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C K Chu

Publications and source records attributed to C K Chu.

At least 109 records · Page 6Linked to original sources
PubMed1990

Comparative pharmacokinetics and interspecies scaling of 3'-azido-3'-deoxythymidine (AZT) in several mammalian species.

Interspecies variation in drug disposition can be considered to be a function of species body weight. Therefore, it is possible to establish allometric relationships between pharmacokinetic parameters and species body weight. Interspecies scaling of pharmacokinetic data yielded from laboratory animals can often provide reliable predictions of pharmacokinetic parameters and drug disposition in humans. Significant correlations between 3'-azido-3'-deoxythymidine (AZT) pharmacokinetic parameters (total clearance, renal clearance, nonrenal clearance and steady-state volume of distribution) from mice, rats, dogs, monkeys and humans and body weight were found. Plasma AZT concentration versus chronological time profiles were markedly different for each species. However, when chronological time was converted to pharmacokinetic (physiologic) time these profiles were superimposible. These results demonstrate that interspecies pharmacokinetic scaling can be used to estimate plasma AZT concentrations in humans and can be used to design initial dosage regimens.

Animals↗
PubMed1990

Synthesis and anti-human immunodeficiency virus (HIV-1) activity of 3'-deoxy-3'-(triazol-1-yl)thymidines and 2',3'-dideoxy-3'-(triazol-1-yl)uridines and inhibition of reverse transcriptase by their 5'-triphosphates.

3'-Deoxy-3'-(1,2,3-triazol-1-yl)thymidines (5a, 6a, 8a, 11a, and 12a) and 2',3'-dideoxy-3'-(1,2,3-triazol-1-yl)uridines (5b, 6b, 8b, 11b, and 12b) were synthesized as cyclic analogues of 3'-azido-3'-deoxythymidine (AZT) and 3'-azido-2',3'-dideoxyuridine (CS-87) by the cyclization of 5'-trityl derivatives (1a, b) of AZT and CS-87 using alpha-ketophosphorus ylides and with acetylenic compounds followed by deprotection of the 5'-trityl group. It was hypothesized that the triazole nitrogen atoms could mimic and distorted azido group. However, no significant activity against human immunodeficiency virus type 1 (HIV-1) was observed with any of these compounds. 5'-Triphosphates (17a and 18a, b), prepared from 5a and 6a, b, were inactive against HIV-1 and Rauscher murine leukemia virus (RLV) reverse transcriptases.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Cellular metabolism of 3'-azido-2',3'-dideoxyuridine with formation of 5'-O-diphosphohexose derivatives by previously unrecognized metabolic pathways for 2'-deoxyuridine analogs.

3'-Azido-2',3'-dideoxyuridine (AzdU, CS-87) is a potent inhibitor of human immunodeficiency virus replication in human peripheral blood mononuclear cells (PBMC) with limited toxicity for human bone marrow cells (BMC). In the present study, metabolism of AzdU was investigated in human PBMC and BMC after exposure of cells to 2 or 10 microM [3H]AzdU. 3'-Azido-2',3'-dideoxyuridine-5'-monophosphate (AzdU-MP) was the predominant metabolite, representing approximately 55 to 65% of intracellular radioactivity in both PBMC and BMC at all times. The AzdU-5'-diphosphate and -5'-triphosphate intracellular levels were 10- to 100-fold lower than the AzdU-MP levels and, of note, AzdU-5'-triphosphate was not detected in human BMC. Using anion exchange chromatography, a new peak of radioactivity, distinct from any known anabolites, was detected. This chromatographic peak was found to be resistant to alkaline phosphatase but was hydrolyzed by 5'-phosphodiesterase, yielding AzdU-MP. Incubation of [3H]AzdU and D-[1-14C]glucose in PBMC and BMC produced a double-labeled peak with the same retention time as the anabolite, suggesting formation of a hexose derivative of AzdU. A novel high performance liquid chromatography method was developed that allowed for the separation of nucleosides, nucleotides, and carbohydrate derivatives thereof. Using this highly specific method, the putative AzdU-hexose actually was separated into two chromatographic peaks. These novel metabolites were identified as 3'-azido-2',3'-dideoxyuridine-5'-O-diphosphoglucose and 3'-azido-2',3'-dideoxyuridine-5'-O-diphospho-N-acetylglucosamine. Following 48 hr of incubation with [3H] AzdU, as much as 20 and 30% of these AzdU metabolites accumulated in PBMC and BMC, respectively. When AzdU was removed from the cell cultures, intracellular AzdU diphosphohexose concentrations decayed in a monophasic manner, with an elimination half-life of 14.3 hr. By 48 hr, levels of 0.3 pmol/10(6) cells were still detected, reflecting a gradual anabolism of these metabolites. Elimination of AzdU-MP and AzdU-5'-diphosphate was characterized by a two-phase process, with a short initial half-life of 0.83 and 0.24 hr and a long terminal half-life of 14.10 and 8.24 hr, respectively. Similar diphosphohexoses of deoxyuridine (dUrd) were also detected in human PBMC and BMC after exposure to [3H]dUrd, suggesting that dUrd derivatives are metabolized in a similar manner. In summary, the discovery of novel metabolic pathways for dUrd analogs demonstrates that AzdU has unique metabolic features that may contribute to the low toxicity of this anti-HIV agent in human BMC and also affect its mechanism of action.(ABSTRACT TRUNCATED AT 400 WORDS)

Antiviral Agents↗
PubMed1989

Pharmacokinetics and saturable renal tubular secretion of zidovudine in rats.

The purpose of this study was to assess the effects of dose on the pharmacokinetics of zidovudine (3'-azido-3'-deoxythymidine; AZT) in rats. Zidovudine (AZT) was administered intravenously at doses of 10, 50, 100, and 250 mg/kg. Plasma and urine AZT concentrations were determined by HPLC. Plasma AZT concentrations declined rapidly with a terminal half-life ranging from 0.76 h at a dose of 10 mg/kg to 1.58 h at 250 mg/kg. Total clearance (CLT) was similar at the doses of 10 and 50 mg/kg, with values of 2.80 and 2.73 L/h/kg, respectively. However, there was a trend toward nonlinearity at the dose of 100 mg/kg (CLT = 2.13 L/h/kg) and a significant decrease in CLT (1.22 L/h/kg) at the dose of 250 mg/kg. Nonrenal clearance remained unaffected by dose with a mean value of 0.98 L/h/kg. Renal clearance (CLR) was similar at the doses of 10 and 50 mg/kg, with values of 1.89 and 1.37 L/h/kg, respectively. However, significant decreases in CLR were observed at the doses of 100 (CLR = 1.30 L/h/kg) and 250 mg/kg (CLR = 0.57 L/h/kg). The maximum transport capacity (Tmax) and the Michaelis-Menten constant (Km) for renal tubular secretion obtained after simultaneously fitting plasma concentration-time profiles at the four doses to a renal clearance model were 215.5 +/- 82.1 mg/h and 119.3 +/- 80.5 mg/L, respectively, thereby yielding an unbound secretory intrinsic clearance (CLus,int) of 1.81 L/h. The high Tmax and Km values account for the high CLR of AZT and explain the linearity of CLR over a wide range of AZT plasma concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Structure-activity relationships of pyrimidine nucleosides as antiviral agents for human immunodeficiency virus type 1 in peripheral blood mononuclear cells.

The structure-activity relationships of several pyrimidine nucleosides related to 3'-azido-3'-deoxythymidine (AZT) were determined in human immunodeficiency virus type 1 (HIV-1) infected human peripheral blood mononuclear cells. These studies indicated that nucleosides with a 3'-azido group on the sugar ring exhibited the most potent antiviral activity. Substitution at C-5 with H, CH3, and C2H5 produced derivatives with the highest potency, whereas alkyl functions greater than C2, including bromovinyl substitution reduced the antiviral potency significantly. Changing the 3'-azido function to an amino or iodo group reduced the antiviral activity. Replacement of the uracil ring by cytosine or 5-methylcytosine produced analogues with high potency and low toxicity. Modification of the 5'-hydroxy group markedly reduced the antiviral activity. Similarly, various C-nucleoside analogues related to AZT and 2',3'-dideoxycytidine were inactive and nontoxic. From these systematic studies 3'-azido-2',3'-dideoxyuridine (5a), 3'-azido-5-ethyl-2',3'-dideoxyuridine (5c), and 3'-azido-2',3'-dideoxycytidine (7a) and its 5-methyl analogue (7b) were identified as potent and selective anti-HIV-1 agent in primary human lymphocytes.

Antiviral Agents↗
PubMed1989

Correlation between preferred sugar ring conformation and activity of nucleoside analogues against human immunodeficiency virus.

Analysis of the solid-state conformations of six active and two inactive anti-human immunodeficiency virus nucleoside analogues is used to correlate conformational features with the relative activities of the compounds. Ten of the 11 observations of the active compounds (3'-azido-3'-deoxythymidine, 3'-azido-2',3'-dideoxyuridine, 3'-azido-2',3'-dideoxy-5-ethyluridine, 2',3'-dideoxyadenosine, 2',3'-dideoxycytidine, and 3'-deoxythymidine) have C3'-exo sugar ring conformations. The only exception is one of the two molecules of 3'-deoxythymidine. Four have unusual low anti glycosyl link conformations coupled with unusual C3'-exo/C4'-endo sugar ring conformations. The inactive compounds, 2',3'-dideoxyuridine and 3'-(propyl-2-ene)-2',3'-dideoxyuridine, have C3'-endo conformations. The C3'-exo and C3'-endo conformations place C5' in axial and equatorial positions, respectively. This affects the location of the 5'-hydroxyl group in relation to the location of the base. The 5'-hydroxyl group is the site of phosphorylation of the nucleoside and the observation of this conformational preference of the active compounds may be of importance for the development of new nucleosides with activity against human immunodeficiency virus.

Antiviral Agents↗
PubMed1989

Phosphorylation of 3'-azido-2',3'-dideoxyuridine and preferential inhibition of human and simian immunodeficiency virus reverse transcriptases by its 5'-triphosphate.

3'-Azido-2',3'-dideoxyuridine-5'-triphosphate was found to be a potent and highly selective inhibitor of human immunodeficiency virus type 1 and simian immunodeficiency virus reverse transcriptases. The affinity of 3'-azido-2',3'-dideoxyuridine-5'-triphosphate for the reverse transcriptases was similar to that observed for 3'-azido-3'-deoxythymidine-5'-triphosphate. Both compounds were competitive inhibitors with respect to the normal substrate dTTP and served at least 100 times better as substrates than did dTTP. In contrast, cellular DNA polymerase alpha showed an about 60-times-higher preference for dTTP as substrate than for either inhibitor. The phosphorylation of thymidine in human peripheral blood mononuclear cell extracts was inhibited in a competitive manner by both 3'-azido-2',3'-dideoxyuridine and 3'-azido-3'-deoxythymidine, with apparent inhibition constants of 290 and 3.4 microM, respectively. The Michaelis-Menten constant, Km, for thymidine was 7.0 microM. 3'-Azido-2',3'-dideoxyuridine and 3'-azido-3'-deoxythymidine both served as substrates, with apparent Km values of 67 and 1.4 microM, respectively. The maximal rates of phosphorylation with 3'-azido-2',3'-dideoxyuridine and 3'-azido-3'-deoxythymidine were 40 and 30%, respectively, of the rate with thymidine. The different affinities of 3'-azido-2',3'-dideoxyuridine and 3'-azido-3'-deoxythymidine for the thymidine kinase and the Km values observed with these compounds as substrates may explain the difference in effects on human immunodeficiency virus type 1 replication in infected peripheral blood mononuclear cells observed when equimolar concentrations of the two compounds are compared.

Cells, Cultured↗
PubMed1989

Nucleosides. CXXXV. Synthesis of some 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-9H-purines and their biological activities.

Seven purine nucleosides containing the 2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl moiety were synthesized and tested for their antitumor activity. Direct condensation of 3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl bromide (1) with N6-benzoyladenine in CH2Cl2 followed by saponification of the product afforded the adenine nucleoside (I, 2'-F-ara-A). Deamination of I with NaNO2 in HOAc gave the hypoxanthine analogue (II, 2'-F-ara-H). The 6-thiopurine nucleoside (III, 2'-F-ara-6MP) was prepared by condensation of 1 with 6-chloropurine by the mercury procedure followed by thiourea treatment and saponification of the product. Methylation of III gave the 6-SCH3 analogue (IV). Raney Ni desulfurization of III afforded the unsubstituted purine nucleoside (V, 2'-F-ara-P). Condensation of 1 with 2-acetamido-6-chloropurine by the silyl procedure afforded the protected 2-acetamido-6-chloropurine nucleoside which served as the precursor for both the guanine and 6-thioguanine nucleosides (VI, 2'-F-ara-G and VII, 2'-F-ara-TG, respectively). Thus, alkaline hydrolysis of the precursor gave VI. Thiourea treatment prior to alkaline hydrolysis gave VII. The new nucleoside, 2'-F-ara-G (VI) is found to be selectively toxic to human T-cell leukemia CCRF-CEM.

Animals↗
PubMed1988

Synthesis and antiviral activity of various 3'-azido analogues of pyrimidine deoxyribonucleosides against human immunodeficiency virus (HIV-1, HTLV-III/LAV).

Various 3'-azido analogues of pyrimidine deoxyribonucleosides have been synthesized and tested against human immunodeficiency virus (HIV-1, HTLV-III/LAV) in human peripheral blood mononuclear cells. Among these compounds, the 3'-azido analogues of thymidine (2), 3-(3-oxo-1-propenyl)thymidine (21), 2'-deoxyuridine (1), 2'-deoxy-5-bromouridine(5), 2'-deoxy-5-fluorocytidine (19), 2'-deoxy-5-iodouridine (6), 2'-deoxycytidine (18), 2'-deoxy-5-fluorouridine (4), 2'-deoxy-5-thiocyoanatouridine (16), 2'-deoxy-5-methylcytidine (20), 2'-deoxy-5-aminouridine (7), and 2'-deoxy-5-hydroxyuridine (10) were found to have significant antiviral activity, with EC50 values of 0.002, 0.01, 0.2, 1.0, 1.0, 1.1, 1.2, 4.8, 5.1, 5.1, 6.2, and 10 microM, respectively. The structure-activity relationships are discussed.

Antiviral Agents↗
PubMed1983

Nucleosides. 123. Synthesis of antiviral nucleosides: 5-substituted 1-(2-deoxy-2-halogeno-beta-D-arabinofuranosyl)cytosines and -uracils. Some structure-activity relationships.

The syntheses of several 2'-halogeno-5-substituted-arabinofuranosylcytosines and -uracils are described, and relationships of structure to anti herpes virus activity in vitro were examined. Those arabinonucleosides containing the 2'-fluoro function exhibit, generally, more potent anti herpes virus (HSV) activity than do their 2'-chloro of 2'-bromo analogues. The importance of the fluorine in the 2'-"up" (arabino) configuration for enhancement of antiviral effectiveness is demonstrated by the superior activity of 2'-fluoro-5-iodo-ara-C [3a, FIAC] to that of 2'-fluoro-5-iodo-ribo-C. Of all the nucleosides tested herein, FIAC exhibited the most potent in vitro activity against HSV. 2'-Chloro-5-iodo- and -5-methyl-ara-C (3b and 4b) were 37 to greater than 500 times more effective in vitro against HSV type 2 than against type 1, suggesting that these latter derivatives might serve clinically as useful probes to distinguish between HSV types 1 and 2 in the diagnosis of HSV infections in man.

Animals↗
PubMed1982

C(2')-substituted purine nucleoside analogs. Interactions with adenosine deaminase and purine nucleoside phosphorylase and formation of analog nucleotides.

Four C(2')-substituted 2'-deoxyadenosines were examined as substrates for human erythrocytic adenosine deaminase and for formation of intracellular nucleotide analogs in human erythrocytes, lymphocytes and murine Sarcoma 180 cells: 9-(2'-deoxy-2'-fluoro-beta-D-ribofuranosyl)adenine, 9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)adenine, 9-(2'-azido-2'-deoxy-beta-D-ribofuranosyl)adenine (2'-N3-riboA) and 9-(2-azido-2'-deoxy-beta-D-arabinofuranosyl)adenine. All four adenosine analogs were substrates of human erythrocytic adenosine deaminase, but the corresponding inosine analogs (synthesized by the adenosine deaminase reaction) were highly resistant to cleavage by human erythrocytic purine nucleoside phosphorylase. Only 9-(2'-deoxy-2'-fluoro-beta-D-ribofuranosyl)hypoxanthine underwent very slow phosphorolysis, and no inhibition of inosine phosphorolysis was detected when a 30 microM concentration of any studied inosine analog was added to a reaction mixture containing 30 microM inosine (the Km concentration). Kinetic parameters were determined for the deamination of the adenosine analogs. The greatest affinity for adenosine deaminase was found with 2'-N3-ribo A (Ki = 2 microM), but the reaction velocity was highest with the F-substituted analogs. All four adenosine analogs formed triphosphate nucleotides after incubation with human erythrocytes, murine Sarcoma 180 cells, or human lymphocytes (tested only with the F analogs) in the presence of deoxycoformycin.

Adenosine Deaminase↗
PubMed1980

Effects of short-term dietary exposure to polychlorinated biphenyls on pharmacokinetics of intravenous pentobarbital in rats.

The intravenous pharmacokinetics of pentobarbital (30 mg/kg as pentobarbital sodium) in rats were studied at 0, 1, 2, 3, and 10 days after pretreatment with 0, 1, 5, 25, and 125 ppm of polychlorinated biphenyls in food. The polychlorinated biphenyls then were removed from the food, and the residual effects of the exposure on pentobarbital pharmacokinetics were studied at 15, 25, 45, and 70 days after initiation of the polychlorinated biphenyl exposure. The pharmacokinetics of pentobarbital were approximated to a one-compartment model. After pretreatment at 2 and 5 ppm for up to 10 days, all pentobarbital pharmacokinetic parameters obtained were comparable to control values. Pretreatment at 125 ppm significantly reduced the biological half-life and raised the total body elimination rate constant, total body clearance, and intrinsic clearance of pentobarbital after a 1-day exposure; all parameters apparently reached a new steady-state value by Days 5--10,. Enhanced pentobarbital elimination at 25 ppm was observed after a 3-day exposure, but, again, the elimination parameters appeared to have reached a steady state after 5--10 days of pretreatment. Upon removal of the polychlorinated biphenyls, the various pharmacokinetic parameters showed a lag phase prior to a gradual return to control values. The study shows that intrinsic clearances rather than total body clearances or half-lives are more appropriate in assessing enzymatic induction in agents undergoing facile liver metabolic clearance that borders on blood flow rate dependency.

Animals↗
PubMed1980

Effect of short-term exposure to polychlorinated biphenyls on first-pass metabolism of pentobarbital in rats.

The enhancement of the first-pass metabolism of orally administered pentobarbital in rats was examined after a 10-day exposure to food contaminated with polychlorinated biphenyls at 25 and 125 ppm. The degree of the first-pass effect and the influence of the polychlorinated biphenyl exposure were quantitated by comparing the areas under the plasma concentration--time curves after oral and intravenous dosing in control and treated animals. By using the clearance model and assuming that pentobarbital was eliminated totally by liver metabolism, the experimentally determined oral availability was predicted adequately from both the oral and intravenous data. The enhanced first-pass effect was principally in the intrinsic clearance term, although liver blood flow rates also appeared to be enhanced in animals treated with polychlorinated diphenyls at 125 ppm.

Animals↗
PubMed1980

Nucleosides. 116. 1-(beta-D-Xylofuranosyl)-5-fluorocytosines with a leaving group on the 3' position. Potential double-barreled masked precursors of anticancer nucleosides.

Syntheses of five pairs of cytosine and 5-fluorocytosinexylofuranosyl nucleosides in which the 3'-hydroxyl group is replaced by Cl, Br, OMs, or OTs are described. Those xylosyl nucleosides with a good leaving group at the 3' position exhibit good inhibitory activity against L5178Y and P815 mouse leukemic cells in vitro at rather low concentrations, and like that of ara-C this cytotoxicity is reversed by 2'-deoxycytidine but not by thymidine. Xylosylcytosines are not active against ara-C resistant lines of L5178Y and P815 cells; however, the corresponding 5-fluorocytosine analogues exhibit significant cytotoxicity against these ara-C resistant leukemic cell lines, and this activity is reversed by thmidine but not by deoxycytidine. These data support the "double-barreled" masked precursor hypothesis in that xylosyl-5-fluorocytosines substituted at the 3' position by a good leaving group exhibit activity akin to that of ara-C in the ara-C sensitive lines, while these nucleosides act as 5-fluoropyrimidines in the ara-C resistant lines.

Animals↗
PubMed1979

Metabolism and effects of 5-(beta-D-ribofuranosyl)isocytosine in P815 cells.

5-(beta-D-Ribofuranosyl)isocytosine (psi l Cyd), a C-nucleoside, has been shown to be active against P815 leukemia in mice. In P815 cells treated with [2-14C]psi l Cyd, we have detected radioactivity in nucleotide fractions and in RNA and DNA. Degradation to nucleosides of the labeled triphosphate nucleotide fraction and of RNA showed that the radioactivity present was chromatographically identical to psi l Cyd. Half-saturation concentrations for the incorporation of [2-14C]psi l Cyd into the triphosphate nucleotide fraction and into RNA and DNA were 370, 280, and 94 microgram/ml, respectively, which were greater than 100-fold higher than those for tritiated cytidine. The incorporation of psi l Cyd was competitively inhibited by cytidine. Phosphorylation and incorporation of psi l Cyd into nucleic acids of P815 cells and of a P815 subline resistant to 1-beta-D-arabinofuranosylcytosine are about 2- to 20-fold higher than in P815 sublines resistant to psi l Cyd or to both 5-azacytidine and 1-beta-D-arabinofuranosylcytosine. These data suggest that the phosphorylation of psi l Cyd and possibly its incorporation into nucleic acids are essential for therapeutic activity in P815 leukemias. In vitro metabolic studies also suggest that psi l Cyd and 5-azacytidine are cross-resistant and that P815 cells resistant to psi l Cyd are collaterally sensitive to 1-beta-D-arabinofuranosylcytosine. These predictions were confirmed by therapeutic experiments carried out in mice bearing P815 leukemias.

Animals↗