Current prodrug strategies for improving oral absorption of nucleoside analogues

Nucleoside analogues are first line chemotherapy in various severe diseases:AIDS(acquired immunodeficiency disease syndrome),cytomegalovirus infections,cancer,etc.However,many nucleoside analogues exhibit poor oral bioavailability because of their high polarity and low intestinal permeability.In order to get around this drawback,prodrugs have been utilized to improve lipophilicity by chemical modification of the parent drug.Alternatively,prodrugs targeting transporters present in the intestine have been applied to promote the transport of the nucleoside analogues.Valacyclovir and valganciclovir are two classic valine ester prodrugs transported by oligopeptide transporter 1.The ideal prodrug achieves delivery of a parent drug by attaching a non-toxic moiety that is stable during transport,but is readily degraded to the parent drug once at the target.This article presents advances of prodrug approaches for enhancing oral absorption of nucleoside analogues.

Microwave-assisted Green and Efficient Synthesis of N^6-(2-Hydroxyethyl)adenosine and its Analogues

An efficient protocol for the synthesis of N^6-（2-Hydroxyethyl）adenosine and its analogues through nucleophilic substitution was developed. All the reactions were completed in 10 rain under microwave irradiation. Using water as solvent makes our method eco-friendly and easy to handle with.

Risk of hepatitis B virus reactivation in oncological patients treated with tyrosine kinase inhibitors:A case report and literature analysis

Hepatitis B virus(HBV)reactivation(HBVr)represents a severe and potentially life-threatening condition,and preventive measures are available through blood test screening or prophylactic therapy administration.The assessment of HBVr traditionally considers factors such as HBV profile,including hepatitis B surface antigen(HBsAg)and antibody to hepatitis B core antigen,along with type of medication(chemotherapy;immunomodulants).Nevertheless,consideration of possible patient’s underlying tumor and the specific malignancy type(solid or hematologic)plays a crucial role and needs to be assessed for decision-making process.

New strategies against drug resistance to herpes simplex virus

Herpes simplex virus （HSV）, a member of the Herpesviridae family, is a significant human pathogen that results in mucocutaneous lesions in the oral cavity or genital infections. Acyclovir （ACV） and related nucleoside analogues can successfully treat HSV infections, but the emergence of drug resistance to ACV has created a barrier for the treatment of HSV infections, especially in immunocompromised patients. There is an urgent need to explore new and effective tactics to circumvent drug resistance to HSV. This review summarises the current strategies in the development of new targets （the DNA helicase/primase （H/P） complex）, new types of molecules （nature products） and new antiviral mechanisms （lethal mutagenesis of Janus-type nucleosides） to fight the drug resistance of HSV.

Subclinical proximal tubulopathy in hepatitis B:The roles of nucleot(s)ide analogue treatment and the hepatitis B virus

BACKGROUND The recommended monitoring tools for evaluating nucleot(s)ide analogue renal toxicity,such as estimated glomerular filtration rate(eGFR)and phosphatemia,are late markers of proximal tubulopathy.Multiple early markers are available,but no consensus exists on their use.AIM To determine the 24 mo prevalence of subclinical proximal tubulopathy(SPT),as defined with early biomarkers,in treated vs untreated hepatitis B virus(HBV)-monoinfected patients.METHODS A prospective,non-randomized,multicenter study of HBV-monoinfected patients with a low number of renal comorbidities was conducted.The patients were separated into three groups:Naïve,starting entecavir(ETV)treatment,or starting tenofovir disoproxil(TDF)treatment.Data on the early markers of SPT,the eGFR and phosphatemia,were collected quarterly.SPT was defined as a maximal tubular reabsorption of phosphate/eGFR below 0.8 mmoL/L and/or uric acid fractional excretion above 10%.The prevalence and cumulative incidence of SPT at month 24(M24)were calculated.Quantitative data were analyzed using analyses of variance or Kruskal-Wallis tests,whereas chi-squared or Fisher’s exact tests were used to analyze qualitative data.Multivariate analyses were used to adjust for any potential confounding factors.RESULTS Of the 196 patients analyzed,138(84 naïve,28 starting ETV,and 26 starting TDF)had no SPT at inclusion.At M24,the prevalence of SPT was not statistically different between naïve and either treated group(21.1%vs 30.7%,P<0.42 and 50.0%vs 30.7%,P=0.32 for ETV and TDF,respectively);no patient had an eGFR lower than 50 mL/min/1.73 m²or phosphatemia less than 0.48 mmoL/L.In the multivariate analysis,no explanatory variables were identified after adjustment.The cumulative incidence of SPT over 24 mo(25.5%,13.3%,and 52.9%in the naïve,ETV,and TDF groups,respectively)tended to be higher in the TDF group vs the naïve group(hazard ratio:2.283,P=0.05).SPT-free survival at M24 was 57.6%,68.8%,and 23.5%for the naïve,ETV,and TDF groups,respectively.The median survival time without SPT,evaluated only in the TDF group,was 5.9 mo.CONCLUSION The prevalence and incidence of SPT was higher in TDF-treated patients compared to naïve patients.SPT in the naïve population suggests that HBV can induce renal tubular toxicity.

Hepatitis B in renal transplant patients

Hepatitis B virus(HBV) poses a significant challenge for both dialysis patients and kidney transplant recipients despite its decreasing rates, especially in developed countries. The best preventive method is vaccination. Patients with chronic renal disease should ideally be vaccinated prior to dialysis, otherwise, reinforced vaccination practices and close antibody titer monitoring should be applied while on dialysis. HBV infected dialysis patients who are renal transplant candidates must be thoroughly examined by HBV-DNA, and liver enzyme testing and by liver biopsy. When needed, one must consider treating patients with tenofovir or entecavir rather than lamivudine. Depending on the cirrhosis stage, dialysis patients are eligible transplant recipients for either a combined kidney-liver procedure in the case of decompensated cirrhosis or a lone kidney transplantation since even compensated cirrhosis after sustained viral responders is no longer considered an absolute contraindication. Nucleoside analogues have led to improved transplantation outcomes with both long-term patient and graft survival rates nearing those of HBs Ag(-) recipients. Moreover, in the cases of immunized HBs Ag(-) potential recipients with concurrent prophylaxis, we are enabled today to safely use renal grafts from both HBs Ag(+) and HBs Ag(-)/antiHBc(+) donors. In so doing, we avoid unnecessary organ discarding. Universal prophylaxis with entecavir is recommended in HBV kidney recipients and should start perioperatively. One of the most important issues in HBV(+) kidney transplantation is the duration of antiviral prophylaxis. In the absence of robust data, it seems that prophylactic treatment may be discontinued in selected stable, low-risk recipients during maintenance immunosuppression and should be reintroduced when the immune status is altered. All immunosuppressive agents in kidney transplantation can be used in HBV(+) recipients. Immunosuppression is intimately associated with increased viral replication; thus it is important to minimize the total immunosuppression burden long term.

Synthesis of 5-Substituted-3-[(2’R,4’R)-4’-Hydroxy-2’-hydroxymethyltetrahydrofuran-4’-yl]-1,2,4-oxadiazoles and Their Epimers

The syntheses of 5-substituted-3-[( 2’ R, 4’ R)-4 ’ -hydroxy-2 ’ -hydroxymethyltetra-hydrofuran-4’ -yl]D-1 ,2, 4-oxadiazoles and their epimers were accomplished with the aid of th construction of 1,2, 4-oxadiazoles by condensation of O-acylated cyanohydrins with hydroxylamine via intramolecular transacylation and subsequent cyclization.

Synthesis and Novel Properties of Alkyl Thiophosphoramidate Derivatives of Nucleosides

Novel alkyl thiophosphoramidate derivatives of nucleoside analogues (5) have been prepared by phosphochloridothioate chemistry. O Isopropyl 2′,3′ O isopropylidene uridine 5′ yl N thiophosphoryl threonine and serine methyl esters (5a and 5b) underwent the intramolecular catalyzed hydrolysis reaction.

Studies on Synthesis and Intramolecular Catalyzed Hydrolysis of Thiophosphoramidate Derivatives of Nucleoside

Novel thiophosphoramidate derivatives of nucleoside analogue as membrane-soluble prodrugs of the bioactive free nucleotides have been prepared by thiophosphorylation reaction. 2′,3′-O, O′-Isopropylidene uridine-5′-yl N-thiophosphoryl serine and threonine methyl esters underwent the intramolecular catalyzed hydrolysis reaction.

A New Synthetic Approach to Elvucitabine

A new synthetic approach to elvucitabine started from L-xylose via the reactions of 10 steps in an overall yield of 20% was developed. The key steps included trimethylsilyl trifluoromethanesulfonate（TMSOT0-mediated stereocontrolled β-glycosidation and exquisite choice of chloroacetyl group for the protection of hydroxyl groups as well as the corresponding deprotection under notably mild conditions. The structure of elvucitabine, in particular, the stereochemistry thereof, was unambiguously determined by comparison of the physical properties, such as 1H NMR data and the specific rotation, of the synthesized sample with those reported.

Comprehensive investigation of HBV-related hepatocellular carcinoma and choice of anti-HBV therapy

Chronic hepatitis B virus(HBV)infection is a global public health problem,which can cause chronic hepatitis,liver cirrhosis,hepatocellular carcinoma(HCC),and other diseases.Antiviral therapy is the most critical measure to slow down the progression of chronic hepatitis B,prevent or delay cirrhosis,HCC,and other kinds of liver decompensation events.At present,the anti-hepatitis B virus drugs are mainly nucleoside(acid)analogues(NAs)and interferon.Each kind of antiviral drug has different effects on the clinical outcome of hepatitis B patients(such as HCC).In this paper,we discussed the biological characteristics,natural course and prognosis of HBV infection,the mechanism of HBV-related HCC,the effect of different antiviral drugs on patients’outcome,predictive biomarkers and model for HBV clinical outcome,predictors of sustained response and recurrence after withdrawal of antiviral therapy,consideration of expanding therapeutic indications and antiviral therapy,hoping to give a hand to the clinical diagnosis and treatment of HBV.