Synthesis of Six-Membered Nucleoside Analogs. Part 1: Pyrimidine Nucleosides Based on the 1,3-Dioxane Ring System

Abstract

The synthesis of pyrimidine nucleosides, cis-N-1-[(2-hydroxymethyl)-1,3-dioxan-5-yl]uracil (4) cis-N-1-[(2-hydroxymethyl)-1,3-dioxan-5-yl]thymine (5) and cis-N-1-[(2-hydroxymethyl)-1,3-dioxan-5-yl]cytosine (6) and their corresponding trans isomers is described. Compound 4 showed modest, selective activity against human immunodeficiency virus in acutely infected primary human lymphocytes.     

Synthesis and Bioactivity of Novel Trisubstituted Triazole Nucleosides

A series of novel trisubstituted 1,2,3-triazole purine nucleosides were efficiently synthesized via Huisgen 1,3-dipolar cycloaddition in good yields. Bioactivity against cytomegalovirus (CMV) and varicella-zoster virus (VZV) in human embryonic lung cell cultures was evaluated and all compounds show low antiviral activity.     

New Acyclic Quinoxaline Nucleosides. Synthesis and Anti-Hiv Activity

A series of acyclonucleosides substituted 1-(4,5-dihydroxypentyl) (13-8) and 2-(4,5-dihydroxypentyloxy)quinoxalines (19-24) were synthesized by the sharpless asymmetric dihydroxylation of the derivatives 1-6 and 7-12, respectively. Treatment of the quinoxaline base 26 with (R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl-p-toluenesulfonate (27) in the presence of NaH/DMF furnished 28. Acid hydrolysis of 28 gave 1-(2,3-dihydroxypropyl)-6,7-dimethyl-quinoxaline-2-one (29). Alternatively, 29 was prepared by sharpless dihydroxylation of 30. All the compounds were evaluated for their in vitro anti-HIV-1 and HIV-2 in MT-4 cell and found inactive, except 29, which showed inhibition of HIV-1 with EC₅₀ value of 0.15 ± 0.1 μg/ml and a therapeutic index (SI) of 73.     

Synthesis of Novel Bicyclic Nucleosides with 3,6-Anhydro Sugar Moiety

Based on the biological importance of conformationally restricted nucleoside analogues, we have efficiently synthesized 3,6-anhydro sugar moiety with 3-C-hydroxymethyl substituent from 1,2;5,6-di-O-isopropylidene-D-glucose and condensed 15 with silylated nucleobases to afford the bicyclic nucleoside with 3,6-anhydro skeleton as potential antiviral agent.     

Asymmetric Synthesis of Apio Fluoroneplanocin a Analogs as Potential AdoHcy Hydrolase Inhibitor

Apio fluoroneplanocin A (apio F-NPA, 3) and its uracil analogue 4 have been designed and asymmetrically synthesized starting from D-ribose. Introduction of fluoro group into vinylic position of 5 was accomplished successfully over 5 steps employing key reactions such as iodination according to an addition-elimination reaction mechanism, stereo- and regioselective reduction of α,β -unsaturated ketone, and electrophilic fluorination. This methodology can be adapted to the synthesis of fluoro compounds extensively.     

Synthesis and antiviral evaluation of fluorinated acyclo-nucleosides and their phosphoramidates

A novel series of tetrafluoro and hexafluoro acyclic nucleosides and their phosphoramidates were successfully prepared from commercially available 2,2,3,3-tetrafluoro-1,4-butanediol and 2,2,3,3,4,4-hexafluoro-1,5-pentanediol in four to six steps. Their ability to block HIV, HCV, HSV-1, and HBV replication along with their cytotoxicity toward HepG2, human lymphocyte, CEM, and Vero cells was assessed.     

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.     

Ionic Liquid Mediated Synthesis of 5-Halouracil Nucleosides: Key Precursors for Potential Antiviral Drugs

Synthesis of antiviral 5-halouracil nucleosides, also used as key precursors for the synthesis of other potential antiviral drugs, has been demonstrated using ionic liquids as convenient and efficient reaction medium.     

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.     

Selective Metalation of 6-Methylpurines: Synthesis of 6-Fluoromethylpurines and Related Nucleosides

Abstract

A selective metalation at the 6-CH3 over C-8 of 6-methylpurine derivative 6 was observed with softer counter cation (Na⁺ or K⁺) of the base, while the harder Li⁺ showed no selectivity. In the presence of N-fluorobenzenesulfonamide (NFSI), this property was utilized for the synthesis of 6-fluoromethylpurine derivatives 4 and 5 as potential toxins for suicide gene therapy.     

Synthesis and antiviral activity of lupane triterpenoids with modified cycle E

A reductive transformation of the peroxide products of ozonolysis of derivatives of 3β-O-acetyl-22(17→28)-abeo-lupa-17(28),20(29)-diene and the subsequent intramolecular ketalization led to a compound with a trioxane fragment. This is a new approach to a skeletal modification of triterpenoid cycle E. An activity of the synthesized compounds was found toward the viruses of type A influenza and herpes simplex.     

A Novel and Enantioselective Approach to the Synthesis of Cyclohexane Carbocyclic Nucleosides Starting from (-)-Carvone

Abstract

3,5-dihydroxy-4-(hydroxymethyl)-1-cyclohexanyl adenine has been synthesized starting from (-)-carvone. The adenine base was introduced via Mitsunobu reaction. Conformational analysis showed that the base still adopts the equatorial position at the expence of three axial substituents.     

Synthesis Of 2,2,3-Tris(Hydroxymethyl)Methylenecyclopropane Analogues Of Nucleosides

Synthesis of 2,2,3-tris(hydroxymethyl)methylenecyclopropane analogues 16a, 16b, 17a, and 17b is described. Diethyl ester of Feist's acid 18b was hydroxymethylated via carbanion formation using formaldehyde under simultaneous isomerization to cis diester to give intermediate 19. Reduction followed by acetylation gave triacetate 22. Addition of bromine afforded reagent 23, which was used for alkylation-elimination of adenine and 2-amino-6-chloropurine to provide Z,E-isomeric mixtures of 24a and 24b. Deacetylation and separation furnished the Z-isomers 16a, 16c and E-isomers 17a, 17c. Hydrolytic dechlorination of 16c and 17c gave guanine analogues 16b and 17b. None of the analogues exhibited a significant antiviral activity. Adenosine deaminase is refractory toward adenine analogues 16a and 17a.     

A Convenient Approach to the Synthesis of Azido-Acyclic Nucleosides

Abstract

The azidation of unprotected acyclic nucleosides (4) was carried out in a one-pot reaction by means of the reagent triphenylphosphine-carbon tetraiodide-sodium azide to give the corresponding mono-azido-acyclic nucleosides (6) in good yields without by-products such as the di-azido-acyclic nucleosides.     

On the Synthesis of 6-Methoxy-2-benzoxazolinone

6-Methoxy-2-benzoxazolinone has been synthesized by a simplified, improved procedure, the formation and reduction of 5-methoxy-2-nitrophenol and subsequent fusion of the corresponding amine hydrochloride with urea. In related work, 4-methoxy-2-(methoxymethoxy)-nitrobenzene was prepared.     

Synthesis and Analysis of Nucleosides Bearing Pyrrolepolyamide Binding to DNA

Abstract

An efficient synthesis of adenosine bearing pyrrolepolyamide 1 was achieved by coupling of 3 with 2. The CD spectra obtained at several [ligand ]/[duplex] ratios allowed verification of the formation complex of the DNA duplex [d(CGCAAATTGGC)/d(GCCAATTTGCG)] with 1.     

Nucleosides,XLIII1) Synthesis and Properties of 04-Alkylthymidines

Abstract

Various 0⁴-alkylthymidines 14–20 have been synthesized by two different methods. 0⁴-Alkylation takes place with 3′,5′-di-0-acetyl- (2) and 3′,5′-di-0-benzoylthymidine (3) respectively in a silver ion catalysed reaction with alkyl halides, whereas the azolide approach makes use of a nucleophilic displacement of the appropriate intermediate by alkoxides and subsequent deacylation to the free nucleosides. Structural proofs are based on elemental analyses, UV- and ¹H-NMR-spectra.     

Utilization Of Tetrabutylammonium Triphenyldifluorosilicate (TBAT) In The Synthesis of 6-Fluoropurine Nucleosides

Abstract

Tetrabutylammonium triphenydifluorosilicate (TBAT) has been found to be a useful reagent for the conversion of 6-chloropurine nucleosides to 6-fluoropurine derivatives. The 6-chloropurine nucleosides were reacted with trimethylamine to form quaternary trimethylammonium salts which were treated in situ with TBAT in DMF to effect conversion to the 6-fluoro derivatives in yields of 59–72%.