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.     

Design and synthesis of carbocyclic versions of furanoid nucleoside phosphonic Acid analogues as potential anti-hiv agents

Novel 5'-norcarbocyclic adenine and guanine phosphonic acid analogues with 6',6'-difluorine moiety were designed and synthesized from commercially available epichlorohydrin 5. A regioselective Mitsunobu reaction successfully proceeded from an allylic functional group 16b at low reaction temperature in polar cosolvent to give purine phosphonate analogues 17 and 24, respectively. The purine nucleoside phosphonate and phosphonic acid analogues were subjected to antiviral screening against HIV-1. Adenine analogue 21 and its SATE prodrug 29 show significant anti-HIV activity in MT-4 cell lines.     

Bicyclic anti-VZV nucleosides: thieno analogues bearing an alkylphenyl side chain have reduced antiviral activity

Thieno analogues of the potent and selective furo-pyrimidine anti-VZV nucleoside family bearing a p-alkylphenyl side chain have been synthesised and tested for their antiviral activity against Varicella-Zoster virus (VZV). While the alkyl chain analogues were shown to retain full antiviral activity against VZV, these new analogues did not when compared to their furo parent nucleosides.     

Synthesis of novel 4'-cyclopropyl-5'-norcarbocyclic adenosine phosphonic acid analogues

Novel 4'-cyclopropyl-5'-norcarbocyclic adenosine phosphonic acid analogues were designed and racemically synthesized from propionaldehyde 5 through a de novo acyclic stereoselective route using triple Grignard addition and ring-closing metathesis (RCM) as key reactions. To improve cellular permeability and enhance the anti-HIV activity of this phosphonic acid, SATE phosphonodiester nucleoside prodrug 23 was prepared. The synthesized adenosine phosphonic acids analogues 17, 18, 19, 21, and 23 were subjected to antiviral screening against HIV-1. Compound 23 exhibits enhanced anti-HIV activity than its parent nucleoside phosphonic acid 18.     

Synthesis of novel 6'-spirocyclopropyl-5'-norcarbocyclic adenosine phosphonic Acid analogues as potent anti-hiv agents

Novel 5'-norcarbocyclic adenosine phosphonic acid analogues with 6'-electropositive moiety such as spirocyclopropane were designed and synthesized from the commercially available diethylmalonate 5. Regioselective Mitsunobu reaction proceeded in the presence of an allylic functional group at a low reaction temperature in polar cosolvent [dimethylformamide (DMF)/1,4-dioxane] to give purine analogue 15. To improve cellular permeability and enhance the anti-human immunodeficiency virus (HIV) activity of this phosphonic acid, a SATE phosphonodiester nucleoside prodrug 23 was prepared. The synthesized adenosine phosphonic acids analogues 18-21 and 23 were subjected to antiviral screening against HIV-1.     

Lipophilic phosphoramidates as antiviral pronucleotides

In order to overcome restrictions imposed by activation (phosphorylation) mechanism of antiviral and antitumor nucleoside analogues several prodrug approaches have been designed. Lipophilic pronucleotides are capable of intracellular delivery of monophosphates of nucleoside analogues, thus circumventing the limitations of enzymic phosphorylation. One of the successful approaches employs lipophilic amino acid ester (alanine) phenyl phosphoramidates as pronucleotides. This approach was applied to AIDS drugs such as AZT, d4T and related analogues but also to nonclassical nucleoside analogues based on allenic and methylenecyclopropane structure. Antiviral effects of the parent analogues were in many cases increased by conversion to phenyl phosphoralaninate (PPA) pronucleotides. Although cytotoxicity increase frequently accompanies antiviral effects of these pronucleotides, a favorable selectivity index can be obtained by manipulation of the parent structure as shown, e.g., for 2,6-diaminopurine methylenecyclopropane pronucleotide 15c. A lack of in vivo toxicity was demonstrated for 2-amino-6-methoxypurine methylenecyclopropane pronucleotide 15e in mice. The PPA pronucleotides can overcome deficiency of phosphorylating enzymes and offer favorable cross-resistance patterns when compared with other antiviral drugs.     

Efficient Electrophilic Fluorination for the Synthesis of Novel 2′-Fluoro-3′-Methyl-5′-Deoxyphosphonic Acid Apiosyl Nucleoside Analogues

Novel 5′-deoxyapiosyl purine phosphonic acid analogues with a 2′-electropositive moiety, such as, a fluorine atom were designed and synthesized from commercially available hydroxylacetone. Condensation of a glycosyl donor 10 with purines under Vorbruggen conditions and cross-metathesis give the desired nucleoside phosphonic acid analogues 14, 17, 21, and 24. The synthesized nucleoside analogues were subjected to antiviral screening against HIV-1, and the adenine analogue 17 exhibited weak in vitro anti-HIV-1 activity (EC₅₀ = 26.6 μM)     

抗病毒核苷酸类似物磷酸化修饰研究进展

核苷(酸)类似物是一类抗病毒前药,其进入人体细胞后经过逐步磷酸化生成核苷三磷酸类似物发挥抗代谢药作用,主要通过抑制病毒复制和促进侵染细胞凋亡,达到疾病治疗效果.其中,核苷类似物在细胞内经激酶活化的代谢转化过程通常是不充分的,导致最后生成的核苷三磷酸类似物浓度较低,降低了作用效果.因此,通过直接制备核苷酸类似物作为抗病毒...     

Fluoroanalogues of anti-cytomegalovirus agent cyclopropavir: synthesis and antiviral activity of (E)- and (Z)-9-{[2,2-bis(hydroxymethyl)-3-fluorocyclopropylidene]methyl}-adenines and guanines

Synthesis of fluorinated cyclopropavir analogues 13a, 13b, 14a, and 14b is described starting from alkene 15. Addition of carbene derived from dibromofluoromethane gave bromofluoro cyclopropane 16. Reduction (compound 17) followed by desilylation gave intermediate 18, which was transformed to 2-nitrophenylselenenyl derivative 19. Oxidation to selenoxide 20 was followed by beta-elimination to afford methylenecyclopropane 21. Addition of bromine provided compound 22 for alkylation-elimination of adenine and 2-amino-6-chloropurine. The resultant E,Z isomeric mixtures of methylenecyclopropanes 23a + 24a and 23c + 24c were resolved and the individual isomers were deprotected to give adenine analogues 13a and 14a as well as compounds 13c and 14c. Hydrolytic dechlorination of 13c and 14c furnished guanine analogues 13b and 14b. The only significant antiviral effects were observed with analogue 13a against HCMV and 14a against VZV in cytopathic inhibition assays.     

Heterocyclic nucleoside analogues: design and synthesis of antiviral, modified nucleosides containing isoxazole heterocycles

We have designed and synthesized novel antiviral nucleoside analogues, which consist of isoxazole rings as modified sugars and nucleobases (thymine, uracil, and 5-fluorouracil) with a methylene linker between them. These compounds represent a new class of modified nucleoside analogues and some of them show potent antiviral activities against Polio virus (Coxsackie B type 3 and Vesicular Stomatitis).     

Are 5'-O-carbamate-2',3'-dideoxythiacytidine new anti-HIV and anti-HBV nucleoside drugs or prodrugs?

In contrast to 5'-O-carbonate 3TC derivatives (23, 24), which are clearly 3TC prodrugs, the corresponding 3TC carbamates (15-21 and 25), found to be very stable compounds with respect to enzymatic hydrolysis (cellular lysates and culture cell media) and still active on both HIV-1 and HBV infected cells, may not be 3TC prodrugs. The antiviral properties as well as the mechanism of action of 3TC analogues have been studied and evaluated.     

Efficacy of S-adenosylhomocysteine hydrolase inhibitors, D-eritadenine and (S)-DHPA, against the growth of Cryptosporidium parvum in vitro

D-eritadenine and (S)-DHPA are aliphatic adenosine analogues known to target S-adenosylhomocysteine hydrolase (SAHH) and potent antiviral compounds. In the present study, we demonstrate that these two compounds also display efficacy against recombinant SAHH enzyme of the protozoan parasite Cryptosporidium parvum, as well as inhibition of parasite growth in vitro. Our data confirm that SAHH could serve as a rational drug target in cryptosporidial infection and antiviral adenosine analogues are potential candidates for drug development against cryptosporidiosis.     

Design of nucleoside, oligonucleotide and polynucleotide analogues as antiviral agents

Several approaches can be envisaged in the design of nucleoside and oligo- or polynucleotide analogues with selective antiviral activity: (i) deoxythymidine (dThd) or deoxycytidine (dCyd) analogues which are specifically recognized as substrate by the virus-induced dThd-dCyd kinase; (ii) adenosine analogues which impair transmethylation reactions (or polyamine biosynthesis), by virtue of an inhibition of S-adenosylhomocysteine hydrolase; (iii) (2'-5')-oligonucleotide analogues derived from pppA(2'p5'A)2, an important intermediate in the antiviral action of interferon; (iv) oligo(deoxy)nucleotides that are complementary to a well-defined nucleotide sequence of the viral genome; (v) single-stranded homopolynucleotides that act as antitemplates for virus-associated RNA or DNA polymerases; and (vi) double-stranded homopolynucleotides that may be pursued for their interferon-inducing potentials.     

慢性乙型肝炎抗病毒治疗研究进展

乙肝病毒的慢性感染是肝纤维化、肝细胞癌的重要病因,积极有效地抗病毒治疗,可显著改善HBV感染者的生活质量。干扰素、核苷（酸）类药物的抗乙肝病毒疗效已得到全球公认,本文就上述两类药物的研究进展进行综述。     

ACYCLIC/CARBOCYCLIC GUANOSINE ANALOGUES AS ANTI-HERPESVIRUS AGENTS

Several guanosine analogues, i.e. acyclovir (and its oral prodrug valaciclovir), penciclovir (in its oral prodrug form, famciclovir) and ganciclovir, are widely used for the treatment of herpesvirus [i.e. herpes simplex virus type 1 (HSV-1), and type 2 (HSV-2),varicella-zoster virus (VZV) and/or human cytomegalovirus (HCMV)] infections. In recent years, several new guanosine analogues have been developed, including the 3-membered cyclopropylmethyl and-methenyl derivatives (A-5021 and synguanol) and the 6-membered D-and L-cyclohexenyl derivatives. The activity of the acyclic/carbocyclic guanosine analogues has been determined against a wide spectrum of viruses, including the HSV-1, HSV-2, VZV, HCMV, and also human herpesviruses type 6 (HHV-6), type 7 (HHV-7) and type 8 (HHV-8), and hepatitis B virus (HBV). The new guanosine analogues (i.e. A-5021 and D- and L-cyclohexenyl G) were found to be particularly active against those viruses (HSV-1, HSV-2, VZV) that encode for a specific thymidine kinase (TK), suggesting that their antiviral activity (at least partially) depends on phosphorylation by the virus-induced TK. Marked antiviral activity was also noted with A-5021 against HHV-6 and with D- and L-cyclohexenyl G against HCMV and HBV. The antiviral activity of the acyclic/carbocyclic nucleoside analogues could be markedly potentiated by mycophenolic acid, a potent inhibitor of inosine 5′-monophosphate (IMP) dehydrogenase. The new carbocyclic guanosine analogues (i.e. A-5021 and D- andL-cyclohexenyl G) hold great promise, not only as antiviral agents for the treatment of herpesvirus infections, but also an antitumor agents for the combined gene therapy/chemotherapy of cancer, provided that (part of) the tumor cells have been transduced by the viral (HSV-1, VZV) TK gene.     

Acyclic/carbocyclic guanosine analogues as anti-herpesvirus agents

Several guanosine analogues, i.e. acyclovir (and its oral prodrug valaciclovir), penciclovir (in its oral prodrug form, famciclovir) and ganciclovir, are widely used for the treatment of herpesvirus [i.e. herpes simplex virus type 1 (HSV-1), and type 2 (HSV-2), varicella-zoster virus (VZV) and/or human cytomegalovirus (HCMV)] infections. In recent years, several new guanosine analogues have been developed, including the 3-membered cyclopropylmethyl and -methenyl derivatives (A-5021 and synguanol) and the 6-membered D- and L-cyclohexenyl derivatives. The activity of the acyclic/carbocyclic guanosine analogues has been determined against a wide spectrum of viruses, including the HSV-1, HSV-2, VZV, HCMV, and also human herpesviruses type 6 (HHV-6), type 7 (HHV-7) and type 8 (HHV-8), and hepatitis B virus (HBV). The new guanosine analogues (i.e. A-5021 and D- and L-cyclohexenyl G) were found to be particularly active against those viruses (HSV-1, HSV-2, VZV) that encode for a specific thymidine kinase (TK), suggesting that their antiviral activity (at least partially) depends on phosphorylation by the virus-induced TK. Marked antiviral activity was also noted with A-5021 against HHV-6 and with D- and L-cyclohexenyl G against HCMV and HBV. The antiviral activity of the acyclic/carbocyclic nucleoside analogues could be markedly potentiated by mycophenolic acid, a potent inhibitor of inosine 5'-monophosphate (IMP) dehydrogenase. The new carbocyclic guanosine analogues (i.e. A-5021 and D- and L-cyclohexenyl G) hold great promise, not only as antiviral agents for the treatment of herpesvirus infections, but also an antitumor agents for the combined gene therapy/chemotherapy of cancer, provided that (part of) the tumor cells have been transduced by the viral (HSV-1, VZV) TK gene.     

Achievements and prospects of the directed search for antiviral agents in the nucleoside series and their derivatives]

Recent advances of antiviral drug design among nucleosides and their derivatives have been summarized. The first chapter deals with the history of nucleic acids components and further developments in this area. Next part discusses the mechanism of action of biologically active nucleosides: 2',3'-dideoxynucleosides, acyclic analogues, phosphonate derivatives and nucleoside antibiotics. The third chapter describes planning of complicated synthesis of nucleoside analogues from branched-chain sugars and stereo-specific formation of glycosidic bond upon synthesis of ribonucleoside and 2'-deoxyribonucleoside. The last part outlines further perspectives, i. e. preparation of antiviral compounds and use of nucleoside analogues in oligonucleotide synthesis.     

Some new acyclic nucleotide analogues as antiviral prodrugs: synthesis and bioactivities in vitro

A series of ester analogues of acyclic nucleotide PMPA and PMEA were synthesized as potent antiviral agents. The antiviral evaluation results indicated that bis benzyl ester prodrug of PMPA 5f and bis allyl ester prodrug of PMEA 5g exhibited potent antiviral activities. The IC(50) of 5f for HBV was 2.15 microM, and the IC(50) of 5g for HIV-1 was 1.61 microM.     

核苷类药物酶法合成研究进展

由于核苷类似物具有很高的抗病毒活性,因为而已成为医药工作者研究的重点。运用酶法合成核苷类似物．已经显示了巨大的优势。本文综述了酶法合成核苷类似物的产生菌种和酶系,以及它们的催化机理,并罗列了已经用于生产或较有使用价值的菌种。     

Synthesis, antiviral, and antitumor activity of 2-substituted purine methylenecyclopropane analogues of nucleosides

The Z- and E-2-fluoro- and 2-chloropurine methylenecyclopropanes 9a,b and 10a,b as well as enantiomeric Z-isoguanine methylenecyclopropanes 11a,b and their phenyl phosphoralaninate pronucleotides 11c,d were synthesized and their antiviral activity against several viruses was evaluated. Fluoro analogues 9a and 10a were active against human cytomegalovirus but they were cytotoxic at approximately the same concentrations. Chloro derivatives 9b and 10b were non-cytotoxic and effective against Epstein-Barr virus in Daudi cells. Isoguanine analogues 11a-d lacked antiviral activity but pronucleotides 11c,d were substrates for porcine liver esterase. From the group of 9a,b and 10a,b, the fluoro analogues 9a and 10a exhibited antitumor activity but only the Z-isomer 9a had a selective effect.