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1.
Synthesis of 2',3'-dideoxynucleosides by enzymatic trans-glycosylation   总被引:1,自引:0,他引:1  
Recently, several pyrimidine and purine 2',3'-dideoxynucleosides have been shown to inhibit the replication of the human immunodeficiency virus-1 (HIV), the causative agent of the acquired immune deficiency syndrome (AIDS). These compounds are usually prepared by reduction of the corresponding 2'-deoxynucleosides. The present experiments demonstrate that 2',3'-dideoxynucleosides can also be made by enzymatic trans-glycosylation, using the trans-N-deoxyribosylase from Lactobacillus helveticus. The broad specificity of this enzyme makes it possible to synthesize for metabolic studies radiochemically pure 2',3'-dideoxynucleosides, using diverse purine and pyrimidine base acceptors.  相似文献   

2.
Several 2',3'-dideoxynucleosides (ddNs), agents that inhibit the replication of human immunodeficiency virus and hepatitis B virus, enter mammalian cells by simple diffusion. In this report, we show that the membrane permeation of 2',3'-dideoxyguanosine (ddG) in human erythrocytes and CCRF-CEM cells, in contrast with that of other ddNs, is transporter-mediated. Inward fluxes of ddG in both cell types were inhibited by adenine, hypoxanthine, and acyclovir, but not by inhibitors of nucleoside transport (nitrobenzylthioinosine, dipyridamole, dilazep). Fluxes of ddG in human erythrocytes were attributable to a single, rate-saturable process (Km, 380 +/- 90 microM and Vmax, 7.9 +/- 0.8 pmol/s/microliter cell water) that was competitively inhibited by adenine (Ki, 16 microM). These results showed that ddG entered human erythrocytes and CCRF-CEM cells by a transporter-mediated process that was also the basis for entry of purine nucleobases. In contrast, inward fluxes of 2,6-diaminopurine-2',3'-dideoxyriboside (ddDAPR), a prodrug of ddG, were not affected by purine nucleobases or nucleoside transport inhibitors in either cell type. Thus, the permeation properties of ddDAPR resembled those of 2',3'-dideoxyadenosine, a diffusional permeant (cell uptake is transporter-independent), and contrasted with those of ddG, the deamination product of ddDAPR. This study demonstrated that the nucleobase moiety of ddNs is an important determinant of membrane permeation.  相似文献   

3.
As a first step toward improving dideoxynucleoside inhibition of human immunodeficiency virus replication in human lymphocytes, we examined the kinetics of 5'-phosphorylation of a series of 2',3'-dideoxynucleosides, using deoxycytidine kinase purified from human thymus extracts. Nucleosides with the 2'-deoxyribose moiety were activated 30 times faster than were 2',3'-dideoxynucleosides. The adenosine deaminase inhibitor, 2'-deoxycoformycin, showed an unexpected ability to inhibit purine and pyrimidine dideoxynucleoside phosphorylation; such inhibition was not competitive and was not observed when 2'-deoxycytidine was the substrate. 2'-Deoxycytidine, the natural substrate, inhibited dideoxynucleoside phosphorylation in a manner similar to that observed with 2'-deoxycoformycin. Thus, dideoxynucleosides are activated by deoxycytidine kinase through a different catalytic interaction than occurs in 5'-activation of 3'-hydroxynucleosides by this enzyme.  相似文献   

4.
The 2',3'-dideoxyriboside (ddDAPR), 2',3'-didehydro-2',3'-dideoxyriboside (ddeDAPR) and 3'-azido-2',3'-dideoxyriboside (AzddDAPR) of 2,6-diaminopurine have been previously recognized as potent inhibitors of human immunodeficiency virus replication. These compounds are also potent inhibitors of adenosine deaminase and inhibit the deamination of 9-beta-D-arabinofuranosyladenine (araA). ddDAPR, ddeDAPR and AzddDAPR markedly potentiate the antiviral activity of araA against herpes simplex virus type 1 (HSV-1), type 2 (HSV-2) and vaccinia virus (VV). When used at a concentration of 20 micrograms/ml, which had by itself no antiviral effect, ddDAPR, ddeDAPR and AzddDAPR increased the ability of araA to suppress HSV-1, HSV-2 and VV yield by several orders of magnitude. The maximum antiviral effect was obtained with the combinations of ddDAPR or ddeDAPR with araA concentrations of 1 and 10 micrograms/ml.  相似文献   

5.
There is a close linear correlation between the log partition coefficient (Pa) of a series of 2'-deoxyriboside (dR), 2',3'-didehydro-3'-dideoxyriboside (ddeR), 2',3'-dideoxyriboside (ddR), 3'-fluoro-2',3'-dideoxyriboside (FddR) and 3'-azido-2',3'-dideoxyriboside (AzddR) derivatives of uracil, cytosine, thymine, guanine, adenine and 2,6-diaminopurine and their retention times (Rt) on a Lichrospher 60 RP-8 HPLC column (correlation coefficient r greater than 0.970). Within each class of compounds the following order of increasing lipophilicity was noted: dR less than ddeR less than ddR less than FddR less than AzddR. A straight-forward structure-lipophilicity relationship for both base and sugar modified purine and pyrimidine 2',3'-dideoxynucleosides could be delineated.  相似文献   

6.
The 2',3'-dideoxyriboside of 2,6-diaminopurine(ddDAPR) is, like 2',3'-dideoxyadenosine (ddAdo), a potent and selective inhibitor of human immunodeficiency virus (HIV) in vitro. The ddDAPR compound inhibits HIV antigen expression and HIV-induced cytopathogenicity in MT4 cells at a 50% effective dose (ED50) of 2.5-3.6 microM, as compared to 3.1-6.4 microM for ddAdo. Both compounds are endowed with a high selectivity index: 112 for ddDAPR and 139 for ddAdo. The 2',3'-unsaturated derivatives of ddDAPR and ddAdo, i.e. ddeDAPR and ddeAdo, are considerably more cytotoxic and less effective against HIV than the parental compounds. Like ddAdo, ddDAPR is only weakly inhibitory to the proliferation and DNA and RNA synthesis of a series of human B-lymphoblast, T-lymphoblast and T-lymphocyte cell lines. In contrast to ddAdo, which is rapidly deaminated by beef intestine adenosine deaminase at an initial velocity (Vi) of 145 mumol/mg protein/min, ddDAPR and ddeDAPR are poor substrates for the enzyme (Vi: 8 and 0.7 mumol/mg protein/min, respectively), which further contributes to the potential of ddDAPR as a chemotherapeutic agent against AIDS.  相似文献   

7.
2',3'-Dideoxy-3'-fluoro-L-ribonucleosides were synthesized as potential antiviral agents. The key intermediate, methyl 5-O-benzoyl-2,3-dideoxy-3-fluoro-L-ribofuranoside, which was prepared from D-sorbitol, was condensed with pyrimidine and purine bases to obtain the respective nucleosides. Among them, the cytosine analogue 2',3'-dideoxy-3'-fluoro-alpha-L-cytidine showed a moderate anti-HBV activity.  相似文献   

8.
A series of 2',3'-didehydro-2',3'-dideoxynucleosides substituted with an alkynylhydroxy- (6, 7, 12 and 13) and alkynylamino- (20) groups at the C-5 position were synthesized. All these five target modified nucleosides were tested for anti-human immunodeficiency virus type 1 activity in CEM-SS and MT-4 cells and unfortunately displayed no improvement in antiviral activity.  相似文献   

9.
A series of 3'-(N-hydroxyimino)-2',3'-dideoxynucleosides bearing different nucleic bases has been prepared. In vitro antiviral activity studies showed that among these compounds the thymine derivative possesses significant activity against HIV, HSV, EBV and HBV. Conveniently 5'-protected 3'-(N-hydroxyimino)-2',3'-dideoxythymidine was further used as a synthon for the preparation of other nucleoside analogues.  相似文献   

10.
5'-Phosphites (5'-hydrogenphosphonates) of 2',3'-dideoxynucleosides (T, A, G, C) were synthesized and studied as inhibitors of human immunodeficiency virus type 1 (HIV-1) in MT4 and CEM13 cell cultures. It was shown that all 5'-phosphites effectively inhibit the production of viral antigens and protect cells from the cytotoxic effect of HIV infection. 5'-Phosphites were more active antiviral compounds than the corresponding nucleosides.  相似文献   

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