Acyclic Nucleoside Analogues Research Articles

Synthesis of Novel Acyclic Nucleoside Analogues with Anti-Retroviral Activity

A series of novel acyclic thymine nucleoside analogues were prepared by the Mitsunobu reaction from appropriately protected chiral triols. The enantiomeric triols were obtained from substituted γ-lactone acids, prepared by asymmetric oxidation of 3-substituted-1,2-cyclopentanediones. The cytotoxic activity of new analogues was evaluated on MCF-7 human breast cancer and HeLa cells, and antiviral activities on human immunodeficiency virus type 1 and hepatitis C virus models. The synthesized compounds revealed specific anti-retroviral activity and no cytotoxic side effects.

Synthesis and antiviral evaluation of new 2,5-disubstituted 1,3,4-oxadiazole derivatives and their acyclic nucleoside analogues

A number of new 5-[(naphthalen-1-yloxy)-methyl]-1,3,4-oxadiazole derivatives were synthesized. Sugar 2-[5-[(naphthalen-1-yloxy)methyl]-1,3,4-oxadiazol-2-ylthio]acetohydrazones were prepared by condensation of the hydrazide with the corresponding monosaccharides. Cyclization of the sugar hydrazones with acetic anhydride afforded the substituted oxadiazoline derivatives. The synthesized compounds displayed different degrees of antiviral activities or inhibitory actions against HCV and HIV viruses.

The unsaturated acyclic nucleoside analogues bearing a sterically constrained ( Z)-4′-benzamido-2′-butenyl moiety: Synthesis, X-ray crystal structure study, cytostatic and antiviral activity evaluations

A series of the novel acyclic unsaturated pyrimidine ( 1– 12) and adenine ( 13) nucleoside analogues bearing conformationally restricted ( Z)-2′-butenyl moiety were synthesized and evaluated for their antiviral and cytostatic activity potency against malignant tumor cell lines and normal human fibroblast (WI38). The N-1 and/or N-3 acyclic side chain substitution in pyrimidine ring in N-3 substituted 5-trifluoromethyluracil derivative ( 11), N-1, N-3 disubstituted 5-fluorouracil derivative ( 12) and adenine derivative ( 13) was deduced from their 1H and 13C NMR spectra and confirmed by single crystal X-ray structure analysis. The X-ray crystal structure analysis 11– 13 revealed also supramolecular self-assemblies, in which infinite chains or dimers built two- and three-dimensional networks. The results of the in vitro cytostatic activity evaluations of 1–13 indicate that the majority of the compounds tested exhibited a non-specific and moderate antiproliferative effect at the highest concentration (100 μM). Of all evaluated compounds on the cell lines tested only the N-1 4″-fluoro-substituted-benzamide uracil derivative ( 7) showed rather marked and selective inhibitory activity against the growth of MCF-7 cells at a concentration of 2.7 μM and no cytotoxic effect on normal fibroblasts WI38. This compound can be therefore considered as a potential antitumor lead compound for further synthetic structure modification.

Synthesis of Novel 6-Azapyrimidine Acyclic Nucleoside Analogues and Antiviral Evaluation

Acyclic nucleosides have been of considerable interest since the approval of aciclovir by the FDA to be used as an antiviral agent in the 1990s. The acyclic moieties and the bases used in the experiment were either available commercially or synthesized using literature methods. Vorbrüggen coupling method was utilized involving reaction of persilylated heterocyclic bases with the appropriate acyclic moiety in the presence of a Lewis acid catalyst. A series of novel 6-azapyrimidine acyclic oxosugar nucleosides was successfully synthesized with a promising yield (more than 50%). An efficient method of protection and deprotection was also investigated.

ChemInform Abstract: Incorporation of Serinol-Derived Acyclic Nucleoside Analogues into Oligonucleotides: Influence on Duplex and Triplex Formation.

Abstract Phosphoramidites 6a-c were readily prepared by an original route and used to incorporate serinol derived units I–III in oligonucleotides which, compared to their natural analogues, exhibited a decreased htbridization capacity for duplex and triplex formation.

ChemInform Abstract: Synthesis and Cytostatic Activity of Nucleosides and Acyclic Nucleoside Analogues Derived from 6-(Trifluoromethyl)purines.

ChemInform Abstract: Synthesis and Cytostatic Activity of Nucleosides and Acyclic Nucleoside Analogues Derived from 6-(Trifluoromethyl)purines.

QSAR Studies on HSV-1 Inhibitors by CoMFA, CoMSIA and HQSAR Approaches

HSV infection has high incidence rate and high prevalence. HSV-1 may cause cold sores, fever blisters, and encephalitis. Moreover, HSV-1 has the ability to cause the latent infection of neurons. Therefore, the QSAR studies of HSV-1 inhibitors and drug design based on QSAR have great importance. This paper focused on the pyrazolo[1,5- a]pyridines, which are not acyclic nucleoside analog. The reported pyrazolopyridines showed potent and selective inhibition activity. In order to find novel compounds with higher activity and to develop better predictive models, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and hologram quantitative structure activity relationship (HQSAR) methods were performed on a series of HSV-1 inhibitors. The models built by CoMFA, CoMSIA, and HQSAR were found to be suitable for the compounds investigated with good predictive power (CoMFA q2=0.669, R2=0.953; CoMSIA q2=0.693, R2=0.919; HQSAR q2=0.619, R2=0.921). 3D contour maps obtained from PLS models of CoMFA and CoMSIA, and the atom contribution map from PLS model of HQSAR indicated that small steric volumes and electron-withdrawing groups in the R2, R3 regions would be useful to improve the activity. Results showed that the established models of the present work would be helpful in studying the relationship between the bioactivity and the molecular structures and discovering more potent HSV-1inhibitors.

Photochemical Synthesis of Nucleoside Analogues from Cyclobutanones: Bicyclic and Isonucleosides

The preparation of two nucleoside analogues are reported. Both syntheses involve a key photochemical ring-expansion of cyclobutanones to an oxacarbene and its subsequent scavenging by 6-chloropurine. The synthesis of a bicyclic (locked) purine starts from a oxabicycloheptanone with a hydroxymethyl pendant. The preparation of an isonucleoside uses a cyclobutanone with an α-substituted 6-chloropurine. Irradiation of the latter produces an isonucleoside and acyclic nucleoside analogues.

Synthesis of some novel hydrazono acyclic nucleoside analogues

The syntheses of novel hydrazono acyclic nucleosides similar to miconazole scaffolds are described. In this series of acyclic nucleosides, pyrimidine as well as purine and other azole derivatives replaced the imidazole function in miconazole and the ether group was replaced with a hydrazone moiety using phenylhydrazine. To interpret the dominant formation of (E)-hydrazone derivatives rather than (Z)-isomers, PM3 semiempirical quantum mechanic calculations were carried out which indicated that the (E)-isomers had the lower heats of formation.

Synthesis, cytostatic and anti-viral activity evaluation of the novel acyclic nucleoside analogues containing a sterically constrained (Z)-4-amino-2-butenyl moiety

A series of the novel pyrimidine (3–6) and purine (12–15, 18–21) acyclic nucleoside analogues in which the sugar moiety was replaced by a sterically constrained Z-4-amino-, 4-aminohydrochloride-2-butenyl, or aliphatic 4-aminohydrochloride-2-butyl moiety were synthesized and evaluated for their anti-viral and cytostatic activity potency. Cytostatic evaluation of the novel compounds on selected panel of human tumour-cell lines showed that the majority of compounds exerted a non-specific anti-proliferative effect at the highest tested concentration (i.e. 1 × 10−4 M) against all cell lines. Nevertheless, a rather moderate but selective anti-proliferative effects on HeLa cell cultures in comparison to normal fibroblasts WI 38, were observed for compounds 15 and 21. No anti-viral activity was observed, except for compounds 3, 4, 5 and 19 that showed anti-HIV activity at 50% effective concentration ranging between 10 and 96 μM.

Synthesis of β-Hydroxyphosphonate and 1,2-Dihydroxy Acyclic Nucleoside Analogs via 1,3-Dipolar Cycloaddition Strategy

A convenient synthetic approach toward nucleoside analogs where β-hydroxyphosphonate- or 1,2-dihydroxy units are connected to the nucleic acid base through a triazole spacer is discussed.

The Resurgence of Acyclic Nucleic Acids

This review examines acyclic nucleoside analogs as therapeutic agents, potential progenitor candidates to RNA, and novel building blocks for nucleic-acid nanotechnology. Together, these areas of research provide new insights into the structural and functional properties of nucleic acids and suggest new paradigms for nucleic acid self-assembly.

Chemo-, regio- and stereospecific addition of adenine and 8-azaadenine to α,β-acetylenic γ-hydroxy nitriles: a short-cut to novel acyclic adenosine analogues

Adenine (9 H-purin-6-amine) adds readily to available α,β-acetylenic γ-hydroxy nitriles under mild conditions (molar ratio 1:1, K 2CO 3, DMF, rt, 10 min) to afford chemo-, regio- and stereospecifically (Z)-3-(6-amino-9 H-purin-9-yl)-4-hydroxy-4-alkyl-2-alkenenitriles, novel functionalized acyclic nucleoside analogues (95–98% yield). Under similar conditions (K 2CO 3, DMF, rt, 1 h), 8-azaadenine (3 H-[1,2,3]triazolo[4,5- d]pyrimidin-7-amine) reacts with 4-hydroxy-4-methyl-2-pentynenitrile nonselectively at the 7-, 8- and 9-positions to give the corresponding adducts in a 1:10.5:9 ratio, the total yield being 81%. Chemo-, regio- and stereospecific addition of 8-azaadenine to the above α,β-acetylenic γ-hydroxy nitriles leading to ( Z)-3-(7-amino-2 H-[1,2,3]triazolo[4,5- d]pyrimidin-2-yl)-4-hydroxy-4-alkyl-2-alkenenitriles in 44–90% yield is attained when the reaction is carried out without solvent in the presence of Et 3N (30 mol %), the molar ratio of 8-azaadenine:α,β-acetylenic nitriles being 1:2.0 (rt, 12–38 h).

A Case of Osteomalacia Related to Adefovir in a Patient with Chronic Hepatitis B

Adefovir dipivoxil, an acyclic nucleoside analogue, has been approved for the treatment of patients with chronic hepatitis B. This agent is efficacious particularly in those who have developed lamivudine resistance. The report according to hypophosphatemia induced by low dose adefovir therapy is very rare. We report one case in which osteomalacia with hypophosphatemia developed in a patient with chronic hepatitis B on adefovir dipivoxil at a low dose, 10 mg daily. A 66-year-old man, who had been taking adefovir for more than 4 years due to lamivudine resistance, presented with muscle weakness and bone pain in both thighs. After 3 years of adefovir therapy, hypophosphatemia and elevated serum alkaline phosphatase levels had been noted. A bone scan showed multiple hot uptakes. All the image findings and clinical symptoms, such as bone pain and muscle weakness were improved after correcting the hypophosphatemia with oral phosphorous supplementation.

N -Alkylation of 4-Trichloromethylpyrimidinones: Synthesis of Some New and Interesting Modified Nucleoside Analogues

The N1-alkylation of 4-(trichloromethyl)pyrimidin-2(1H)-one, 4-methoxy-4-(trichloromethyl)-3,4-dihydropyrimidin- 2(1H)-one, and 5-bromo-4-methoxy-4-(trichloromethyl)-3,4-dihydropyrimidin-2(1H)-one with selected alkylating agents such as 2-chloroacetamide, diethyl 2-bromomalonate, and 5-bromo-1,1,1-trichloro-4-methoxypent-3-en-2-one, is presented. Further reactions of 1-[5,5,5-trichloro-2-methoxy-4-oxo-penten-2-yl]4-trichloromethyl-pyrimidin-2(1H)-one with primary amines and aminoalcohols furnished a series of unexpected new acyclic nucleoside analogues.

Anti-HIV Activity of New Substituted 1,3,4-Oxadiazole Derivatives and their Acyclic Nucleoside Analogues

A number of new 5-[(naphthalen-5-yloxy)methyl]-1,3,4-oxadiazole derivatives, 2-5 and 8-11, were synthesized. The 2-{5-[(naphthalen-5-yloxy)methyl]-1,3,4-oxadiazol-2-ylthio}acetohydrazones 6a and 6b were synthesized by the reaction of the hydrazide 4 with the corresponding monosaccharides. Cyclization of the sugar hydrazones 6a and 6b with acetic anhydride afforded the substituted oxadiazoline derivatives 7a and 7b. The synthesized compounds were evaluated for their antiviral activity against, the human immunodeficiency virus (HIV-1) and some of these compounds showed moderate to high antiviral activity.

Maribavir Inhibits Epstein-Barr Virus Transcription in Addition to Viral DNA Replication

Although many drugs inhibit the replication of Epstein-Barr virus (EBV) in cell culture systems, there is still no drug that is effective and approved for use in primary EBV infection. More recently, maribavir (MBV), an l-ribofuranoside benzimidazole, has been shown to be a potent and nontoxic inhibitor of EBV replication and to have a mode of action quite distinct from that of acyclic nucleoside analogs such as acyclovir (ACV) that is based primarily on MBV's ability to block the phosphorylation of target proteins by EBV and human cytomegalovirus protein kinases. However, since the antiviral mechanisms of the drug are complex, we have carried out a comprehensive analysis of the effects of MBV on the RNA expression levels of all EBV genes with a quantitative real-time reverse transcription-PCR-based array. We show that in comparisons with ACV, the RNA expression profiles produced by the two drugs are entirely different, with MBV causing a pronounced inhibition of multiple viral mRNAs and with ACV causing virtually none. The results emphasize the different modes of action of the two drugs and suggest that the action of MBV may be linked to indirect effects on the transcription of EBV genes through the interaction of BGLF4 with multiple viral proteins.

C-3 Diagnosis and monitoring of adenovirus infections in immunocompromised patients

The collaboration between Antonín Holý [Institute of Organic Chemistry and Biochemistry (IOCB, Prague, Czech Republic)] and Erik De Clercq (Rega Institute for Medical Research, K.U. Leuven, Belgium) started exactly 30 years ago. It led to the discovery of a (rather small) series of acyclic nucleoside analogues (prototype: DHPA), followed by the discovery of a large number of nucleotide analogues [acyclic nucleoside phosphonates (ANPs)] (prototype: HPMPA). From HPMPA originated three compounds, which have been approved by regulatory agencies worldwide for clinical use: (i) HPMPC [cidofovir (Vistide®)] for the treatment of cytomegalovirus (CMV) retinitis in AIDS patients, and “off label” for the treatment of polyoma-, papilloma-, adeno-, herpes- and poxvirus infections; (ii) PMEA [adefovir (in its oral prodrug form, adefovir dipivoxil (Hepsera®)] for the treatment of chronic HBV (hepatitis B virus) infections, and (iii) PMPA [tenofovir (in its oral prodrug form, tenofovir disoproxil fumarate (Viread®)] for the treatment of HIV infections (AIDS). The latter has also been approved, in combination with emtricitabine (Truvada®), and in combination with emtricitabine and efavirenz (Atripla®) for the treatment of HIV infections. Many other ANPs such as the DAP derivatives HPMPDAP, PMEDAP and PMPDAP, and the DAPy derivatives HPMPO-DAPy, PMEO-DAPy, and PMPO-DAPy, were found to exhibit an antiviral activity spectrum and potency comparable to that of the parent compounds HPMPA (and HPMPC), PMEA and PMPA, respectively.

ChemInform Abstract: New Acyclic Nucleosides Analogues as Potential Analgesic, Antiinflammatory, Antioxidant and Antimicrobial Derived from Pyrimido[4,5‐b]quinolines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Short Synthesis and Antiviral Activity of Acyclic Phosphonic Acid Nucleoside Analogues.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.