the parent compound, 1.
 ...
PMID:Synthesis and anti-HIV activity of various 2'- and 3'-substituted 2',3'-dideoxyadenosines: a structure-activity analysis. 349 15

Four hundred forty-five bronchoalveolar lavage specimens from patients with the human immunodeficiency virus were preserved in Saccomano's fixative and stained for Pneumocystis carinii cysts by a modified method with Fungi-Fluor Solution A (Polysciences, Warrington, Pa) and the Genetic Systems Pneumocystis carinii Immunofluorescence Antibody (Genetic Systems Corp, Seattle, Wash). The majority of patients had been treated for suspected P carinii pneumonia for a few days prior to collection of bronchoalveolar lavage specimens. P carinii cysts were detected in 194 (43.6%) specimens. Both stains identified P carinii in 166 (37.3%) specimens and were negative in 251 (56.4%), yielding a concordance rate of 93.7%. P carinii cysts were detected in 25 (5.6%) specimens by the Genetic Systems stain only, and in 3 (0.7%) specimens by the Fungi-Fluor stain only. The sensitivity for detecting cysts of P carinii was significantly greater with the Genetic Systems stain (P < .01).
 ...
PMID:Modification of the fungi-fluor and the genetic systems fluorescent antibody methods for detection of Pneumocystis carinii in bronchoalveolar lavage specimens. 753 27

(2'R,5'S-)-cis-5-Fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine (524W91) is a nucleoside analog with potent anti-human immunodeficiency virus and anti-human hepatitis B virus activities in vitro. The pharmacokinetics and bioavailability of 524W91 after oral dosing were studied in mice dosed with 10, 100, and 600 mg of 524W91 per kg of body weight by the oral and intravenous routes. Cynomolgus monkeys were dosed with 10 and 80 mg of 524W91 per kg. In both species, the clearance of 524W91 was rapid, via the kidney, and was independent of dose. In monkeys, the total body clearance of 10 mg of 524W91 per kg was 0.7 +/- 0.1 liter/h/kg, and the volume of distribution at steady state was 0.8 +/- 0.02 liter/kg. The terminal elimination half-life was 1.0 +/- 0.2 h. The absolute bioavailability after oral dosing was 63% +/- 4% at 10 mg/kg. Concentrations of 524W91 in the cerebrospinal fluid were 4% +/- 0.7% of the corresponding levels in plasma. In mice, the total clearance of 10 mg of 524W91 per kg was 2.3 liters/kg/h, and the volume of distribution at steady state was 0.9 liter/kg. Absolute bioavailability in mice after oral dosing was 96% at a dose of 10 mg/kg. The metabolism of orally administered [6-3H]524W91 was studied in cynomolgus monkeys at a dose of 80 mg/kg and in mice at a dose of 120 mg/kg. Monkeys excreted 41% +/- 6% of the radioactive dose in the 0- to 72-h urine, 33% +/- 10% in the feces, and 10% +/- 7% in the cage wash. Unchanged 524W91 was 64% of the total radiolabeled drug recovered in the urine. The glucuronide was a minor urinary metabolite. 5-Fluorouracil was not detected (less than 0.02% of the dose). Mice dosed orally with 120 mg of [6-3H]524W91 per kg excreted 67% +/- 7% of the radiolable in the )- to 48-h urine. Small amounts of the 3' -sulfoxide and glucuronide metabolites were observed in the urine, but 5-fluorouracil was not detected. Good bioavailability after oral dosing and resistance to metabolism recommend 524W91 for further preclinical evaluation.
 ...
PMID:Pharmacokinetics, oral bioavailability, and metabolism in mice and cynomolgus monkeys of (2'R,5'S-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine, an agent active against human immunodeficiency virus and human hepatitis B virus. 769 53

-2',3'-Seco nucleosides 5 carrying fluorine and sulfur substituents at C-3' and C-5', respectively, of acyclic sugar moiety were synthesized in enantiomerically and diastereoisomerically pure form. These products and some structurally similar 1',2'-seco-2'-nor-and 1',2'-seco-nucleosides 3 and 4 were tested in vitro for cytotoxicity and antiviral activity. At non-cytotoxic concentrations the compounds were inactive against human immunodeficiency virus and herpes simplex virus type-1.
 ...
PMID:Synthesis and evaluation of the antiviral activity of acyclic nucleosides carrying fluorine and sulfur substituents. 821 73

Enzymes of the purine salvage pathway play an important role in altering the in vivo pharmacokinetics of 2',3'-dideoxypurine nucleosides. This study examines the pharmacokinetics of enzyme-resistant 2'-beta-fluoro analogues of 2',3'-dideoxyinosine (ddI) and 2',3'-dideoxyadenosine (ddA). 2'-beta-Fluoro-2',3'-dideoxyinosine (F-ddI) is an acid-stable analogue of ddI that is highly resistant to purine nucleoside phosphorylase, the principal enzyme in ddI metabolism. 2'-beta-Fluoro-2',3'-dideoxyadenosine (F-ddA), an acid-stable and purine nucleoside phosphorylase-resistant analogue of ddA, is converted in vivo to F-ddI by adenosine deaminase (ADA) but is a much poorer substrate for this enzyme than is ddA. Both F-ddA and F-ddI have been shown to have activity against human immunodeficiency virus in vitro, and F-ddA has been selected by the National Cancer Institute for clinical trials as a new human immunodeficiency virus reverse transcriptase inhibitor. The pharmacokinetics of F-ddI and ddI were compared at equivalent doses in chronically catheterized rats. Because ddI and F-ddI are isosteres having nearly identical lipophilicity, this comparison is likely to reflect primarily metabolic differences. The clearance of F-ddI was substantially reduced, in comparison with that of ddI (27.3 ml/min/kg vs. 90.9 ml/min/kg), resulting in higher systemic concentrations at steady state and prolonged retention of F-ddI after termination of infusions, consistent with a significant metabolic component in the clearance of ddI. Concentrations of F-ddA and F-ddI during and after infusions of F-ddA were determined in both untreated and 2'-deoxycoformycin-pretreated rats. In untreated rats, F-ddA was rapidly eliminated from plasma, with a total clearance of 68.5 ml/kg/min. Metabolic clearance of F-ddA to F-ddI accounted for 58% of this value (bioconversion t1/2 = 9.8 +/- 1.9 min). Pretreatment with 2'-deoxycoformycin, an ADA inhibitor, reduced the clearance of F-ddA to 23.8 ml/min/kg, leading to 2.9 +/- 0.4-fold higher steady-state plasma concentrations of F-ddA, in agreement with a 2.5-fold enhancement predicted by a compartmental model assuming complete ADA inhibition.
 ...
PMID:Role of altered metabolism in dideoxynucleoside pharmacokinetics. Studies of 2'-beta-fluoro-2',3'-dideoxyinosine and 2'-beta-fluoro-2',3'-dideoxyadenosine in rats. 889 19


1 2 3 4 Next >>