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PubMed1984

Quantitative determination of nucleosides and their phosphate esters--1. The acidic nucleosides, 3-deazauridine and 6-azauridine.

A relatively rapid, high-resolution chromatographic procedure, using mini-columns of DEAE cellulose equilibrated with 10 mM sodium phosphate, pH 6.0, is described in sufficient detail to permit ready replication. This initial paper demonstrates the quantitative separation, using suction, of the acidic nucleosides, 3-deazauridine and 6-azauridine, from their phosphorylated derivatives. The chemically stable, tritium-labeled nucleosides are eluted from the mini-columns (capacity approximately equal to 1.8 ml) with 10 mM sodium phosphate, pH 6.0; subsequently, the nucleotides are eluted completely with 0.5 M HCl/0.5 M NaCl. Quantitation is based on liquid scintillation counting of aliquots of the eluates.

3-Deazauridine↗
PubMed1985

Inhibition of HSV-transformed murine cells by nucleoside analogs, 2'-NDG and 2'-nor-cGMP: mechanisms of inhibition and reversal by exogenous nucleosides.

A murine cell line transformed with HSV TK (LH-1) exhibits a greatly enhanced cytotoxicity to the nucleoside analog 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy) methyl]guanine (2'-NDG) as compared to the parental LM cell line (I50 LH-1 = 0.4 microM; I50 LM = 44.4 microM). Toxicity of 2'-NDG for LH-1 and LM is reversed only by the addition of 100 microM thymidine (dThd), indicating that 2'-NDG is a substrate for the viral and cellular TK. In LM(TK-) cells--murine cells expressing no TK activity, 2'-NDG cytotoxicity is partially reversed only with dGuo. A cyclic phosphate derivative of 2'-NDG, 2'-nor-cGMP, contains a phosphodiester bond, is also taken up by cells, and does not depend on viral TK for activation. LH-1 cells and LM(TK-) cells are inhibited by similar concentrations of this analog (5.1 and 4.1 microM, respectively). In all three cell lines (LM, LH-1, LM(TK-], the toxicity of 2'-nor-cGMP is significantly reversed with dGuo or cyclic dGMP. This pattern of reversal differs significantly from that observed with 2'-NDG, suggesting that 2'-nor-cGMP is metabolized as a guanosine analog, similar to acyclovir, in LM and LM(TK-) cells. These results indicate that a cyclic monophosphate analog of 2'-NDG can be activated independently of viral TK expression and that cellular metabolic pathways resulting in elevated dGTP concentrations are important for reversal of toxicity induced by guanosine-like nucleoside analogs.

Acyclovir↗
PubMed1981

Nucleosides. 114. 5'-O-Glucuronides of 5-fluorouridine and 5-fluorocytidine. Masked precursors of anticancer nucleosides.

5'-O-Glucuronides of anticancer nucleosides, 5-fluorouridine and 5-fluorocytidine, were synthesized by three different methods. The best preparative procedure was the one starting from benzyl 5-O-(methyl 2', 3', 4'-tri-O-acetyl-beta-D-glucopyranosyluronate)-2,3-O-isopropylidene-beta-D-ribof uranoside (15) that was obtained almost quantitatively by condensation of benzyl 2,3-O-isopropylidene-beta-D-ribofuranoside (8) with methyl (2,3,4-tri-O-acetyl-alpha-D-glucopyranosyl bromide)uronate (2). After de-O-isopropylidenation of 15, the crystalline product, benzyl 5-O-(methyl 2', 3', 4'-tri-O-acetyl-beta-D-glucopyranosyluronate)-beta-D-ribofuranoside (16), was de-O-benzylated catalytically to 5-O-(methyl 2', 3', 4'-tri-O-acetyl-beta-glucopyranosyluronate)-D-ribofuranose (17). Compound 17 was acetylated to crystalline 5-O-(methyl 2',3',4'-tri-O-acteyl-beta-D-glucopyranosyluronate)-1,2,3-tri-O-acetyl-beta-D-ribofuranose (18) and condensed with trimethylsilylated 5-fluorouracil of 5-fluorocytosine in the presence of SnCl4 to afford the corresponding protected nucleosides 5 and 19 in good yields. Saponification of these compounds gave 5'-O-beta-D-glucuronides of 5-fluorouridine and 5-fluorocytidine (20 and 21) isolated as their crystalline N salts. These glucuronides were substrates of both bacterial and bovine beta-glucuronidase. They were, as expected, much less toxic against several leukemia cell lines in tissue culture.

Antineoplastic Agents↗
PubMed1984

Nucleosides. 129. Synthesis of antiviral nucleosides: 5-alkenyl-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracils.

Synthesis of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracils containing a vinyl (4a), 2-halovinyl (4b-d), or ethyl substituent at C-5 was achieved. These nucleosides were found to be about a log order less active than 2'-fluoro-5-iodo-ara-C (FIAC) against HSV-1, but they are much less cytotoxic against normal human lymphocytes than FIAC. Nucleosides 4a and 4e showed good activity against HSV-1 (ED50 = 0.16 and 0.24 microM, respectively) and HSV-2 (ED50 = 0.69 and 0.65 microM) with very little cytotoxicity (ID50 greater than 100 microM).

Animals↗
PubMed1996

Nucleoside conjugates. 15. Synthesis and biological activity of anti-HIV nucleoside conjugates of ether and thioether phospholipids.

A series of the anti-HIV nucleoside conjugates of either (1-O-alkyl) and thioether (1-S-alkyl) lipids linked by a pyrophosphate diester bond has been synthesized as micelle-forming prodrugs of the nucleosides to improve their therapeutic efficiency. These include AZT 5'-diphosphate-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (1), 3'-azido-2',3'-dideoxyuridine 5'-diphosphate-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (2) 2',3'-dideoxycytidine 5'-diphosphate-rac-1-S-octadecyl-2-O-palmitoyl-1-thioglycerol (3), and AZT 5'-diphosphate-rac-1-O-tetradecyl-2-O-palmitoylglycerol (4). The conjugates form micelles by sonication (mean diameters ranging 6.8-55.5 nm). Conjugate 1 protected 80% of HIV-infected CEM cells as low as 0.58 microM and lost the protection at 180 microM due to prevailing cytotoxicity, while the conjugate started to show the cytotoxicity at 100 microM. Pharmacokinetics studies showed a significant increase of half-life values (t1/2) of AZT and AZddU2 (respective t1/2 = 5.69 and 6.5 h) after administration of conjugates 1 and 2, while those after administration of AZT and AZddU were 0.28 and 0.89 h, respectively. The fractions of the prodrugs 1 and 2 converted to the parent compounds AZT and AZddU were 36% and 55%, respectively. The results indicate that AZT and AZddU thioether lipid conjugates 1 and 2 warrant further investigation.

Animals↗
PubMed1998

Nucleosides and nucleotides. 180. Synthesis and antitumor activity of nucleosides that have a hydroxylamino group instead of a hydroxyl group at the 2'- or 3'-position of the sugar moiety.

The design and synthesis of potential antitumor antimetabolites 2'-deoxy-2'-(hydroxylamino)uridine (15), -cytidine (19, 2'-DHAC), and -adenosine (35), their regioisomers, 3'-deoxy-3'-(hydroxylamino)uridine (40) and -cytidine (45, 3'-DHAC), and their 2'-deoxy analogues, 2', 3'-dideoxy-3'-(hydroxylamino)uridine (49) and -cytidine (52, 3'-dDHAC), are described. We measured the pKa values of the hydroxylamino group in 15 and 40 using 13C NMR spectroscopy as a function of pH to be 2.9 and 3.4, respectively. We also found that these nucleosides gradually decomposed in neutral solution but not in acidic solution. This decomposition may be related to the generation of aminoxy radicals at the sugar moiety. The in vitro cytotoxicity of these nucleosides was evaluated using L1210 and KB cells. 2'-DHAC (19) inhibited the growth of L1210 and KB cells, with IC50 values of 1.58 and 1.99 microM, respectively. 3'-DHAC (45) and 3'-dDHAC (52) were also cytotoxic against L1210 cells, with IC50 values of 4.03 and 1.84 microM, respectively, but not against KB cells. The cytotoxicity of 2'-DHAC (19) and 3'-DHAC (45) against L1210 cells in vitro was reversed by the addition of cytidine, while that of 3'-dDHAC (52) was reversed by 2'-deoxycytidine. 2'-DHAC (19) and 3'-dDHAC (52) mainly inhibited DNA synthesis in L1210 cells, while 3'-DHAC (45) inhibited RNA synthesis. We also evaluated the antitumor activities of 2'-DHAC (19) and 3'-DHAC (45) against murine Meth-A fibrosarcoma cells in vivo. 2'-DHAC (19) was more active than 3'-DHAC (45) when administered intravenously on days 1-10 consecutively at 10 mg/kg/day. 2'-DHAC (19) inhibited tumor growth at a rate of 66.9%.

Animals↗
PubMed2004

Complex peptidyl nucleoside antibiotics: efficient syntheses of the glycosyl nucleoside amino acid cores.

Employing an amino acid chiral template strategy, the present research describes a general and highly efficient protocol for the rapid construction of enantiopure furanosyl and pyranosyl nucleoside amino acid cores as present in various complex peptidyl nucleoside antibiotics. Starting from easily available d-serine, the strategy and the approach involve rapid and efficient stereoselective synthesis of five- or six-membered lactone amino alcohols, followed by incorporation of the required functionalities of the target molecules on these strategically functionalized chiral templates.

Anti-Bacterial Agents↗
PubMedDate not supplied

Structural determinants of HIV-1 reverse transcriptase stereoselectivity towards (beta)-L-deoxy- and dideoxy-pyrimidine nucleoside triphosphates: molecular basis for the combination of L-dideoxynucleoside analogs with non-nucleoside inhibitors in anti HIV chemotherapy.

We have compared the HIV-1 RT mutants containing the single substitutions L100I, K103N, V106A, V179D, Y181I and Y188L, known to confer NNI-resistance in treated patients, to HIV-1 RT wt for their sensitivity towards inhibition by D- and L-deoxy- and dideoxy-nucleoside tiphosphates. The results showed a differential effect of the substitutions on the affinity for both D- and L-enantiomers of deoxy- and dideoxy-nucleoside triphosphates and provide a rationale for the utilization of L-dideoxynucleoside analogs with NNI in combination chemotherapy.

Anti-HIV Agents↗
PubMed2003

Susceptibility of herpes simplex virus isolates to nucleoside analogues and the proportion of nucleoside-resistant variants after repeated topical application of penciclovir to recurrent herpes labialis.

Subjects received topical penciclovir for 4 days during successive episodes of recurrent herpes labialis. Isolation of herpes simplex virus (HSV) was attempted from lesions obtained before initiation of treatment and on each day of therapy. Isolates remained sensitive to penciclovir when tested by a plaque reduction assay, and there was no significant change in sensitivity during any treatment course or between successive treatments. The proportion of nucleoside-resistant variants present within a subset of these isolates was further investigated using a more-sensitive plating efficiency assay. Although the proportion of antiviral-resistant HSV variants increased on successive days, it invariably remained a minor subpopulation. Moreover, isolates from successive episodes obtained before treatment showed no change in the proportion of resistant HSV variants. We conclude that antiviral-resistant variants, which are readily detected in HSV isolates from peripheral lesions, do not accumulate in the sensory ganglia of immunocompetent patients receiving multiple courses of nucleoside analogues.

Acyclovir↗
PubMed1976

Nucleoside-3'-phosphotriesters as key intermediates for the oligoribonucleotide synthesis. III. An improved preparation of nucleoside 3'-phosphotriesters, their 1H NMR characterization and new conditions for removal of 2-cyanoethyl group.

An improved procedure for the transformation of 5'-O-monomethoxytrityl-2'-O-acetyl-3'-phosphates of uridine la, inosine ib and 6-N-benzoyladenosine lc into corresponding 3'/2,2,2-trichloroethyl, 2-cyanoethyl/-phosphates iiaic is reported. H NMR characterization of nucleoside 3'-phosphotriesters is presented. New conditions i.e. anhydrous triethylamine-pyridine treatment have been found for the selective removal of 2-cyanoethyl group from nucleoside 3'-phosphotriesters in the presence of neighbouring 2'-O-acetyl one.

Adenosine↗
PubMed2003

Nucleoside analogue mutations and Q151M in HIV-1 subtype A/E infection treated with nucleoside reverse transcriptase inhibitors.

OBJECTIVES: To investigate genotypic drug resistance in HIV-1 subtype A/E infection associated with failure of double/triple-nucleoside reverse transcriptase (RT) inhibitor therapy. METHODS: Patients from HIV-NAT 002 [stavudine (d4T)/didanosine (ddI) dose reduction study] and HIV-NAT 003 (zidovudine (ZDV)/lamivudine (3TC) versus ZDV/3TC/ddI) whose HIV-1 RNA was > 1000 copies/ml at week 48 and/or week 96 were tested for genotypic resistance. In both studies, after 48 weeks, patients were switched to the other dual or triple-nucleoside RT inhibitor (NRTI) either according to randomization or to the occurrence of virological failure. RESULTS: Resistance mutations found in the d4T/ddI, ZDV/3TC, and ZDV/3TC/ddI groups: none at baseline; at week 48, nucleoside analogue mutations (NAM), 2/17 (12%), 2/10 (20%), and 1/8; Q151M complex, 3/17 (18%), 0%, and 0%; M184V, 0%, 10/10 (P < 0.001), 3/8; V75T, 3/17 (18%), 0%, and 0%; L74V, 3/7 (18%), 0%, and 0%, respectively. At week 96, among the switchers, i.e., group A d4T/ddI to ZDV/3TC, group B ZDV/3TC to d4T/ddI, and group C ZDV/3TC/ddI to d4T/3TC/abacavir: NAM, 12/21 (57%), 4/7 and 1/3; Q151M, 4/21 (19%), 0% and 1/3, respectively. Interestingly, four or more NAM were observed in a higher proportion in group A (4/17 versus none in the others). CONCLUSIONS: Multi-NRTI resistance (NAM and Q151M) and M184V (only in 3TC failure) are commonly found in HIV-1 subtype A/E infection associated with NRTI failure. Suboptimal d4T/ddI therapy led to a high incidence of V75T and L74V mutations. Switching from d4T/ddI to ZDV/3TC may be associated with a higher incidence of four or more NAM. Thus, suboptimal and dual NRTI therapy is not recommended for global application.

Anti-HIV Agents↗
PubMed1991

Methanol esterification reactions catalyzed by snake venom and bovine intestinal 5'-nucleotide phosphodiesterases. Formation of nucleoside 5'-monophosphate methyl esters from guanosine 5'-triphosphate and other nucleoside 5'-polyphosphates.

It is not known whether the enzymes 5'-nucleotide phosphodiesterase/nucleotide pyrophosphatase (EC 3.1.4.1/EC 3.6.1.9) catalyze the transfer of nucleotides to acceptors other than water. We have investigated the action of snake venom and bovine intestinal mucosa phosphodiesterases on nucleoside 5'-polyphosphates in the presence of methanol. In those conditions, GTP was converted by snake venom phosphodiesterase to a mixture of GMP and another compound with a different retention time in reverse-phase high-performance liquid chromatography. That compound, by ultraviolet, 1H- and 13C-nuclear magnetic resonance spectroscopic analysis, and by enzyme analysis, was characterized as the methyl ester of GMP (GMP-OMe). The molar fraction [GMP-OMe]/[GMP + GMP-OMe] formed was higher than the molar fraction of methanol as a solvent in reaction mixtures. Similar reactions took place at comparable rates with snake venom and bovine intestinal mucosa phosphodiesterases using several nucleoside 5'-polyphosphates as substrates. The ability of 5'-nucleotide phosphodiesterases to catalyze transfer reactions to a non-water acceptor is relevant to the mechanism of the enzymes, to their use as analytical tools, and to their possible use/role in the preparative/in vivo synthesis of nucleotide esters.

Animals↗
PubMed2006

Inhibition of MRP1/ABCC1, MRP2/ABCC2, and MRP3/ABCC3 by nucleoside, nucleotide, and non-nucleoside reverse transcriptase inhibitors.

Many drug interactions with drugs used for the therapy of human immunodeficiency virus (HIV) occur at the level of different cytochrome P450 isozymes. Increasing evidence suggests that antiretrovirals may also modify activity and expression of active drug transport systems. Such interactions may alter drug absorption, elimination, and also drug distribution and reach clinical importance if thereby access to the target site is affected. Beyond P-glycoprotein, the family of multidrug resistance-related proteins (MRP/ABCC) substantially contributes to the elimination of numerous drugs and their metabolites. Because the interaction of MRPs with non-HIV protease inhibitor antiretrovirals has not been studied thoroughly, we investigated whether important non-nucleoside reverse transcriptase inhibitors (NNRTI) (delavirdine, efavirenz, and nevirapine), nucleoside reverse transcriptase inhibitors (NRTI) (abacavir, emtricitabine, and lamivudine), and tenofovir as a nonnucleotide reverse transcriptase inhibitor can interact with MRP1, MRP2, and MRP3 in vitro. Inhibition of these ABC transporters was quantified by confocal laser-scanning microscopy using the 5-chloromethylfluorescein diacetate assay. With the exception of abacavir, which had no effect on MRP3, all the test compounds increased intracellular 5-chloromethylfluorescein fluorescence in a concentration-dependent manner, and this effect was observed in all the overexpressing cell lines but not in the parental cell line, indicating inhibition of MRP1, MRP2, and MRP3. In conclusion, the present study provides the first evidence for a significant and concentration-dependent inhibition of MRPs by NNRTI, NRTI, and tenofovir, which was most pronounced for delavirdine, efavirenz, and emtricitabine, suggesting that this might contribute to some of the known drug interactions impairing HIV therapy and also to the superior effectiveness of combination pharmacotherapy.

Animals↗
PubMed2001

Nucleoside phosphate analogues of biological interest, and their synthesis via aryl nucleoside H-phosphonates as intermediates.

This review presents a brief account of the chemistry and mechanistic aspects of aryl H-phosphonates, and selected applications of this class of compounds as intermediates in the synthesis of a wide range of biologically important analogues of nucleoside phosphates, and oligonucleotides, in which the phosphate moieties are replaced by other structurally related groups. The aryl nucleoside H-phosphonates, compounds of controlled reactivity, have proven to be more versatile and superior to various mixed anhydrides as synthetic intermediates, particularly for preparation of nucleotide analogues bearing P-N or P-S bonds in various configurational arrangements at the phosphate moiety.

Catalysis↗
PubMed2000

Nucleosides, nucleotides and their biological applications--XIV International Roundtable. Recent Advances in Nucleosides Chemistry and Chemotherapy. 10-14 September 2000, San Francisco, CA, USA.

This satellite symposium honoring Dr Jack J Fox, provided a forum for reviewing recent advances in nucleoside research. The topics covered were: novel chemistries, applications to current problems in biology, antiviral and antitumor agents, and aspects of enzymology and mechanism of action of important nucleoside analogs.

Journal Article↗
PubMed1979

[Fractionation of nucleosides and nucleoside-5'-mono-, di and triphosphates by thin layer chromatography in silufol].

New solvent systems--dioxane--isopropanol--water--ammonium (4:2:4:1) and dioxane--water--ammonium (6:4:1)--for rapid qualitative and quantitative estimation of nucleosides, nucleoside-5'-mono-, di- and triphosphates by thin layer chromatography is Silufol UV-254 are proposed. The Rf values for 40 ribo- and deoxyribonucleotides of these systems are given.

Chromatography, Thin Layer↗
PubMed2006

A simple and efficient synthesis of puromycin, 2,2'-anhydro-pyrimidine nucleosides, cytidines and 2',3'-anhydroadenosine from 3',5'-O-sulfinyl xylo-nucleosides.

Synthesis of antibiotics, puromycin and 3'-amino-3'-deoxy-N6,N6-dimethyladenosine 11 was achieved by utilizing the cyclic sulfite 6a of the xylo-3',5'-dihydroxy group as a new protective group. The key synthetic step is the deprotection of the sulfite moiety through the intramolecular cyclization of 2-alpha-carbamate 7. In a similar manner 2,2'-anhydro-pyrimidine nucleosides 15, ribo-cytidines 17 and 2',3'-anhydroadenosine 14 were prepared in high yields from the corresponding sulfites 4, 5, and 6b, respectively.

Adenosine↗