ABSTRACT
Recently, we reported the racemic synthesis of 3'-fluoro-5'-norcarbocyclic nucleoside phosphonates bearing adenine as the heterocyclic base. For this study, to evaluate the antiviral activity of each enantiomer, we synthesized both enantiomers, as well as their corresponding bis(POM) prodrugs. Anti-HIV-1 evaluation against the LAI strain and clinically NRTI-resistant HIV-1 strains are presented. The activities against these different strains show that the activities of bis(POM) prodrug (-)-9 are equivalent or even superior to those of (R)-PMPA.
Subject(s)
Anti-HIV Agents , Organophosphonates , Prodrugs , Organophosphonates/pharmacology , Anti-HIV Agents/pharmacology , Nucleosides/pharmacology , Adenine , Tenofovir , Antiviral AgentsABSTRACT
The synthesis and anti-HIV evaluation of hitherto unknown 3'-fluoro-5'-norcarbocyclic nucleoside phosphonates bearing adenine with modifications at the 4' position (ethynyl, vinyl, ethyl, hydroxymethyl) is described. One of the synthesized compounds was found to be an inhibitor of HIV-1 replication, but with moderate efficiency relative to (R)-9-(2-phosphonylmethoxypropyl)adenine ((R)-PMPA, tenofovir), with no concomitant cytotoxicity.
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Nucleosides/chemical synthesis , Nucleosides/pharmacology , Organophosphonates/chemistry , Adenine/chemistry , Blood Cells , Cell Survival/drug effects , Drug Evaluation, Preclinical/methods , Humans , Molecular Structure , Structure-Activity Relationship , Tenofovir/pharmacology , Virus Replication/drug effectsABSTRACT
The synthesis and the antiviral evaluation of 3'-halo (iodo and fluoro) 5'-norcarbocyclic nucleoside phosphonates is described. No antiviral activity was observed against Zika virus, Dengue virus 2, HSV-1, HSV-2 and Chikungunya virus. In contrast, some of the synthesized compounds are potent inhibitors of the replication of HIV-1, comparatively to (R)-PMPA, with no concomitant cytotoxicity.
Subject(s)
Anti-HIV Agents/pharmacology , HIV-1/drug effects , Nucleosides/pharmacology , Organophosphonates/pharmacology , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Dose-Response Relationship, Drug , Humans , Leukocytes, Mononuclear , Molecular Structure , Nucleosides/chemical synthesis , Nucleosides/chemistry , Organophosphonates/chemical synthesis , Organophosphonates/chemistry , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
AMP mimics constitute an important class of therapeutic derivatives to treat diseases where the pool of ATP is involved. A new phosphonate derivative of 9-(5-hydroxymethylfuran-2-yl)adenine was synthesized in a multi-step sequence from commercially available adenosine. Its ability to behave as a substrate of human adenylate kinases 1 and 2 was assessed. The phosphonate was shown to be a moderate but selective substrate of the mitochondrial human AK2, better than well-known antiviral acyclic phosphonates 9-(2-phosphonomethoxyethyl)adenine (PMEA, Adefovir) and (R)-9-(2-phosphonomethoxypropyl)adenine (PMPA, Tenofovir). Putative binding mode within adenylate kinase NMP site revealed by molecular docking in comparison to AMP native substrate allowed to illustrate this selective behavior.
Subject(s)
Adenine/analogs & derivatives , Adenylate Kinase/antagonists & inhibitors , Organophosphonates/pharmacology , Adenine/chemical synthesis , Adenine/chemistry , Adenine/pharmacology , Adenylate Kinase/metabolism , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Molecular Structure , Organophosphonates/chemical synthesis , Organophosphonates/chemistry , Structure-Activity RelationshipABSTRACT
Reaction of dialkylzincs with lithiated acetylenic epoxides is described to give zincates that undergo a 1,2-metallate rearrangement by an anti-S(N)2' pathway. This rearrangement occurs with the transfer of an alkyl or a silyl group affording allenylzinc intermediates. Allenic and/or homopropargylic alcohols are obtained upon hydrolysis. Quenching the reaction mixture with aldehydes or ketones is shown to give access to 2-alkynyl-1,3-diols in a stereoselective manner.
