RESUMEN
Three series of nucleotide analogues were synthesized and evaluated as potential CD73 inhibitors. Nucleobase replacement consisted in connecting the appropriate aromatic or purine residues through a triazole moiety that is generated from 1,3-dipolar cycloaddition. The first series is related to 4-substituted-1,2,3-triazolo-ß-hydroxyphosphonate ribonucleosides. Additional analogues were also obtained, in which the phosphonate group was replaced by a bisphosphonate pattern (P-C-P-C, series 2) or the ribose moiety was removed leading to acyclic derivatives (series 3). The ß-hydroxyphosphonylphosphonate ribonucleosides (series 2) were found to be potent inhibitors of CD73 using both purified recombinant protein and cell-based assays. Two compounds (2a and 2b) that contained a bis(trifluoromethyl)phenyl or a naphthyl substituents proved to be the most potent inhibitors, with IC50 values of 4.8 ± 0.8 µM and 0.86 ± 0.2 µM, compared to the standard AOPCP (IC50 value of 3.8 ± 0.9 µM), and were able to reverse the adenosine-mediated immune suppression on human T cells. This series of compounds illustrates a new type of CD73 inhibitors.
Asunto(s)
5'-Nucleotidasa/antagonistas & inhibidores , Algoritmos , Nucleótidos/farmacología , Triazoles/farmacología , 5'-Nucleotidasa/metabolismo , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/metabolismo , Humanos , Cinética , Estructura Molecular , Nucleótidos/síntesis química , Nucleótidos/química , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/químicaRESUMEN
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.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Nucleósidos/síntesis química , Nucleósidos/farmacología , Organofosfonatos/química , Adenina/química , Células Sanguíneas , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos/métodos , Humanos , Estructura Molecular , Relación Estructura-Actividad , Tenofovir/farmacología , Replicación Viral/efectos de los fármacosRESUMEN
We herein report the first enantioselective synthesis of two new monocyclic sesquiterpenes from Artemisia chamaemelifolia starting from an enantiopure building block. The key feature of the present approach is to allow complete control of all the stereogenic centers present in the natural products and to elucidate their absolute stereochemistry, which to date is unknown.