RESUMEN
Recent evidence suggests that fibrotic liver injury in patients with chronic hepatitis C correlates with cellular senescence in damaged liver tissue. However, it is still unclear how senescence can affect replication of the hepatitis C virus (HCV). In this work, we report that an inhibitor of cyclin-dependent kinases 4/6, palbociclib, not only induced in hepatoma cells a pre-senescent cellular phenotype, including G1 arrest in the cell cycle, but also accelerated viral replicon multiplication. Importantly, suppression of HCV replication by direct acting antivirals (DAAs) was barely affected by pre-senescence induction, and vice versa, the antiviral activities of host-targeting agents (HTAs), such as inhibitors of human histone deacetylases (HDACi), produced a wide range of reactions-from a dramatic reduction to a noticeable increase. It is very likely that under conditions of the G1 arrest in the cell cycle, HDACi exhibit their actual antiviral potency, since their inherent anticancer activity that complicates the interpretation of test results is minimized.
Asunto(s)
Senescencia Celular/fisiología , Hepacivirus/metabolismo , Replicación Viral/fisiología , Antivirales/farmacología , Carcinoma Hepatocelular/metabolismo , Línea Celular , Genotipo , Hepacivirus/genética , Hepacivirus/patogenicidad , Hepatitis C/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Hígado/patología , Fenotipo , Piperazinas/farmacología , Piridinas/farmacología , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
A set of ortho-, meta- and para-substituted cinnamic hydroxamic acids (CHAs) was synthesized. In each series of structural isomers, a phenyl substituent was linked to an aromatic ring of the parent cinnamic acid via a linker of one to four atoms in length. Using a cell test system with the full-length replicon of hepatitis C virus (HCV), we established a relationship between the suppression of HCV replicon propagation and the inhibition of class I/IIb histone deacetylases (HDACs). Anti-HCV activity correlated with the inhibition of HDAC8 in the case of ortho-CHAs, while in the case of meta-CHAs it correlated with the inhibition of HDAC1/2/3 and HDAC6. The antiviral activity of para-CHAs was many times stronger than that of meta-CHAs with about the same efficiency of HDAC1/2/3/6 inhibition, which indicated the existence of an additional cell target that does not belong to the studied group of HDACs.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Cinamatos/química , Cinamatos/farmacología , Hepacivirus/efectos de los fármacos , Hepacivirus/fisiología , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Humanos , Isomerismo , Replicación Viral/efectos de los fármacosRESUMEN
N'-Propylhydrazide analogs of hydroxamic inhibitors of histone deacetylases (HDACs), including tubastatin A, vorinostat and belinostat, were synthesized. All prepared compounds inhibited HDAC1/2/3, but not HDAC6, except for one hydrazide analog of HDAC4/5/7 inhibitor that was completely inactive. A novel 4-substituted derivative of N'-propylbenzohydrazide with extremely high anti-HCV activity was discovered.
Asunto(s)
Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Hidrazinas/farmacología , Antivirales/síntesis química , Antivirales/química , Relación Dosis-Respuesta a Droga , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Humanos , Hidrazinas/síntesis química , Hidrazinas/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Proteínas Represoras/antagonistas & inhibidores , Proteínas Represoras/metabolismo , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Catalytic reaction of arylhydroxamic acids with alkenes represents a convenient method for preparation of biologically active dihydroisoquinolones. Here, the rhodium(III) complex [(C5 H2 tBu2 CH2 tBu)RhCl2 ]2 , which allows one to carry out such reactions with high regioselectivity to obtain 4-substituted dihydroisoquinolones in 72-97 % yields, is described. The regioselectivity is provided by the bulky cyclopentadienyl ligand of the catalyst, which is formed through a [2+2+1] cyclotrimerization of tert-butylacetylene. The catalytic reaction tolerates various distant functional groups in alkenes, but is inhibited by bulky (e.g., tBu) or strongly coordinating (e.g., imidazolyl) substituents. Some of the prepared dihydroisoquinolones effectively inhibit growth of phytopathogenic fungi.
RESUMEN
Recently we reported benzohydroxamic acids (BHAs) as potent and selective inhibitors of hepatitis C virus (HCV) replicon propagation. In this work 12 pyridine hydroxamic acids (PHAs) were synthesized and tested in full-genome replicon assay. It was found that PHAs possessed very similar anti-HCV properties compared to BHAs. Both classes of hydroxamic acids caused hyperacetylation of α-tubulin pointing to inhibition of histone deacetylase 6 (HDAC6) as part of their antiviral activity. The tested compounds did not inhibit the growth of poliovirus, displaying high selectivity against HCV.
Asunto(s)
Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Histona Desacetilasas/metabolismo , Ácidos Hidroxámicos/farmacología , Piridinas/química , Antivirales/química , Línea Celular Tumoral , Regulación de la Expresión Génica/efectos de los fármacos , Histona Desacetilasa 6 , Histona Desacetilasas/genética , Humanos , Ácidos Hidroxámicos/química , Estructura Molecular , Poliovirus/efectos de los fármacos , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacos , VirusRESUMEN
A diverse collection of 40 derivatives of benzohydroxamic acid (BHAs) of various structural groups were synthesized and tested against hepatitis C virus (HCV) in full-genome replicon assay. Some of these compounds demonstrated an exceptional activity, suppressing viral replication at sub-micromolar concentrations. The compounds were inactive against key viral enzymes NS3, and NS5B in vitro assays, suggesting host cell inhibition target(s). The testing results were consistent with metal coordination by the BHAs hydroxamic group in complex with a target(s). Remarkably, this class of compounds did not suppress poliomyelitis virus (PV) propagation in RD cells indicating a specific antiviral activity of BHAs against HCV.