Synthesis and Antiviral Activities of Enantiomeric 1-[2-(Hydroxymethyl) Cyclopropyl] Methyl Nucleosides

Abstract

Cyclopropyl carbocyclic nucleosides have been synthesized from the key intermediate 2 which was converted to the mesylated cyclopropyl methyl alcohol 3. Condensation of compound 3 with various purine and pyrimidine bases gave the desired nucleosides. All synthesized nucleosides were evaluated for antiviral activity and cellular toxicity. Among them adenine 22 and guanine 23 derivatives showed moderate antiviral activity against HIV-1 and HBV. None of the other compounds showed any significant antiviral activities against HIV-1, HBV, HSV-1 and HSV-2 in vitro up to 100μM.     

Synthesis of 2',3'-dideoxy-2'-fluoro-L-threo-pentofuranosyl nucleosides as potential antiviral agents

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 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 of novel apionucleosides: a short and concise synthesis of 2-deoxyapio-L-furanosyl acetate from D-lactose

A series of 2'-deoxyapio-L-furanosyl pyrimidine nucleosides were efficiently synthesized starting from D-lactose via condensation of lactitor acetates with silylated pyrimidine bases under standard Vorbrüggen conditions. Their structures were determined by 1D and 2D NMR spectroscopy. All the synthesized nucleosides were assayed against several viruses such as HIV-1, HBV, HSV-1, HSV-2, and HCMV. However, none of these compounds had any significant antiviral activity at concentrations up to 100 microM.     

Simple synthesis of novel acyclic (e)-bromovinyl nucleosides as potential antiviral agents

In these study, novel acyclic (E)-bromovinyl nucleosides were synthesized as potential antiviral agents. The coupling of the allylic bromide 9 with bases (thymine, uracil, 5-fluorouracil, 5-iodouracil, cytosine, adenine) afforded a series of novel acyclic nucleosides. The synthesized compounds were evaluated for their antiviral activity against various viruses such as HIV-1, HSV-1, HSV-2, and HCMV. 5-Iodouracil analogue 19 showed weak anti-HIV-1 activity.     

Synthesis of new nucleoside analogues comprising a geminal difluorocyclopropane moiety as potential antiviral/antitumor agents

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.     

Synthesis and antiviral activity of D- and L-2'-azido-2',3'-dideoxy-4'-thiopyrimidine and purine nucleosides

Novel D- and L-2'-azido-2',3'-dideoxy-4'-thionucleosides were synthesized starting from L- and D-xylose via D- and L-4-thioarabitol derivative as key intermediates and evaluated for antiviral activity, respectively. When the final nucleosides were tested against HIV-1, HSV-1, HSV-2, and HCMV, they were found to be only active against HCMV without cytotoxicity up to 100 micrograms/ml.     

Synthesis of (Z)- and (E)-9-[(2-hydroxyethylidene)cyclopropyl]adenine--new methylenecyclopropane analogues of adenosine and their substrate activity for adenosine deaminase

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.     

Racemic synthesis and antiviral evaluation of 4'(alpha)-hydroxymethyl and 6'(alpha)-methyl substituted apiosyl nucleosides

This article reports the novel synthesis of substituted apiosyl nucleosides. The key apiosyl intermediate 9 was constructed by sequential ozonolysis, reductions, and acetylation from the ester derivative 6. The nucleosides of uracil, thymine, cytosine, and adenine were synthesized using the glycosyl condensation procedure (silyated base and TMSOTf). The antiviral activities of the synthesized compounds against the HIV-1, HSV-1, HSV-2, and HCMV viruses were evaluated. The adenine derivative 26 showed weak anti-HIV activity (EC(50) = 10.1 microg/ml) without exhibiting any cytotoxicity up to a concentration of 100 microM.     

Synthesis and antiviral activities of N-9-oxypurine 1,3-dioxolane and 1,3-oxathiolane nucleosides

Two series of 1,3-dioxolanes and 1,3-oxathiolane nucleosides containing N-9-oxypurine were synthesized as potential antiviral agents. These compounds were prepared by reacting the sugar moieties with iodo- or bromotrimethylsilane, followed by treatment with a mixture of sodium hydride and the desired N-hydroxy purine base. The preparation of these N-hydroxybases was also described. No significant antiviral activity was observed against HIV, HBV, HSV-1, HSV-2, or HCMV.     

Synthesis and Biological Evaluation of Pyrimidine and Purine α-L-2′,3′-Dideoxy Nucleosides

Abstract

A series of α-L-2′,3′-dideoxy nucleosides was prepared as potential antiviral agents. The pyrimidine nucleosides were prepared by standard Vorbrüggen coupling reactions. The purine analogues were prepared by enzymatic transfer of the dideoxy sugar from a pyrimidine to a purine base. These compounds were inactive against HIV-1, HBV, HSV-1 and -2, VZV, and HCMV.     

Synthesis and antiviral activity of D- and L-isodideoxy nucleosides with exocyclic-methylene.

Novel D- and L-isodideoxynucleosides were synthesized starting from D- and L-xylose and evaluated for antiviral activities against HIV-1, HSV-1, HSV-2, HBV and HCMV, respectively.     

Simple synthesis and anti-HIV activity of novel 3'-vinyl branched apiosyl pyrimidine nucleosides

Novel vinyl branched apiosyl nucleosides were synthesized in this study. Apiosyl sugar moiety was constructed by sequential ozonolysis and reductions. The bases (uracil and thymine) were efficiently coupled by glycosyl condensation procedure (persilyated base and TMSOTf). The antiviral activities of the synthesized compounds were evaluated against the HIV-1, HSV-1, HSV-2, and HCMV. Compound 10beta displayed moderate anti-HIV activity (EC50 = 17.3 microg/mL) without exhibiting any cytotoxicity up to 100 microM.     

Simple Synthesis and Anti-Hiv Activity of Novel 3′-Vinyl Branched Apiosyl Pyrimidine Nucleosides

Novel vinyl branched apiosyl nucleosides were synthesized in this study. Apiosyl sugar moiety was constructed by sequential ozonolysis and reductions. The bases (uracil and thymine) were efficiently coupled by glycosyl condensation procedure (persilyated base and TMSOTf). The antiviral activities of the synthesized compounds were evaluated against the HIV-1, HSV-1, HSV-2, and HCMV. Compound 10β displayed moderate anti-HIV activity (EC₅₀ = 17.3 μg/mL) without exhibiting any cytotoxicity up to 100 μM.     

5-substituted 2'-fluoro-arabinonucleosides as potential antiviral agents

In order to study the electronic effects of 5-substituents of 2'-fluoro-ara-U on antiviral activity, eight nucleosides were synthesized and screened for their activity. Preliminary in vitro studies revealed that 5-thiocyano-, 5-hydroxy- and 5-formyl-ara-U are moderately active against HSV-1, HSV-2 and VZV, but they are also cytotoxic. None of these showed significant activity against CMV.     

Synthesis and antiviral activity of L-2'-deoxy-2'-up-fluoro-4'-thionucleosides.

L-2'-Deoxy-2'-up-fluoro-4'-thionucleosides were efficiently synthesized from D-xylose via L-4-thioarabitol derivative as a key intermediate and evaluated for antiviral activities against HIV-1, HSV-1,2 and HBV.     

Chiral carbocylic nucleosides: The synthesis and antiviral activity of 4′-hydroxy and 4′-fluorocarbocyclic - 2′- deoxyguanosines

The chiral carbocyclic nucleosides 2 and 3 were prepared from aristeromycin. The 4′-hydroxy compound 2 displays good antiviral activity against HSV-1 and HSV-2 with low toxicity.     

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.     

Antiviral activities of Janus-type nucleosides and their related oxime-intermediates

Herpes simplex virus (HSV) infection has been recognized as the most common mucosal disease in humans, manifesting as a life-threatening infection especially for patients with compromised immunity. When combined with the emergence of resistance due to the long-term use of classical antiviral agents, these threats make novel therapeutics for HSV a clinically necessity. We therefore designed and synthesized a series of Janus-type nucleosides by combining the natural genetic alphabets into a singular nucleoside structural unit. We also synthesized a series of new compounds and systematically evaluated their antiviral activity and structure-antiviral activity relationship. The results indicated that both nucleosides and their related intermediates exhibited high anti-HSV-1 activity. Compounds HY17 and HY19, in particular, possessed excellent anti-HSV-1 activity with IC₅₀ values of 0.05 and 0.04 µg/mL, respectively. They also showed broad-spectrum antiviral activity against a multitude of diverse viruses, such as HSV-2, influenza virus A (H3N2), CVB3, HBV, HCV, and HPV. These results suggest that once their mechanisms are fully elucidated, these compounds will prove to be promising candidates as antiviral agents.