RESUMEN
MK-8591 (4'-ethynyl-2-fluoro-2'-deoxyadenosine) is a novel nucleoside analog that displays a differentiated mechanism of action as a nucleoside reverse transcriptase translocation inhibitor (NRTTI) compared to approved NRTIs. Herein, we describe our recent efforts to explore the impact of structural changes to the properties of MK-8591 through the synthesis and antiviral evaluation of carbocyclic derivatives. Synthesized analogs were evaluated for their antiviral activity, and the corresponding triphosphates were synthesized and evaluated in a biochemical assay. 4'-Ethynyl-G derivative (±)-29 displayed a promising IC50 of 33 nM in a hPBMC cell-based antiviral assay, and its triphosphate (TP), (±)-29-TP, displayed an IC50 of 324 nM in a biochemical RT-polymerase assay. Improved TP anabolite delivery resulting in improved in vitro potency was achieved by preparing the corresponding phosphoramidate prodrug of single enantiomer 29b, with 6-ethoxy G derivative 34b displaying a significantly improved IC50 of 3.0 nM, paving the way for new directions for this novel class of nucleoside analogs.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Desoxiadenosinas/síntesis química , Desoxiadenosinas/farmacología , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Animales , Antivirales/metabolismo , Antivirales/farmacocinética , Línea Celular , Técnicas de Química Sintética , Desoxiadenosinas/metabolismo , Desoxiadenosinas/farmacocinética , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/química , Transcriptasa Inversa del VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/enzimología , Humanos , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Conformación Proteica , Ratas , Inhibidores de la Transcriptasa Inversa/metabolismo , Inhibidores de la Transcriptasa Inversa/farmacocinética , Distribución TisularRESUMEN
The first example of a nucleoside analogue bearing a 5'-deoxy-beta-D-allo-septanose as a seven-membered ring sugar moiety, namely 9-(5-deoxy-beta-D-allo-septanosyl)-adenine, is reported. This compound was synthesized in 14 steps from the commercially available D-glycero-D-gulo-1,4-lactone. When evaluated in cell culture experiments against a broad range of viruses, it did not exhibit any significant antiviral effect or cytotoxicity.
Asunto(s)
Nucleósidos/química , Nucleósidos/síntesis química , Oligosacáridos/química , Oligosacáridos/síntesis química , Antivirales/síntesis química , Antivirales/química , Antivirales/farmacología , Flavivirus/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Modelos Químicos , Estructura Molecular , Nucleósidos/farmacología , Pestivirus/efectos de los fármacosRESUMEN
We report the synthesis and the functional studies of multiple crown alpha-helical peptides designed to form artificial ion channels. The approach combines the versatility of solid phase peptide synthesis, the conformational predictability of peptidic molecules, and the solution synthesis of crown ethers with engineerable ion-binding abilities. Several biophysical methods were employed to characterize the activity and the mode of action of these crown peptide nanostructures. The 21 residue peptides bearing six 21-EC-7 turned out to facilitate the translocation of ions in a similar fashion to natural ion channels.