A Novel Type of Spironucleosides: 2′,5′-O-bis-TBDMS Uridine-3′-spiro-3′-isoxazolidin-5′-one and Its Thymidine Congener

Abstract

TSAO analogues, 2′,5′-O-bis-TBDMS uridine-3′-spiro-3′-isoxazolidin-5′-one (9) and its thymidine congener 10, as well as model spiro sugar derivatives (3 and 4) have been prepared from the corresponding nitrones through a stereospecific tandem nucleophilic attack. Compounds 9 and 10 which are bioisosters of TSAO-U and T respectively but which lack an amino group on the spiro ring, were found inactive against both HIV-1 and HIV-2.

     

Structure-Activity Relationships Among a New Class of Antiviral Heterosubstituted 2′,3′-Dideoxynucleoside Analogues

Abstract

3′-Oxa-4′-thiocytidine nucleoside analogues 14–17 were prepared from oxathiolanes 10 and 11, and evaluated for activity against HIV-1 and HBV in vitro. The nucleoside analogues were found to possess potent activities against HIV-1 in a panel of cell lines. Compound 16 is moderately active against HBV in 2.2.15 cells.     

Synthesis and Antiviral Evaluation of 3′-Substituted Thymidine Analogues Derived from 3′-Amino-3′-deoxythymidine

Abstract

To assess the structure-activity relationship for antiviral activity, a series of 3′-deoxy-3′-N-functionalized thymidine analogues were synthesized. Several of these thymidine analogues show moderate in vitro activity against HIV-1 and HIV-2.     

Synthesis and Anti-HIV-1 Activity of 4- and 5-Substituted 1,2,3-Triazole-TSAO Derivatives

Abstract

Several 4- or 5-monosubstituted and 4,5-disubstituted 1,2,3-triazole analogues of the anti-HIV-1 lead compound [1-[2′,5′-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]thymine]-3′-spiro-5″-(4″-amino-1″,2″-oxathiole-2″,2″-dioxide) (TSAO-T) have been prepared and evaluated for their inhibitory effect against HIV-1-induced cytopathicity.     

Synthesis of (Z)- and (E)-9-[(2-Hydroxyethylidene)cyclopropyl]adenine—New Methylenecyclopropane Analogues of Adenosine and Their Substrate Activity for Adenosine Deaminase

Abstract

Synthesis of Z- and E-methylenecyclopropane analogues of adenosine 3 and 4 by alkylation of adenine with novel alkylating agent 5 is described. The E-isomer 4 is a substrate for adenosine deaminase. Compounds 3 and 4 were tested for antiviral activity against HCMV, HSV-1, HSV-2, EBV, VZV, HBV and HIV-1.     

Synthesis of 2′,3′-Dideoxy-2′-Fluoro-l-threo-Pentofuranosyl Nucleosides as Potential Antiviral Agents

Abstract

A series of 2′,3′-dideoxy-2′-fluoro-L-threo-pentofuranosyl nucleosides has been synthesized as potential antiviral agents. The synthesized compounds were evaluated against HIV-1, HBV, HSV-1, and HSV-2. Among the synthesized analogues, only the cytosine derivative showed moderate antiviral activity against HIV and HBV.     

Synthesis and Antiviral Activity of C-5 Substituted Analogues of D4T Bearing Methylamino- or Methyldiamino-Linker Arms

Abstract

A general strategy is reported for the preparation of C-5-methylamino- or methyldiamino-d4T analogues of “different sizes”. Reactions of the 2′,3′-didehydro-2′,3′-dideoxy-C-5 hydroxymethyl precursor (7) with either polymethylene diamines (n = 6, 8, 10 and 12) or propargylamine proceed regioselectively via subtitution reactions at the C-5 position of uracil. The compounds were evaluated for antiviral activity and cytotoxicity. No significant activity was observed for compounds 9, 11, and 13, but 10 and 12 exhibited a weak activity against HIV-1.     

Synthesis of 3′-Deoxy-3′-[4-(pyrimidin-1-yl)methyl-1,2,3-triazol-1-yl]thymidine via 1,3-Dipolar Cycloaddition

Abstract

The synthesis of new 3′-deoxy-3′-[4-(pyrimidin-1-yl)methyl-1,2,3-triazol-1-yl]thymidine 6a–f, from 3′-azido-3′-deoxy-5′-O-monomethoxytrityl-thymidine is described. The key step is the 1,3-dipolar cycloaddition between the azido group of the protected AZT 3 and N-1-propargylpyrimidine derivatives 2a–f. All new derivatives 6a–f were evaluated for their inhibitory effects against the replication of HIV-1 (IIIB), HIV-2 (ROD). No marked activity was found.     

Phosphodiester Amidates of Unsaturated Nucleoside Analogues as Anti-HIV Agents

Abstract

Lipophilic phosphodiester L-alaninates of acyclic unsaturated nucleoside analogues 1d, 1e, 2d, 2e, 3d, 3e, 4d and 5d were prepared and their antiretroviral activity was examined in ATH8 cell culture infected with HIV-1. A possible mechanism of action of these analogues is discussed.     

Microwave-Assisted Synthesis and Anti-HIV Activity of New Acyclic C-Nucleosides of 3-(D-Ribo-Tetritol-1-yl)-5-Mercapto-1,2,4-Triazoles. Part 1

Microwave-assisted synthesis of novel acyclic C-nucleosides of 6-alkyl/aryl-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (5–12) and the 6-aryl-thiomethyl analogues 25–27 has been described. Deblocking of 5–12 and 25–27 afforded the free acyclic C-nucleosides 13–20, and 28–30, respectively. All of the synthesized compounds showed no inhibition against HIV-1 and HIV-2 replication in MT-4 cells. However, 6-(3,4-dichlorophenyl)-3-(1,2-O-isopropylidene-D-ribo-tetritol-1-yl)-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole (6) is a potent inhibitor, in vitro, of the replication of HIV-2. These results suggest that compound 6 should be considered as a new lead in the development of antiviral agent.     

Synthesis of Novel 2′-Spirocyclopropyl-5′- Deoxyphosphonic Acid Furanosyl Nucleoside Analogues as Potent Antiviral Agents

Novel 5′-deoxyfuranosyl purine phosphonic acid analogues with 2 ′-electropositive moiety, such as spirocyclopropanoid, were designed and synthesized from commercially available diethyl malonate. Condensation reaction successfully proceeded from a glycosyl donor 15 at low reaction temperature in Vorbruggen conditions to give desired phosphonate analogues 16b and 23b. The synthesized nucleotide analogues 19, 22, 26, and 29 were subjected to antiviral screening against HIV-1. Adenine phosphonic acid analogue 22 shows significant anti-HIV activity (EC₅₀ = 7.9 μM).     

Design and Synthesis of Regioisomeric Analogues of a Specific Anti-HIV-1 Agent 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)

Abstract

Regioisomeric analogues of the anti-HIV-1 lead 1-[(2-hydroxy-ethoxy)methyl]-6-(phenylthio)thymine (1: HEPT) have been synthesized. These compounds, having an ethoxymethyl side chain at C-5 and an ethyl group at the N-1 position of the uracil ring, also possess activity against HIV-1.     

Synthesis of New Nucleoside Analogues Comprising a Geminal Difluorocyclopropane Moiety as Potential Antiviral/Antitumor Agents

Abstract

Geminal difluorocyclopropane analogues of nucleosides 7a–7e were synthesized. Compounds 7a and 7c–7e were obtained by alkylation of nucleic acid bases or their appropriate precursors with (cis)-1-benzyloxymethyl-2-bromomethyl-3,3-difluorocyclopropane (8). Analogue 7b was prepared by hydrolysis of 2-amino-6-chloropurine derivative 7e. Compounds 7a–7d did not exhibit any antiviral activity against HCMV, HSV-1, HSV-2, EBV, VZV, HBV and HIV-1 or antitumor effects against murine leukemia L1210, mouse tumors PO3 or C38 and human tumor H15.     

3′-Deoxy-3′-C-trifluoromethyl Nucleosides: Synthesis and Antiviral Evaluation

Abstract

2′,3′-Dideoxy-3′-C-trifluoromethylthymidine 9a and -uridine 9b and 3′-C-trifluoromethyl-d4T 11 were prepared in a few steps from 3′-deoxy-3′-C-trifluoromethyl-D-ribose, which synthesis was recently reported. The biological assessment of these nucleoside analogues did not reveal interesting antiviral properties against HIV-1, HSV-1, CMV, Vaccine, and Cox B4.     

Phosphoralaninate Pronucleotides of Pyrimidine Methylenecyclopropane Analogues of Nucleosides: Synthesis and Antiviral Activity

The Z- and E-thymine and cytosine pronucleotides 3d, 4d, 3e, and 4e of methylenecyclopropane nucleosides analogues were synthesized, evaluated for their antiviral activity against human cytomegalovirus (HCMV), herpes simplex virus 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), human immunodeficiency virus type 1 (HSV-1), and hepatitis B virus (HBV) and their potency was compared with the parent compounds 1d, 2d, 1e, and 2e. Prodrugs 3d and 4d were obtained by phosphorylation of parent analogues 1d or 2d with reagent 8. A similar phosphorylation of N⁴-benzoylcytosine methylenecyclopropanes 9a and 9b gave intermediates 11a and 11b. Deprotection with hydrazine in pyridine–acetic acid gave pronucleotides 3e and 4e. The Z-cytosine analogue 3e was active against HCMV and EBV. The cytosine E-isomer 4e was moderately effective against EBV.     

Design and Synthesis of Novel 1′,3′-Dioxolane 5′-Deoxyphosphonic Acid Purine Analogues as Potent Antiviral Agents

Electronic parameters of 1′,3 ′-oxygen play significant roles in steering the conformation of nucleoside phosphonic acid analogues. To investigate the relationship of two oxygen atoms with antiviral enhancement, novel 1′,3 ′-dioxolane 5 ′-deoxyphosphonic acid purine analogues were synthesized via de novo acyclic stereoselective route from acrolein and glycolic acid. The synthesized nucleoside phosphonic acid analogues 14 and 19 were subjected to antiviral screening against several viruses, such as HIV-1, HSV-1, HSV-2, and HCMV. The guanine analogue 19 exhibits in vitro anti-HIV-1 activity similar to that of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) in MT-4 cells.     

Novel synthesis of new pyrazole thioglycosides as pyrazomycin analogues

This study reports a novel method for the synthesis of a new class of pyrazole thioglycosides 7a-h as pyrazomycin analogues. These series of compounds were designed through the reaction of sodium 2-cyano-3-oxo-3-(4-substitutedphenylamino)prop-1-ene-1,1-bis(thiolate) salts 2 with phenyl hydrazine in ethanol at room temperature to give the corresponding sodium 5-amino-4-(substitutedphenylcarbamoyl)-1-phenyl-1H-pyrazole-3-thiolates 3a-d. The latter compounds were treated with tetra-acetylated glycosyl bromides 4a,b in DMF at ambient temperature to give the corresponding pyrazole thioglycosides 6a-h. Treatment of pyrazole salts 3a–d with hydrochloric acid at room temperature afforded the corresponding 3-mercaptopyrazole derivatives 5. The latter compounds were treated with tetra-acetylated glycosyl bromides 4 in sodium hydride-DMF to tolerate the S-glycosyl 6a-h compounds. Ammonolysis of the latters afforded the corresponding free thioglycosides 7a-h. The structures of the reaction products were elucidated based on spectral data and elemental analysis.     

Synthesis and Biological Evaluation of 1,3-Oxathiolane 5-Azapyrimidine, 6-Azapyrimidine,and Fluorosubstituted 3-Deazapyrimidine Nucleosides

Abstract

(2R,5S)-5-Amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,2,4-triazine-3(2H)-one (8) and (2R,5R)-5-amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,2,4-triazine-3(2H)-one (9) have been synthesized via a multi-step procedure from 6-azauridine. (2R,5S)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,3,5-triazine-2(1H)-one (11) and (2R,5R)-4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-y1]-1,3,5-triazine-2(1H)-one (12), and the fluorosubstituted 3-deazanucleosides (19–24) have been synthesized by the transglycosylation of (2R,5S)-1-{2-[[(tert-butyldiphenylsilyl) oxy]methyl]-1,3-oxathiolan-5-y1} cytosine (2) with silylated 5-azacytosine and the corresponding silylated fluorosubstituted 3-deazacytosines, respectively, in the presence of trimethylsilyl trifluoromethanesulfonate as the catalyst in anhydrous dichloroethane, followed by deprotection of the blocking groups. These compounds were tested in vitro for cytotoxicity against L1210, B₁₆F₁₀, and CCRF-CEM tumor cell lines and for antiviral activity against HIV-1 and HBV.     

Synthesis of various 5-alkoxymethyluracil analogues and structure-cytotoxic activity relationship study

A number of 5-alkoxymethyluracil analogues were synthesized to evaluate their cytotoxic activity. 5-Alkoxymethyluracil derivatives 1 were prepared via known nucleophilic substitution of 5-chloromethyluracil 5 and subsequently transformed to their corresponding nucleosides 2. All prepared compounds were submitted to cytotoxic activity testing against drug sensitive and drug resistant leukaemia cells and solid tumour derived cell lines. In addition, the cytotoxic activity of 5-alkoxymethyluracil analogues 1 and 2 was compared with the previously published 5-[alkoxy(4-nitrophenyl)methyl]uracil analogues 3 and 4. Extensive structure–cytotoxic activity relationship studies are reported.     

Stereospecificity of 6′-C-Neplanocin A Analogues as Inhibitors of S-Adenosylhomocysteine Hydrolase Activity and Human Immunodeficiency Virus Replication†

Abstract

The R- and S-isomers of 6′-C-neplanocin A analogues, which are all known as inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase, were studied for their inhibitory effects on Human Immunodeficiency Virus type 1 (HIV-1) replication and HIV-1 Tat-mediated transactivation. The R-isomers showed much greater activity against AdoHcy hydrolase than the S-isomers. The same differential activity was observed against the HIV-1 replication and the Tat transactivation.