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1.
Sci Rep ; 13(1): 1639, 2023 01 30.
Article in English | MEDLINE | ID: mdl-36717567

ABSTRACT

The total synthesis of four novel mono-methoxy and hydroxyl substituted ring-A dihydronarciclasine derivatives enabled identification of the 7-hydroxyl derivative as a potent and selective antiviral agent targeting SARSCoV-2 and HSV-1. The concentration of this small molecule that inhibited HSV-1 infection by 50% (IC50), determined by using induced pluripotent stem cells (iPCS)-derived brain organ organoids generated from two iPCS lines, was estimated to be 0.504 µM and 0.209 µM. No significant reduction in organoid viability was observed at concentrations up to 50 mM. Genomic expression analyses revealed a significant effect on host-cell innate immunity, revealing activation of the integrated stress response via PERK kinase upregulation, phosphorylation of eukaryotic initiation factor 2α (eIF2α) and type I IFN, as factors potentiating multiple host-defense mechanisms against viral infection. Following infection of mouse eyes with HSV-1, treatment with the compound dramatically reduced HSV-1 shedding in vivo.


Subject(s)
Amaryllidaceae Alkaloids , Antineoplastic Agents , Herpesvirus 1, Human , Interferon Type I , Mice , Animals , Antiviral Agents/pharmacology , Amaryllidaceae Alkaloids/pharmacology , Phosphorylation
2.
Bioorg Med Chem Lett ; 30(24): 127559, 2020 12 15.
Article in English | MEDLINE | ID: mdl-32961320

ABSTRACT

The synthesis of a lead anti-viral cyclopropyl carboxy acyl hydrazone 4F17 (5) and three sequential arrays of structural analogues along with the initial assessment and optimization of the antiviral pharmacophore against the herpes simplex virus type 1 (HSV-1) are reported.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Herpesvirus 1, Human/drug effects , Hydrazones/chemistry , Hydrazones/pharmacology , Antiviral Agents/chemical synthesis , Cell Line , Chemistry Techniques, Synthetic , Herpes Simplex/drug therapy , Humans , Hydrazones/chemical synthesis , Structure-Activity Relationship
3.
Nat Prod Res ; 29(1): 70-6, 2015.
Article in English | MEDLINE | ID: mdl-25229804

ABSTRACT

A new metabolite 1 has been isolated from the marine soft coral Sarcophyton ehrenbergi along with two known diterpenoids 2 and 3 and cholesterol 4. The structure of 1 was determined by means of detailed spectroscopic analysis and unambiguously confirmed to have the S configuration by the synthesis of both enantiomers using 4-benzyl-2-oxazolidinone auxiliaries. (S)- and (R)-1, 3 and some of the synthetic intermediates were evaluated for cytotoxic activity against human lung cancer (A549), prostate cancer (DU145), cervical cancer (HeLa) and breast cancer (MCF-7) cell lines in an in vitro bioassay.


Subject(s)
Antineoplastic Agents , Diterpenes , Oxazolidinones , Propionates/chemical synthesis , Animals , Anthozoa/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Breast Neoplasms , Diterpenes/chemical synthesis , Diterpenes/chemistry , Diterpenes/isolation & purification , Diterpenes/pharmacology , Drug Screening Assays, Antitumor , Female , HeLa Cells , Humans , Male , Marine Biology , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Oxazolidinones/chemical synthesis , Oxazolidinones/chemistry , Oxazolidinones/isolation & purification , Oxazolidinones/pharmacology , Propionates/chemistry , Stereoisomerism
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