RESUMEN
Herein, we report the identification, design, and synthesis of a series of 4-substituted 2-amino-3,4-dihydroquinazolines with hairpin turn side chains as novel inhibitors of BACE-1. The dihydroquinazoline derivatives were rationally designed by modifying the amide group and relocating the α -hydrophobic substituent on the hairpin turn side chain of lead compound 2 to the C4-position on the 3,4-dihydroquinazoline scaffold to facilitate interactions with the S1, S2 and S1' subsites of BACE-1. Among these derivatives, two compounds exhibited potent BACE-1 inhibitory activity: 4-methyl-substituted (22a, BACE-1 CFA IC50â¯=â¯0.38⯵M; BACE-1 WCA IC50â¯=â¯0.14⯵M) and 4-cyclohexylmethyl-substituted (22b, BACE-1 CFA IC50â¯=â¯0.49⯵M; BACE-1 WCA IC50â¯=â¯0.14⯵M) 2-amino-3,4-dihydroquinazoline, each bearing a side chain of N-cyclohexyl-N-((1-methyl-1H-pyrazol-4-yl)methyl amide. The results suggest that the structural modifications maintain the hairpin turn topology similar to that of compound 2 and provide an additional interaction with the S2 subsite.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Conformación Molecular , Quinazolinas/síntesis química , Quinazolinas/farmacología , Relación Estructura-ActividadRESUMEN
Glioblastoma is the most fatal type of primary brain cancer, and current treatments for glioblastoma are insufficient. HDAC6 is overexpressed in glioblastoma, and siRNA-mediated knockdown of HDAC6 inhibits glioma cell proliferation. Herein, we report a high-selective HDAC6 inhibitor, J22352, which has PROTAC (proteolysis-targeting chimeras)-like property resulted in both p62 accumulation and proteasomal degradation, leading to proteolysis of aberrantly overexpressed HDAC6 in glioblastoma. The consequences of decreased HDAC6 expression in response to J22352 decreased cell migration, increased autophagic cancer cell death and significant tumor growth inhibition. Notably, J22352 reduced the immunosuppressive activity of PD-L1, leading to the restoration of host anti-tumor activity. These results demonstrate that J22352 promotes HDAC6 degradation and induces anticancer effects by inhibiting autophagy and eliciting the antitumor immune response in glioblastoma. Therefore, this highly selective HDAC6 inhibitor can be considered a potential therapeutic for the treatment of glioblastoma and other cancers.
Asunto(s)
Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Histona Desacetilasa 6/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/síntesis química , Neoplasias Experimentales/tratamiento farmacológico , Quinazolinas/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Autofagia , Línea Celular Tumoral , Supervivencia Celular , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Histona Desacetilasa 6/metabolismo , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Masculino , Ratones , Ratones Desnudos , Estructura Molecular , Quinazolinas/química , Quinazolinas/farmacologíaRESUMEN
We designed and synthesized quinazolin-2,4-dione-based hydroxamic acids to serve as selective competitive inhibitors of histone deacetylase-6 (HDAC6). The most potent and selective compound, 3d (IC50, 4 nM, HDAC6; IC50 > 10 µM, HDAC1), substantially increased acetylation of α-tubulin instead of histones in the lung cancer cell line, LL2. Paclitaxel in combination with 3d had a synergistic anticancer effect on reduction of programmed death-ligand 1 expression in LL/2 cells. When given orally, 3d was mainly found to locate in the liver and lungs, at a concentration 18- to 70-fold greater, respectively, than in plasma. As an orally active HDAC6 inhibitor, 3d (20 mg/kg) potentiated paclitaxel antitumor activity (percentage tumor growth inhibition, 67.5%) in a xenograft syngeneic non-small cell lung cancer mouse model.
Asunto(s)
Apoptosis/efectos de los fármacos , Histona Desacetilasa 6/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/química , Ácidos Hidroxámicos/química , Quinazolinonas/química , Acetilación/efectos de los fármacos , Animales , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Sinergismo Farmacológico , Histona Desacetilasa 6/metabolismo , Inhibidores de Histona Desacetilasas/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Ácidos Hidroxámicos/metabolismo , Ácidos Hidroxámicos/farmacología , Ácidos Hidroxámicos/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos C57BL , Paclitaxel/farmacología , Relación Estructura-Actividad , Distribución Tisular , Trasplante Homólogo , Tubulina (Proteína)/metabolismoRESUMEN
HDAC6 receives great attention because of its therapeutic potential for the treatment of various diseases. Selective fluorescence imaging for HDAC6 is important for its pathological and biological studies. However, specific detection of HDAC6 by using a fluorescent small molecule probe remains a great challenge. Herein, a series of fluorescent HDAC6-selective inhibitors incorporating a naphthalimide skeleton were designed and synthesized. A structure-activity relationship study identified that compound JW-1 had the greatest inhibitory activity and superior specificity against HDAC6. JW-1 could substantially increase α-tubulin acetylation and was active against a panel of six cancer cell lines. Photophysical characterization and cellular imaging of MDA-MB-231 cells demonstrated that JW-1 is a highly fluorescent, cell penetrable, small-molecule inhibitor of HDAC6 that can be used for the detection of HDAC6 in complex cellular environments.
Asunto(s)
Colorantes Fluorescentes/química , Histona Desacetilasa 6/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/química , Línea Celular Tumoral , Colorantes Fluorescentes/síntesis química , Inhibidores de Histona Desacetilasas/síntesis química , Humanos , Simulación del Acoplamiento Molecular , Imagen Óptica , Relación Estructura-ActividadRESUMEN
Herpes simplex virus (HSV), a common latent virus in humans, causes certain severe diseases. Extensive use of acyclovir (ACV) results in the development of drug-resistant HSV strains, hence, there is an urgent need to develop new drugs to treat HSV infection. Houttuynia cordata (H. cordata), a natural herbal medicine, has been reported to exhibit anti-HSV effects which is partly NF-κB-dependent. However, the molecular mechanisms by which H. cordata inhibits HSV infection are not elucidated thoroughly. Here, we report that H. cordata water extracts (HCWEs) inhibit the infection of HSV-1, HSV-2, and acyclovir-resistant HSV-1 mainly via blocking viral binding and penetration in the beginning of infection. HCWEs also suppress HSV replication. Furthermore, HCWEs attenuate the first-wave of NF-κB activation, which is essential for viral gene expressions. Further analysis of six compounds in HCWEs revealed that quercetin and isoquercitrin inhibit NF-κB activation and additionally, quercetin also has an inhibitory effect on viral entry. These results indicate that HCWEs can inhibit HSV infection through multiple mechanisms and could be a potential lead for development of new drugs for treating HSV.