SYNTHESIS AND ANTIVIRAL ACTIVITY OF NOVEL EXOMETHYLENE CYCLOPROPYL NUCLEOSIDES

Novel cyclopropyl nucleosides were synthesized as potential antiviral agents. The key intermediate 5, prepared from Feist's acid 1 was condensed with purine derivatives by the S_N2 type reaction. All the synthesized compounds were evaluated for antiviral activity.     

A Convenient Synthesis of Acyclic Adenosines with an Unsaturated Side Chain by Modification of 9-(2,3-O-Isopropylidene-D-Ribityl)Adenine

Abstract

In expectation of discovering their antiviral activity, acyclic adenosine derivatives 7, 11, 12, and 16 were designed as analogs of neplanocin A (NPA) and L-eritadenine which are strong inhibitors of S-adenosyl-L-homocysteine hydrolase. The 1′,5′-seco-analog of 4′-deoxymethyl-NPA (DHCA) 7 was synthesized by dideoxygenation of 9-(2,3-O-isopropylidene-D-ribityl)adenine (2). Acyclic DHCA analogs 11 and 16 were obtained by Wittig reaction of the aldehyde 3 with Ph₃P=CHCO₂Et and Ph₃P=CHCN, respectively. Hydrolysis of the ester 11 afforded a vinylog of L-eritadenine 12. The synthesized acyclic nucleosides 7, 10, and 11 were evaluated for antiviral activity, however, none of them showed any significant antiviral activity.     

Synthesis and Biological Study of the Cyclopentenyl Carbocyclic Nucleoside Analogue of 5-Azacytidine

Abstract

Cyclopentenyl cytosine (CPE-C, 3) possesses excellent antitumor and antiviral activity. The synthesis of the analogous cyclopentenyl triazine nucleoside, 5-aza-CPE-C (4), was accomplished by a novel approach that utilized a key 1-cyclopentenyl-4-methylisobiuret intermediate (7) produced from the corresponding cyclopentenylamine 5. 5-Aza-CPE-C was more than six-hundred times less potent than CPE-C both in its capacity to reduce CTP levels as well as in its antitumor and antiviral activity.     

Methylenecyclopropane Analogues of Nucleosides: Synthesis,Absolute Configuration,and Enantioselectivity of Antiviral Effect of (R)-(-)- and (S)-(+)-Synadenol

Abstract

Synthesis, absolute configuration and antiviral activity of enantiomeric antiviral agents (R)-(-)- and (S)-(+)-synadenol (2 and 3a) are described.     

Synthesis and Antiviral Activities of Enantiomeric 1-[2-(Hydroxymethyl) Cyclopropyl] Methyl Nucleosides

Abstract

Cyclopropyl carbocyclic nucleosides have been synthesized from the key intermediate 2 which was converted to the mesylated cyclopropyl methyl alcohol 3. Condensation of compound 3 with various purine and pyrimidine bases gave the desired nucleosides. All synthesized nucleosides were evaluated for antiviral activity and cellular toxicity. Among them adenine 22 and guanine 23 derivatives showed moderate antiviral activity against HIV-1 and HBV. None of the other compounds showed any significant antiviral activities against HIV-1, HBV, HSV-1 and HSV-2 in vitro up to 100μM.     

Synthesis and Biological Evaluation of Pyrimidine Nucleosides Fused with 3′,4′-Tetrahydrofuran Ring

Abstract

Pyrimidine nucleosides fused with 3′,4′-tetrahydrofuran ring were synthesized, starting from 1,2;5,6-di-O-isopropylidene-D-glucose and assayed for antiviral activities. Thymine analogue 1 and its corresponding 2′-deoxy analogue 3 exhibited high cytotoxicity instead of giving antiviral activities.     

Synthesis,Antiviral and Cytostatic Activities of Carbocyclic Nucleosides Incorporating a Modified Cyclopentane Ring. Part 2:1 Adenosine and Uridine Analogues

Abstract

Six new carbocyclic nucleosides were prepared by mounting a purine (compounds 5–7), 8-azapurine (compounds 9 and 10) or pyrimidine (compound 13) base on the amino group of (1R,cis)-3-(aminornethyl)-1,2,2-trimethylcyclopentylmethanol (2). The antiviral activity of compounds 5–7, 10 and 13, and their cytostatic activity, were evaluated. At subtoxic concentrations, the compounds showed no or marginal antiviral activity. Compound 5 showed moderate inhibition on tumor cell proliferation.     

组织蛋白酶S抑制塞内卡病毒在IBRS-2细胞中的复制

[目的] 本研究旨在探究猪源组织蛋白酶S （cathepsin S,CTSS）对塞内卡病毒（Seneca Valley virus,SVV）复制的影响。[方法] SVV感染IBRS-2细胞,采用RT-qPCR在转录水平探究SVV感染对内源性CTSS表达的调控;采用ELISA测定SVV感染对CTSS酶活性的影响;通过Western blotting （WB）和RT-qPCR检测过表达CTSS对SVV复制及SVV诱导的抗病毒细胞因子的调控作用;合成针对CTSS的特异性siRNA,利用WB和RT-qPCR检测siRNA对CTSS的干扰效果以及CTSS被干扰后对SVV复制的影响。[结果] 结果表明SVV感染IBRS-2细胞能显著上调内源性CTSS表达并增强CTSS酶活性;过表达CTSS能显著抑制SVV在IBRS-2细胞中的复制,同时促进宿主抗病毒细胞因子的表达;siRNA-2947下调内源性CTSS表达进而促进SVV复制。[结论] CTSS通过增强宿主抗病毒细胞因子上调表达而抑制SVV复制,本研究为进一步深入探究宿主CTSS在抗SVV免疫应答中的作用及机制提供参考依据。     

SYNTHESIS AND ANTIVIRAL EVALUATION OF 3′-C-TRIFLUOROMETHYL NUCLEOSIDE DERIVATIVES BEARING ADENINE AS THE BASE

3′-deoxy-3′-C-trifluoromethyl- (3), 2′,3′-dideoxy-3′-C-trifluoromethyl- (5) and 2′,3′-dideoxy-2′,3′-didehydro-3′-C-trifluoromethyladenosine (6) derivatives have been synthesized and their antiviral properties examined. All these derivatives were stereospecifically prepared by glycosylation of adenine with a trifluoromethyl sugar precursor (1), followed by appropriate chemical modifications. The prepared compounds were tested for their activity against HIV, but they did not show an antiviral effect.     

Design,Synthesis and Anti-HIV Activity of Homologous PMEA Derivatives

This article describes an efficient route for synthesizing novel cyclopropyl homologous PMEA analogues. The condensation of the bromide 8 with nucleosidic bases (A, U, T, C, 5-FU, G) under standard nucleophilic substitution and deprotection conditions, afforded the target phosphonic acid analogues 14～18 and 21. These compounds were evaluated for their potential antiviral properties against various viruses. Guanine derivative 21 showed significant antiviral activity.     

Antiviral activity of an aqueous extract derived from Aloe arborescens Mill. against a broad panel of viruses causing infections of the upper respiratory tract

BackgroundA number of antiviral therapies have evolved that may be effectively administered to treat respiratory viral diseases. But these therapies are very often of limited efficacy or have severe side effects. Therefore there is great interest in developing new efficacious and safe antiviral compounds e.g. based on the identification of compounds of herbal origin.HypothesisSince an aqueous extract of Aloe arborescens Mill. shows antiviral activity against viruses causing infections of the upper respiratory tract in vitro we hypothesised that a product containing it such as Biaron C^® could have an antiviral activity too.Study designAntiviral activity of Bioaron C^®, an herbal medicinal product consisting of an aqueous extract of Aloe arborescens Mill., Vitamin C, and Aronia melanocarpa Elliot. succus, added as an excipient, was tested in vitro against a broad panel of viruses involved in upper respiratory tract infections.MethodsThese studies included human adenovirus and several RNA viruses and were performed either with plaque reduction assays or with tests for the detection of a virus-caused cytopathic effect.ResultsOur studies demonstrated an impressive activity of Bioaron C^® against members of the orthomyxoviridae – influenza A and influenza B viruses. Replication of both analysed influenza A virus strains – H1N1 and H3N2 – as well as replication of two analysed influenza B viruses – strains Yamagatal and Beiying – was significantly reduced after addition of Bioaron C^® to the infected cell cultures. In contrast antiviral activity of Bioaron C^® against other RNA viruses showed a heterogeneous pattern. Bioaron C^® inhibited the replication of human rhinovirus and coxsackievirus, both viruses belonging to the family of picornaviridae and both representing non-enveloped RNA viruses. In vitro infections with respiratory syncytial virus and parainfluenza virus, both belonging to the paramyxoviridae, were only poorly blocked by the test substance. No antiviral activity of Bioaron C^® was detected against adenovirus – a non-enveloped DNA virus.ConclusionsThese results represent the first proof of a selective antiviral activity of Bioaron C^® against influenza viruses and create basis for further analyses of type and molecular mechanisms of the antiviral activity of this herbal medicine.     

Selective Synthesis and Application to the Synthesis of (E)-Fluorovinyl Nucleosides

A selective method for synthesizing (E)-fluorovinyl was developed. Novel acyclic (E)-fluorovinyl versions of neplanocin A were designed and selectively synthesized as potential antiviral agents. The condensation of the bromide 7 with the nucleosidic bases (5-FU, C, A, G) and the deprotection afforded the desired acyclic fluorovinyl nucleosides. The synthesized compounds 11, 12, 13, and 16 were evaluated for their antiviral activity. The guanine derivative 16 showed toxicity-dependent anti-HIV-1 activity in MT-4 cells.     

Preparation and Antiviral Activity of Several Deoxygenated Ribavirin and Tiazofurin Derivatives

Abstract

Ribavirin and tiazofurin, two nucleosides of known antiviral activity, have been transformed by previously reported methods to yield several deoxy,epoxy, or dideoxy analogues. The deoxygenated derivatives were evaluated for antiviral activity against a host of DNA and RNA viruses; however, no significant in vitro activity was detected.     

SYNTHESIS AND IN VITRO ANTIVIRAL ACTIVITY EVALUATION OF 9-(2-AZIDO-2,3-DIDEOXY-β-D-THREO-PENTOFURANOSYL)ADENINE DERIVATIVES

9-(2-Azido-2,3-dideoxy-β-D-threo-pentofuranosyl)adenine derivatives (1a–e) containing a lipophilic function at the N-6 position in the purine ring were prepared and evaluated for their antiviral activity. The compounds 1a–e turned out to be inactive as antiviral agents.     

Synthesis of Racemic 5-Substituted 1-(2,3-Dihydroxypropyl)-6-azauracils and Their Isosteric Isomers

Abstract

Acyclic nucleoside analogues of antiviral DHPA and HPMPA have been prepared. Coupling of silylated 6-azauracils with benzyl glycidyl ether and stannic chloride followed by the deprotection with boron trichloride gave 1-(2,3-dihydroxypropyl)-6-azauracils (3) in good overall yields. Reaction of silylated 6-azauracil and epichlorohydrin with or without catalytic stannic chloride afforded 1-(2-chloro-3-hydroxypropyl)-6-azauracil (4a) and 1-(3-chloro-2-hydroxypropyl)-6-azauracil (6a) respectively. Coupling of silylated 6-azaisocytosine under the same reaction conditions provided 1-(2,3-dihydroxypropyl)-6-azaisocytosine (9) and 1-(2-chloro-3-hydroxypropyl)-6-azaisocytosine (10) respectively. None of the compounds exhibited significant antiviral activity against herpes simplex viruses.     

Phosphorylation of Anti-HIV Nucleoside Analogs by Nucleoside Diphosphate Kinase

Abstract

The reaction of NDP kinase with antiviral nucleoside triphosphates used in antiviral therapies was studied at the presteady state by fluorescence stopped-flow and compared with the steady-state parameters. The affinity of the analogs was determined by fluorescence titration of a mutated enzyme with an inserted Trp in the binding site. The lack of the 3′ hydroxyl in analogs is shown to decrease the k_cat more than the K_D.     

Inhibition of HAdV-14 induced apoptosis by selenocystine through ROS-mediated PARP and p53 signaling pathways

BackgroundHuman Adenovirus (HAdV) can cause severe respiratory symptoms in people with low immunity and there is no targeted treatment for adenovirus infection. Anti-adenoviral drugs have high clinical significance for inhibiting adenovirus infection. Selenium (Se) plays an important role in anti-oxidation, redox signal transduction, and redox homeostasis. The excellent biological activity of Se is mainly achieved by being converted into selenocystine (SeC). Se participates in the active sites of various selenoproteins in the form of SeC. The ability of SeC to resist the virus has raised high awareness due to its unique antioxidative activity in recent years. The antiviral ability of the SeC was determined by detecting the infection rate of the virus in the cells.MethodsThe experiment mainly investigated the antiviral mechanism of SeC by locating the virus in the cell, detecting the generation of ROS, observing the DNA status of the cell, and monitoring the mitochondrial membrane potential.ResultsIn the present study, SeC was designed to resist A549 cells infections caused by HAdV-14. SeC could prevent HAdV-14 from causing cell apoptosis-related to DNA damage. SeC significantly inhibited ROS generation and protect the cells from oxidative damage induced by ROS against HAdV-14. SeC induced the increase of antiviral cytokines such as IL-6 and IL-8 by activating the Jak2 signaling pathway, and repaired DNA lesions by suppressing ATR, p53, and PARP signaling pathways.ConclusionSeC might provide an effective selenium species with antiviral properties for the therapies against HAdV-14.     

Straightforward Synthesis of 1-(2,3-Dideoxy-β-D-Glycero-Pent-2-Enofuranosyl)-Thymine

Abstract

A two steps synthesis of the antiviral drug (d4T) 3 from thymidine 1 is proposed, which implies a concomitant deprotection-elimination process by action of t-BuOK in DMF on 5′-O-t-butyldimethylsylil-3′-O-methanesulfonyl-thymidine 2.     

Synthesis and Antiviral Evaluation of 2-Mercapto-5,6-dichlorobenzimidazole-β-D-ribofuranonucleoside Derivatives

Abstract

2-Mercapto-5,6-dichlorobenzimidazole β-D-ribofuranonucleoside derivatives 8–10 have been synthesized and their antiviral properties examined. According to the glycosylation procedure used, the β-D-N-1 isomer (and the N, N-bis-riboside) or the β-D-S²-isomer have been obtained. All the prepared compounds were tested for their activity against a variety of RNA and DNA viruses, but they did not show significant antiviral activity.     

Synthesis and Evaluation of 2′,3′-Dideoxy-9-Deazaadenoslne and Some Related Derivatives

Abstract

In this paper we report the synthesis of 2′,3′-dideoxy-9-dearaadenosine (2) and the corresponding 2′,3′-unsaturated- and 3′-deoxy- analogs, 6 and 8. These C-nucleosides are very stable towards acid and thus overcome one of the main drawbacks of 2′,3′-dideoxy-purine-nucleosides, such as the antiviral agent 2′,3′-dideoxyadenosine (ddA). However, evaluation of these compounds and some related 2′-deoxy derivatives (10-14) in the antiviral assay for the human immunodeficiency virus has revealed no significant activity.