共查询到20条相似文献,搜索用时 15 毫秒
1.
Roy A Schneller SW Keith KA Hartline CB Kern ER 《Bioorganic & medicinal chemistry》2005,13(14):4443-4449
As a surrogate for 4'-hydroxy-5'-noraristeromycin and related carbocyclic nucleosides, an efficient, enantiodivergent synthetic route to both enantiomers of 5-(6-amino-9H-purin-9-yl)-3,3-difluorocyclopentane-1,2-diol (6 and ent-6) has been developed from a common starting material ((+)-(1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate, 10). Both compounds were assayed versus a series of viruses. The only response found was for compound 6 toward vaccinia and cowpox (EC50 of 143 and 94 microM, respectively) and human cytomegalovirus (EC50 of 6.2 microM). Both compounds were non-cytotoxic. While not as active as cidofovir toward the orthopox viruses and ganciclovir toward cytomegalovirus, compound 6 offers a new structural prototype upon which to build for uncovering new agents effective against these viral types. 相似文献
2.
Carangio A McGuigan C Cahard D Andrei G Snoeck R De Clercq E Balzarini J 《Nucleosides, nucleotides & nucleic acids》2001,20(4-7):653-656
A series of alkyl-aryl, -phenoxy, and -thiophenoxy bicyclic furo pyrimidine nucleosides have been successfully synthesised by Pd-coupling of 5-iodo-2'-deoxyuridine (IDU) with terminal alkynes, followed by in situ copper-cyclisation. Synthesised compounds (4a-i) showed an anti-VZV activity at low microM concentration, comparable to that of current treatment acyclovir. 相似文献
3.
5-Formyl-2'-deoxyuridine-3',5'-diacetate was converted to a small library of 5-substituted pyrimidine nucleoside N-acylamino acid amides by means of a Ugi multicomponent reaction. The reaction allowed introduction of various substituents at the acyl moiety, at the amino acid alpha-amide group, and at the amino acid carboxyl function. Evaluation of these novel 5-substituted nucleosides against vaccinia virus and cowpox virus provided one compound with discernable activity against cowpox virus but five- to eightfold less active than the Cidofovir standard. More promising activity was seen for the inhibition of Leishmania donovani promastigotes. Several synthetic products showed antileishmanial activity in the 10(-5)M range. When compared to earlier studies demonstrating anti-orthopoxviral and antileishmanial activity of 5-substituted pyrimidine nucleosides, these results imply that the 5-(N-acylamino acid amide)-derivatized pyrimidine nucleosides may possess more steric bulk, greater hydrophobicity, and more flexibility than is compatible with these particular biological activities. 相似文献
4.
In this short review, including 187 references, the issues of biological activity of stilbene derivatives and nucleosides and the biological and medicinal potential of fusion of these two classes are discussed. The stilbenes, especially the stilbenoids, and nucleosides are both biologically active. Hybrids formed from binding of these compounds have not yet been broadly studied. However, those that have been investigated exhibit desirable medicinal properties. The review is divided in such parts: I. Derivative of stilbene (biomedical investigations, biological activities in cells, enzymes and hazard), parts II. naturally occurred nucleoside and its derivatives: uridine, thymidine and 5-methyluridine, cytidine, adenosine, guanosine and part III. hybrid molecules- drugs and hybrid molecules- nucleoside - stilbene and its derivative. 相似文献
5.
Escuret V Aucagne V Joubert N Durantel D Rapp KL Schinazi RF Zoulim F Agrofoglio LA 《Bioorganic & medicinal chemistry》2005,13(21):6015-6024
In this article, we report the synthesis of hitherto unknown 5-haloethynyl and 5-(1,2-dihalo)vinyluracil nucleosides in the 2'-deoxy, 3'-deoxy- and ribosyl series, and we discuss their in vitro anti-HIV and anti-HCV activities and cellular toxicitites. As a result, on the basis of their selectivity index (SI) obtained with the HCV replicon system, but also on their cytotoxicity on peripheral blood mononuclear, CEM and VERO cell lines, the best compounds were the 5-bromoethynyluridine (SI = 3.2) and the 5-(1-chloro-2-iodo)vinyluridine (SI > 2.8). 相似文献
6.
Mourier NS Eleuteri A Hurwitz SJ Tharnish PM Schinazi RF 《Bioorganic & medicinal chemistry》1999,7(12):44-2766
Base-modified carborane-containing nucleosides such as 5-o-carboranyl-2'-deoxyuridine (CDU) when combined with neutrons have potential for the treatment of certain malignancies. Lack of toxicity in various cells, high accumulation in cancer cells and intracellular phosphorylation are desirable characteristics for modified nucleosides used in boron neutron capture therapy (BNCT) for brain tumors and other malignancies. The aim of this work was to synthesize the two beta-enantiomers of several 5-o-carboranyl-containing nucleosides. These derivatives may possess favorable properties such as high lipophilicity, high transportability, the ability to be phosphorylated, and resistance to catabolism. Beta-isomers of 2',3'-dihydroxynucleosides and analogues containing a heteroatom in the sugar moiety were also synthesized. Carboranyl pyrimidine nucleosides were prepared either from the parent beta-D-nucleoside, beta-L-nucleoside, or by a coupling reaction. The dioxolane derivative 7 was prepared by a coupling reaction between protected 5-o-carboranyluracil (8, CU) and the corresponding protected heterocycle. Specific catalysts were used during the N-glycosylation process to favor the formation of the beta-isomer. Biological evaluation of these new chiral 5-o-carboranyl pyrimidine derivatives indicated that most of these compounds have low toxicity in a variety of normal and malignant cells and achieved high cellular levels in a lymphoblastoid cell line. Increasing the number of hydroxyl groups on the sugar moiety decreased the cellular accumulation and serum binding to different extents. Five compounds were identified for further biological evaluation as potential agents for BNCT. 相似文献
7.
The reaction of 5-azapyrimidine nucleosides Ia-IXa with zinc powder in acetic acid afforded the respective 5,6-dihydro derivatives Ib-IXb in high yields. This procedure represents a convenient and general method for preparation of the title compounds. The effects of some dihydro-5-azapyrimidine nucleosides on the growth in vitro of L1210 mouse leukemic cells were estimated. 相似文献
8.
Burthe S Telfer S Begon M Bennett M Smith A Lambin X 《The Journal of animal ecology》2008,77(1):110-119
1. Cowpox virus is an endemic virus circulating in populations of wild rodents. It has been implicated as a potential cause of population cycles in field voles Microtus agrestis L., in Britain, owing to a delayed density-dependent pattern in prevalence, but its impact on field vole demographic parameters is unknown. This study tests the hypothesis that wild field voles infected with cowpox virus have a lower probability of survival than uninfected individuals. 2. The effect of cowpox virus infection on the probability of an individual surviving to the next month was investigated using longitudinal data collected over 2 years from four grassland sites in Kielder Forest, UK. This effect was also investigated at the population level, by examining whether infection prevalence explained temporal variation in survival rates, once other factors influencing survival had been controlled for. 3. Individuals with a probability of infection, P(I), of 1 at a time when base survival rate was at median levels had a 22.4% lower estimated probability of survival than uninfected individuals, whereas those with a P(I) of 0.5 had a 10.4% lower survival. 4. At the population level, survival rates also decreased with increasing cowpox prevalence, with lower survival rates in months of higher cowpox prevalence. 5. Simple matrix projection models with 28 day time steps and two stages, with 71% of voles experiencing cowpox infection in their second month of life (the average observed seroprevalence at the end of the breeding season) predict a reduction in 28-day population growth rate during the breeding season from lambda = 1.62 to 1.53 for populations with no cowpox infection compared with infected populations. 6. This negative correlation between cowpox virus infection and field vole survival, with its potentially significant effect on population growth rate, is the first for an endemic pathogen in a cyclic population of wild rodents. 相似文献
9.
Characterization of three rabbit liver lysosomal proteinases with fructose 1,6-bisphosphatase converting enzyme activity 总被引:3,自引:0,他引:3
E Melloni S Pontremoli F Salamino B Sparatore M Michetti B L Horecker 《Archives of biochemistry and biophysics》1981,208(1):175-183
A large number of nucleoside analogs have been found to inactivate S-adenosylhomocysteine (AdoHcy) hydrolase in a time-dependent irreversible manner. There are two classes of these irreversible inhibitors: (A) analogs that inactivate the enzyme in a pseudofirst-order process and are devoid of any side chain at the 5′-OH group; (B) analogs that inactivate the enzyme in a time-dependent but curvilinear process, and generally have a side chain at the 5′ position. Among the more potent irreversible inhibitors are 2-chloroadenosine, 9-β-d-arabinofuranosyladenine (Ara-A), and (±)aristeromycin. Release of adenine base from adenosine or Ara-A in the presence of AdoHcy hydrolase was observed, thus supporting the proposed catalytic mechanism of AdoHcy hydrolase, that entails the transient formation of 3′-ketoadenosine during enzymatic catalysis of either the formation or hydrolysis of AdoHcy. Both Ara-A and adenosine may exert their irreversible inactivation by a suicide mechanism, but nucleosides such as 5′-iodo-5′-deoxyadenosine and 3′-deoxyadenosine are probably strictly irreversible inhibitors per se in view of the catalytic mechanism proposed for AdoHcy hydrolase. Labeling of AdoHcy hydrolase, perhaps covalent in nature, by radioactive Ara-A and adenosine was demonstrated by gel electrophoresis. 相似文献
10.
Direct comparison of radiolabeled probes FMAU, FHBG, and FHPG as PET imaging agents for HSV1-tk expression in a human breast cancer model 总被引:4,自引:0,他引:4
2'-Deoxy-2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (FMAU), 9-(4-fluoro-3-hydroxy-methyl-butyl)guanine (FHBG) and 9-[(3-fluoro-1-hydroxy-2-propoxy)methyl]-guanine (FHPG) have been evaluated in a human breast cancer model as potential radiotracers for PET imaging of HSV1-tk gene expression. In vitro accumulation of [14C]FMAU, [18F]FHBG, and [18F]FHPG in HSV1-tk-expressing cells was 14- to 16-fold (p <.001), 9- to 13-fold (p <.001), and 2- to 3-fold (p <.05) higher than tk-negative control cells, respectively, between 30 and 240 min. Accumulation of FMAU and FHBG in vector-transduced cells was 10- to 14-fold and 6- to 10-fold higher than wild-type cells, respectively. At 2 hr, uptake of [(14)C]FMAU in tkpositive cells was 6.3-fold and 60-fold higher than [18F]FHBG and [18F]FHPG, respectively. In vivo, tumor uptake of [14C]FMAU in HSV1-tk-expressing cells was 3.7-fold and 5.5-fold (p <.001) higher than tk-negative control cells at 1 and 2 hr, respectively. Tumor uptake of [18F]FHBG was 4.2-fold and 12.6-fold higher (p <.001) than tk-negative cells at the same time points. Incorporation of [14C]FMAU in tk-positive tumor was 18-fold and 24-fold higher (p <.001) than [18F]FHBG at 1 and 2 hr, respectively. Micro-PET images support the biodistribution results and indicate that both [18F]FMAU and [18F]FHBG are useful for imaging HSV1-tk expression in breast cancer. Although FMAU demonstrates higher total incorporation (%dose/g) in tumor tissue compared with the other tracers, FHBG is superior in terms of specific accumulation in transfected cells at later time points. 相似文献
11.
Cieśluk B Dzieciatkowski T Majewska A Łuczak M 《Medycyna do?wiadczalna i mikrobiologia》2008,60(2):163-168
Infections with human herpesviruses types 1 and 2 (HHV-1 and HHV-2) are common worldwide and cause a wide range of signs and symptoms. Antiviral drugs, in particular aciclovir are used in therapy of herpetic infections. The aim of the study was determination of susceptibilities of HHV-1 isolates (n+46) for antiviral drugs (acyclovir and cidofovir) in vitro. Swabs taken from different lesions were used for infection of Vero cells and cythopathic effect was observed. Viruses from cell cultures with positive CPE were later identified with in-house PCR and efficacy of acyclovir and cidofovir in HHV-1 infected Vero cell monolayer cultures was tested by the yield reduction assay. Obtained data indicate, that aciclovir ID50 average value for HHV-1 clinical isolates was 0.74 microg/ml--the value about 10% greater then described in literature. Similarly in vitro analysis of sensitivity of viruses for cidofovir, shows that concentrating is over ten-fold higher in comparison for aciclovir. 相似文献
12.
Cottrell DM Capers J Salem MM DeLuca-Fradley K Croft SL Werbovetz KA 《Bioorganic & medicinal chemistry》2004,12(11):2815-2824
A series of 5-thiocyanatomethyl- and 5-alkyl-3-aryl-1,2,4-oxadiazoles were synthesized and evaluated for their activity against kinetoplastid parasites. Formation of the oxadiazole ring was accomplished through the reaction of benzamidoximes with acyl chlorides, while the thiocyanate group was inserted by reacting the appropriate 5-halomethyl oxadiazole with ammonium thiocyanate. The thiocyanate-containing compounds possessed low micromolar activity against Leishmania donovani and Trypanosoma brucei, while the 5-alkyl oxadiazoles were less active against these parasites. 3-(4-Chlorophenyl)-5-(thiocyanatomethyl)-1,2,4-oxadiazole (compound 4b) displayed modest selectivity for L. donovani axenic amastigote-like parasites over J774 macrophages, PC3 prostate cancer cells, and Vero cells (6.4-fold, 3.8-fold, and 9.1-fold, respectively), while 3-(3,4-dichlorophenyl)-5-(thiocyanatomethyl)-1,2,4-oxadiazole (compound 4 h) showed 30-fold selectivity against Vero cells but was not selective against PC3 cells. In a murine model of visceral leishmaniasis, compound 4b decreased liver parasitemia caused by L. donovani by 48% when given in five daily i.v. doses at 5mg/kg and by 61% when administered orally for 5 days at 50 mg/kg. These results indicate that aromatic thiocyanates hold promise for the treatment of leishmanial infections if the selectivity of these compounds can be improved. 相似文献
13.
A gas-liquid chromatographic method employing on-column alkylation and a nitrogen-sensitive detector was developed for the analysis of 5-fluoro-2'-deoxyuridine, 5-fluorouridine, and 5-fluorouracil in plasma and urine. Samples (0.72 ml) containing the fluoropyrimidine and internal standard (5-chloro-2'-deoxyuridine for nucleoside analyses and 6-methyluracil for 5-fluorouracil analyses) were prepared for gas-liquid chromatography by sequential cation-exchange and anion-exchange column chromatography. Recoveries of fluoropyrimidines were 71-95% over the concentration ranges studied. The dried eluate from the anion-exchange column was dissolved in p-tolyltrimethylammonium hydroxide in methanol before gas-liquid chromatographic analysis. Columns packed with either 3% SP-2100 on Supelcoport or 3% OV-1 on Gas-Chrom Q were suitable for nucleoside analyses; a column packed with 0.75% Carbowax 20M-5% KOH on Chromsorb G was used for 5-fluorouracil analyses. The fluoropyrimidine nucleosides were well separated from each other and from the potentially interfering endogenous compounds 2'-deoxyuridine and uridine; 5-fluorouracil was well separated from uracil. Linear standard curves (peak area ratio method) were obtained for plasma containing 0.025 to 20 micrograms FdUrd (0.1 to 81 microM) or 0.05 to 1.0 microgram FUrd (0.2 to 3.8 microM), and for urine containing 0.2 to 1.0 microgram (0.8 to about 4 microM) of the nucleosides. Standard curves for 5-fluorouracil (1.5 to 7.9 microM) and 2'-deoxyuridine (0.9 to 4.4 microM) were also linear. A measurable amount of 5-fluorouracil, equivalent to 4 to 7% of the 5-fluoro-2'-deoxyuridine injected, was formed from the nucleoside on the gas-liquid chromatographic column, requiring correction of 5-fluorouracil concentrations measured in the presence of 5-fluoro-2'-deoxyuridine. 相似文献
14.
Kifli N Thet Htar T De Clercq E Balzarini J Simons C 《Bioorganic & medicinal chemistry》2004,12(12):3247-3257
Methodology previously described by us was applied to the formation of novel conformationally restrained bicyclic sugar modified nucleosides, with introduction of an oxazole and a thiocarbamate ring at the 2('),3(')-positions of the ribonucleosides. Two novel alkyl derivatives of 2('),3(')-dideoxy-2('),3(')-oxazole-beta-d-uridine and a novel uridine 2('),3(')-thiocarbamate were successfully synthesised. Conformational evaluation of all the synthesised compounds was conducted using the theoretical potential energy calculation via the macromodel v.6.0 molecular modelling programme. The conformationally restrained nucleosides described were evaluated against a wide range of DNA and RNA viruses. None of the compounds showed specific antiviral effects at subtoxic concentrations. 相似文献
15.
Ruiz J Beadle JR Buller RM Schreiwer J Prichard MN Keith KA Lewis KC Hostetler KY 《Bioorganic & medicinal chemistry》2011,19(9):2950-2958
Alkoxyalkyl esters of cidofovir (CDV) are orally active agents which inhibit the replication of a variety of double stranded DNA (dsDNA) viruses including variola, vaccinia, ectromelia, herpes simplex virus, cytomegalovirus, adenovirus and others. One of these compounds, hexadecyloxypropyl-CDV (HDP-CDV, CMX001) is in clinical development for prevention and treatment of poxvirus infection, vaccination complications, and for infections caused by cytomegalovirus, adenovirus, herpesviruses and other dsDNA viruses. This class of lipid analogs is potentially prone to undergo omega oxidation of the alkyl moiety which can lead to a short chain carboxylic acid lacking antiviral activity. To address this issue, we synthesized a series of alkoxyalkyl or alkyl glycerol esters of CDV and (S)-HPMPA having modifications in the structure of the alkyl residue. Antiviral activity was assessed in cells infected with vaccinia, cowpox or ectromelia viruses. Metabolic stability was determined in S9 membrane fractions from rat, guinea pig, monkey and human liver. All compounds had substantial antiviral activity in cells infected with vaccinia, cowpox or ectromelia. Metabolic stability was lowest in monkey liver S9 incubations where rapid disappearance of HDP-CDV and HDP-(S)-HPMPA was noted. Metabolic stability in monkey preparations increased substantially when a ω-1 methyl group (15-methyl-HDP-CDV) or a terminal cyclopropyl residue (14-cyclopropyl-tetradecyloxypropyl-CDV) was present in the alkyl chain. The most stable compound was 1-O-octadecyl-2-O-benzyl-sn-glycero-3-CDV (ODBG-CDV) which was not metabolized extensively by monkey liver S9. In rat, guinea pig or human liver S9 incubations, most of the modified antiviral compounds were considerably more stable. 相似文献
16.
Dietary nucleosides and nucleotides reduce Cryptosporidium parvum infection in dexamethasone immunosuppressed adult mice. 总被引:5,自引:0,他引:5
Numerous studies have demonstrated that dietary sources of nucleosides and nucleotides are important for the maintenance of cellular and humoral immune responses. To determine the immunological effects of feeding a nucleoside-nucleotide mixture to dexamethasone-immunosuppressed C57BL/6 adult mice infected with Cryptosporidium parvum, we examined fecal oocyst shedding, lymphoproliferative responses to concanavalin (Con) A, and C. parvum antigen, interleukin (IL-2), and gamma-interferon (IFN-gamma) production by cultured spleen cells. Mice were fed a nucleotide-free 20% casein diet (control group) or this diet supplemented with a 0. 5% nucleoside-nucleotide mixture before and after inoculation with C. parvum. Spleens from mice receiving the supplemented diet had higher (P < 0.05) Con A and antigen-specific induced cell proliferation than those from control mice. In addition to the increased cell proliferation, the spleen cells from the supplemented mice produced significantly more IL-2 (P < 0.002) and significantly more IFN-gamma (P <; 0.004) than cells from the control mice. Mice fed the supplemented diet excreted fewer (P < 0.05) C. parvum oocysts in the feces than control mice. The cumulative survival rate in the nucleoside-nucleotide mixture-fed group was higher compared with the control group (P < 0.05). We conclude that nucleosides and nucleotides may partially counteract the immunosuppressive effects of dexamethasone in C. parvum-challenged mice. 相似文献
17.
B Drewinko M A Dipasquale L Y Yang B Barlogie J M Trujillo 《Chemico-biological interactions》1985,55(1-2):1-12
Human tumor cells were treated in vitro with combinations of cis- or trans-dichlodiammineplatinum (DDP) and natural nucleosides (thymidine, uridine, cytidine and adenosine). Effects were measured by inhibition of colony-formation (cell survival) and DNA alkaline elution (DNA cross-links). No increments in cell lethality or DNA cross-links were elicited by any combination of trans-DDP and nucleosides. In contrast, every combination of cis-DDP and nucleoside was eminently synergistic with 5- and 10-fold increases in cell lethality over the predicted sum of each agent alone. These increments in cell kill correlated linearly with increases in DNA crosslinks suggesting that the nucleosides interact with cis-DDP to enhance its cytotoxic crosslinking mode of action. 相似文献
18.
Pchelintseva AA Skorobogatyj MV Petrunina AL Andronova VL Galegov GA Astakhova IV Ustinov AV Malakhov AD Korshun VA 《Nucleosides, nucleotides & nucleic acids》2005,24(5-7):923-926
Eight 5-alkynyl-2'deoxyuridines containing different bulky substituents have been prepared and tested against HSV-1 in Vero cells. The compounds show positive antiviral activity. There is no obvious correlation between activity and substituent size. The nature of the linker between uracil and a substituent appears to be more important for antiviral properties: nucleosides containing arylethynyl groups show higher activity. 相似文献
19.
Mikhailov SN Efimtseva EV Ermolinsky BS Bobkov GV Andreeva OI Golubeva AS Kochetkov SN Van Aerschot A Schepers G Herdewijn P 《Nucleosides, nucleotides & nucleic acids》2003,22(5-8):1117-1118
The efficient synthesis of oligonucleotides containing 2'-O-beta-D-ribofuranosyl (and beta-D-ribopyranosyl)nucleosides, 2'-O-alpha-D-arabinofuranosyl (and alpha-L-arabinofuranosyl)nucleosides. 2'-O-beta-D-erythrofuranosylnucleosides, and 2'-O-(5'-amino-5-deoxy-beta-D-ribofuranosyl)nucleosides have been developed. 相似文献
20.
Krzysztof Dziewiszek Raymond F. Schinazi Ting-Chao Chou Tsann-Long Su Jolanta M. Dzik Wojciech Rode 《Nucleosides, nucleotides & nucleic acids》2013,32(1-3):77-94
Abstract A number of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)uracil and -cytosine nucleosides substituted at the 5 position with a nitrophenyl or nitrobenzyl group were synthesized from 5-phenyl- and 5-benzyluracil via condensation of the fluorinated sugar, followed by nitration. The corresponding amino analogues were also prepared by reduction of the nitro nucleosides. The uracil nucleosides were converted into the corresponding cytosine nucleosides by way of the triazole intermediates. None of these nucleosides exhibited significant activity against herpes simplex virus type 1 in Vero cells. However, cytosine nucleosides containing the o-nitrophenyl, p-nitrophenyl, p-nitrobenzyl or p-aminobenzyl substituent were found to be toxic (even at 1 μM) to uninfected Vero cells, although they were essentially nontoxic in HL-60 cells. The 5′-monophosphates of the uracil nucleosides were inhibitors of the reaction catalyzed by purified Ehrlich ascites carcinoma thymidylate synthase, the 5-phenyluracil nucleotides causing a strong inhibition, competitive vs dUMP, described by the Ki value of 0.01 μM. 相似文献