Lian Jin Liu

Short Synthesis and Antiviral Activity of Acyclic Phosphonic Acid Nucleoside Analogues

An efficient route for synthesizing novel allylic and cyclopropanoid phosphonic acid nucleoside analogues is described. The condensation of the bromine derivatives 6 and 18 with nucleoside bases (A, U, T, C, G) under standard nucleophilic substitution and deprotection conditions, afforded the target phosphonic acid nucleoside analogues. These compounds were evaluated for their antiviral properties against various viruses. Cyclopropanoid phosphonic adenine nucleoside analogue 23 showed significant anti-HIV activity.

Efficient synthesis of 4'-cyclopropylated carbovir analogues with use of ring-closing metathesis from glycolate.

The first synthetic route of novel 4′-cyclopropylated carbovir analgues is described. The construction of cyclopropylated quaternary carbon at 4′-position of carbocyclic nucleosides was successfully made via sequential Johnsons orthoester rearrangement and ring-closing metathesis (RCM) starting from ethyl glycolate. Synthesized compounds 15 and 16 showed moderate antiviral activity without any cytotoxicity up to 100 μmol.

Design and Synthesis of Novel Threosyl-5′- Deoxyphosphonic Acid Purine Analogues as Potent Anti-Hiv Agents

The discovery of threosyl phosphonate nucleoside (PMDTA, EC50 = 2.53 μM) as a potent anti-HIV agent has led to the synthesis and biological evaluation of 5 ′-deoxyversions of threosyl phosphonate nucleosides from 1,4-dihydroxy-2-butene. The synthesized nucleoside phosphonic acid analogues 14 and 19 were tested for anti-HIV activity as well as cytotoxicity. The adenine analogue 14 exhibits moderate in vitro anti-HIV-1 activity (EC50 = 12.6 μM).

Design and Synthesis of Dually Branched 5′-Norcarbocyclic Adenosine Phosphonodiester Analogue as a New Anti-HIV Prodrug

A novel 3′,4′-dimethyl-5′-norcarbocyclic adenosine phosphonic acid was prepared using acyclic stereoselective route from 4-hydroxybutan-2-one (4). To improve the cellular permeability and enhance the anti-HIV activity of this phosphonic acid, a (bis)SATE phosphonodiester nucleoside prodrug (20) was prepared and its chemical stability was evaluated. The newly synthesized bis(SATE) analogue (20) and its parent nucleoside phosphonic acid (18) were assayed for anti-HIV activity using an in vitro assay system in a CEM cell line.

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.

Synthesis and anti-HIV activity of 4'-modified cyclopentenyl pyrimidine C-nucleosides.

Novel syntheses of 4′-modified cyclopentenyl pyrimidine C-nucleosides were performed via C-C bond formation using SN2 alkylation via the key intermediate mesylates 6 and 16, which were prepared from acyclic ketone derivatives. When antiviral evaluation of synthesized compound was performed against various viruses such as HIV-1, HSV-1 and HSV-2, isocytidine analogue 20 showed moderate anti-HIV activity in CEM cell line (EC50 = 13.1 μmol).7

Synthesis and Anti-Hepatitis C Virus Activity of 2′(β)-Hydroxyethyl and 4′(α)-Hydroxymethyl Carbodine Analogues

2′(β)-Hydroxyethylated adenosine is a potent and selective inhibitor of hepatitis C virus (HCV) replication targeting the RNA-dependent RNA polymerase of HCV, NS5B. The synthesis and anti-HCV evaluation of carbodine analogues are described. The cyclopentene intermediate 10 was successfully made via sequential Johnson-Claisen orthoester rearrangement and ring-closing metathesis. Coupling of bases via a Pd(0) catalyst, selective dihydroxylation, and desilylation yielded the target carbodine analogues. Cytosine analogue 17 weakly inhibited the replication of the HCV replicon in Hua-7 cells by 50% at 21.1 μM.

Design and Synthesis of Novel Sate Derivatives of Acyclic Isocytosine and 9-Deazaadenine C-Nucleosides

This article describes a very simple route for synthesizing novel lipophilic phosphate bis(t-bu-SATE) prodrugs of acyclic cyclobutylated C-nucleosides such as isocytosine 12 and 9-deazaadenine 19, which were prepared from 1,1-gem cyclobutyl dicarboxylate. Synthesized compounds were evaluated as potential antiviral agents against HIV virus. Some phosphate SATE prodrugs were more active against HIV than parent nucleosides.

First Synthesis and Anti-HIV Evaluation of 4′-Methyl-Cyclopentanyl 9-Deazaadenosine

The first synthesis of a 4′-methylated carbocyclic C-nucleoside 16 was achieved via the mesylate intermediate 10, which was prepared using ring-closing metathesis and SN2 alkylation from acetol 5. When antiviral evaluation of synthesized compound 16 was performed against various viruses such as HIV, HSV-1, HSV-2, and HCMV, it showed moderate anti-HIV activity in MT-4 cell line (EC50 = 14.7 μmol).

Synthesis of 2′-Fluoro and 2′,4′-Dimethyl Pyrimidine C-Nucleoside Analogues as Potential Anti-HCV Agents

Stereoselective synthesis of novel 2′-fluoro and 2′,4′-dimethyl carbocyclic pyrimidine C-nucleoside analogues using selective fluorination of an epoxide opening reaction is described. The key fluorinated intermediate 7 was prepared from the epoxide intermediate 5 via selective ring opening of the epoxide. Synthesis of isonucleosidic bases through the mesylate 7 and final deprotection provided the target carbocyclic pyrimidine C-nucleoside analogues. The synthesized compounds 15 and 18 were evaluated as inhibitors of the hepatitis C virus (HCV) in the Huh-7 cell line in vitro.