RESUMEN
Epigenetics, particularly deacetylation, plays a critical role in tumorigenesis as many carcinogens are under tight control by post-translational modification. HDAC6, an important and special histone deacetylase (HDAC) family member, has been indicated to increase carcinogenesis through various functions. Recent studies demonstrated the effects of HDAC6 inhibitors in mitotic arrest, however, detailed mechanisms still remain unknown. Herein, we review and summarize HDAC6-associated proteins that have been implicated in important roles in mitosis. We also discuss the development of medicinal agents targeting HDAC6.
RESUMEN
The multitarget-directed ligands approach represents a potential strategy to provide effective treatments for Alzheimer's disease (AD) given its multifactorial pathology. Herein, a series of N-benzyl piperidine derivatives were designed, synthesized, and biologically characterized for dual inhibitions of histone deacetylase (HDAC) and acetylcholinesterase (AChE). Among the compounds tested, d5 and d10 exhibited dual enzyme inhibitions (d5: HDACIC50 = 0.17 µM, AChEIC50 = 6.89 µM, d10: HDACIC50 = 0.45 µM, AChEIC50 = 3.22 µM), and both compounds showed activities on scavenging free radical, metal chelating, and inhibiting Aß aggregations. More importantly, both compounds exhibited promising neuroprotective activities in PC-12 cells and good AChE selectivity. Collectively, the multifunctional profiles of compound d5 and d10 encourage further optimization and exploration to develop more potent analogues as potential treatments for AD.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Acetilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Relación Estructura-Actividad , Inhibidores de Histona Desacetilasas/farmacología , Piperidinas/farmacología , Diseño de Fármacos , Péptidos beta-AmiloidesRESUMEN
HDAC6, a member of the histone deacetylase family, mainly is a cytosolic protein and regulates cell growth by acting on non-histone substrates, such as α -tubulin, cortactin, heat shock protein HSP90, programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1), that are closely related to the proliferation, invasion, immune escape and angiogenesis of cancer tissues. The approved drugs targeting the HDACs are all pan-inhibitors and have many side effects due to their lack of selectivity. Therefore, development of selective inhibitors of HDAC6 has attracted much attention in the field of cancer therapy. In this review, we will summarize the relationship between HDAC6 and cancer, and discuss the design strategies of HDAC6 inhibitors for cancer treatment in recent years.
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Antineoplásicos , Neoplasias , Humanos , Histona Desacetilasa 6/metabolismo , Inhibidores de Histona Desacetilasas/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Histona Desacetilasas/metabolismoRESUMEN
As the vital component of innate immune system, the NLRP3 inflammasome is implicated in the onset and progression of a variety of inflammatory diseases and has emerged as an attractive drug target. Herein a series of novel phenyl vinyl sulfone based NLRP3 inflammasome inhibitors were designed, synthesized and biologically characterized. The most potent two hits 7a and 5b showed inhibition on the NLRP3 inflammasome with the IC50 of 1.83 ± 0.28 µM and 0.91 ± 0.06 µM, respectively. Further characterization confirmed their inhibition of NLRP3-mediated IL-1ß release in vivo. Collectively, our findings encourage further research of more potent inhibitors based on this chemical scaffold.
Asunto(s)
Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR , Sulfonas/farmacologíaRESUMEN
C-Jun N-terminal kinase (JNK) is a member of mitogen-activated protein kinases (MAPKs) family, with three isoforms, JNK1, JNK2 and JNK3. Alzheimer's disease (AD) is a neurological disorder and the most common type of dementia. Two well-established AD pathologies are the deposition of Aß amyloid plaques and neurofibrillary tangles caused by Tau hyperphosphorylation. JNK3 is involved in forming amyloid Aß and neurofibrillary tangles, suggesting that JNK3 may represent a target to develop treatments for AD. Therefore, this review will discuss the roles of JNK3 in the pathogenesis and treatment of AD, and the latest progress in the development of JNK3 inhibitors.
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Enfermedad de Alzheimer , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Ovillos Neurofibrilares/metabolismo , Proteínas tau/metabolismoRESUMEN
Through rational drug design, we previously identified an indenoprazole derivative, 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)acetamide (LL01), as a potent tubulin polymerization inhibitor targeting the tubulin colchicine binding site. In this study, we further demonstrated that LL01 was not a P-gp substrate. It potently inhibited the growth of a variety of tumor cells, including those with multidrug resistance, with GI50 values in the low nanomole ranges. In vitro liver microsome stability assay, LL01 was modest stable in the liver microsomes of human, mouse and rat, but was fast metabolized in dog. After single oral administration of LL01 at a dose of 10 mg/kg in SD male rats, LL01 showed acceptable PK properties with a mean bioavailability of 41%. In human HepG2 hepatoma xenograft, at the oral doses of 25 mg/kg/day and 12.5 mg/kg/day, LL01 inhibited the tumor growth by 61.27%, and 43.74%, respectively, which is much better than the positive drug sorafenib (29.45%; 30 mg/kg/day). Therefore, LL01 might be a potential drug candidate for further investigation for hepatocellular carcinoma therapy.
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Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Colchicina/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Moduladores de Tubulina/farmacología , Tubulina (Proteína)/metabolismo , Animales , Antineoplásicos/química , Apoptosis , Sitios de Unión , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Proliferación Celular , Resistencia a Múltiples Medicamentos , Femenino , Humanos , Técnicas In Vitro , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Ratas , Ratas Sprague-Dawley , Moduladores de Tubulina/química , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In order to develop multitarget-directed ligands as potential treatments for Alzheimer's disease, twenty-eight new tacrine-hydroxamate derivatives were designed, synthesized, and biologically evaluated. As expected, most of the compounds exhibited inhibitory activities against cholinesterases (ChEs) and histone deacetylase (HDACs). Among the tested compounds, A10 showed not only potent and selective inhibition on AChE at sub-nanomolar potency (AChEIC50 = 0.12 nM, BChEIC50 = 361.52 nM) but also potent inhibition on HDAC (IC50 = 0.23 nM). Moreover, A10 exhibited inhibitory activity on Aß1-42 self-aggregation as well as disaggregation activity on pre-formed Aß fibrils. Furthermore, A10 exhibited antioxidant activity and metal chelating properties. Further mechanistic studies demonstrated that A10 is a pan-inhibitor of HDACs and a mixed-type inhibitor for AChE. It shown that A10 is a BBB penetrant by online prediction. Taken together, the results indicate that A10 can serve as a lead compound to develop promising candidate analogs as AD therapeutics.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Antioxidantes/farmacología , Inhibidores de la Colinesterasa/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Tacrina/farmacología , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Antioxidantes/síntesis química , Antioxidantes/química , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Electrophorus , Células HeLa , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Histona Desacetilasas/metabolismo , Caballos , Humanos , Ácidos Hidroxámicos/química , Ligandos , Modelos Moleculares , Estructura Molecular , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/metabolismo , Agregado de Proteínas/efectos de los fármacos , Relación Estructura-Actividad , Tacrina/químicaRESUMEN
Histone deacetylases (HDACs) have been indicated important roles in neurodegenerative disorders including Alzheimer's disease (AD). Herein, a series of novel compounds that contain a memantine moiety were designed to target HDACs and N-methyl-d-aspartate receptor (NMDAR) which are related to the treatment of AD. Biological characterization established that compound 9d exhibited a balanced inhibitory activity on NMDAR and HDACs. This compound is relatively selective to HDAC6 with IC50 of 0.18 µM and also maintains comparable activity on NMDAR (Ki = 0.59 µM) as memantine. Functionally, treatment with 9d increased the level of AcTubulin in MV4-11 cells and rescued PC-12 cells from H2O2-induced cytotoxicity with EC50 of 0.94 µM. Studies in mice also demonstrated that compound 9d efficiently penetrates the blood brain barrier to reach the brain tissue. Collectively, the results strongly encourage further development of 9d as a potential therapeutic agent for AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Diseño de Fármacos , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Fármacos Neuroprotectores/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Enfermedad de Alzheimer/metabolismo , Animales , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Humanos , Peróxido de Hidrógeno/antagonistas & inhibidores , Peróxido de Hidrógeno/farmacología , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Células PC12 , Ratas , Receptores de N-Metil-D-Aspartato/metabolismo , Relación Estructura-ActividadRESUMEN
Histone deacetylases inhibitors (HDACIs) represents effective treatments for cancer. In continuing our efforts to develop novel and potent HDACIs, a series of N-hydroxycinnamamide-based HDACIs with aromatic ring and various aliphatic linker have been successfully designed and synthesized. Biological evaluations established that compounds 4h, 4i, 4j, 4l, 4r showed superior inhibition on histone deacetylase and antiproliferative activity in some solid tumor cell lines [HeLa, SK-N-BE(2), PC-3] compared to the known inhibitor SAHA. Among these analogs, 4l exhibited selectivity to HDAC1.
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Diseño de Fármacos , Histona Desacetilasa 1/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/síntesis química , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Histona Desacetilasa 1/metabolismo , Inhibidores de Histona Desacetilasas/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Indoles/química , Indoles/metabolismo , Indoles/farmacología , Simulación del Acoplamiento Molecular , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
Histone deacetylase inhibitors (HDACIs) are effective small molecules in the treatment of human cancers. In our continuing efforts to develop novel N-hydroxyterephthalamide-based HDACIs, herein we report the design and development of a new class of N-hydroxybenzamide-based HDACIs. In this new class of analogs, we inserted an ethylene moiety in the linker and used indole as a part of the Y-shaped cap group. Biological characterization identified compounds 4o, 4p, 4q and 4t to show improved HDAC inhibition, while no isoform selectivity for HDACs was observed. These compounds also exhibited improved anti-proliferative activity against multiple cancer cell lines when compared to their parent compound and positive control SAHA.
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Antineoplásicos/síntesis química , Benzamidas/química , Inhibidores de Histona Desacetilasas/síntesis química , Histona Desacetilasas/metabolismo , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Benzamidas/metabolismo , Benzamidas/farmacología , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Células HeLa , Inhibidores de Histona Desacetilasas/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/química , Humanos , Conformación Molecular , Simulación del Acoplamiento Molecular , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Relación Estructura-ActividadRESUMEN
As a continuous research for the discovery of coumarin-based targeted anticancer agents, we designed and synthesized a series of novel histone deacetylases (HDAC) inhibitors using the 8-ethoxy-3-nitro-2H-chromene as the surface binding or cap group, linear dicarboxylic acid or ω-amino acid moiety with different length as the linking motif, ortho-aminoanilides, amides or α-aminoamides as the zinc binding group and the internal cavity motifs. Most of these 3-nitro-2H-chromene derivatives exhibited good growth inhibitory activity against K562, A549, MCF-7, PC3 and Hela cells and were more potent than the reference drug SAHA and MS-275. At the concentration of 10µM, the ortho-aminoanilide series and the d-Phe derived α-aminoamide derivatives 16a and 16b displayed more potent activity toward HADC1 over HADC2, and only moderate to weak activity over HADC6. In contrast, the amide ZBG analogues, 12a and 12b, 14 and 15, were only moderate HDAC6 inhibitors, but more selective over HDAC1 and HDAC2. The ortho-aminoanilides 9b, 9c, 10b, 10c, 11b, and the α-aminoamides 16a and 16b were potent HADC1 inhibitors with the IC50 values in the nanomolar ranges. The ortho-aminoanilides 10b and10c with a phenyl internal cavity motif were more potent than MS-275 as HADC1 inhibitors and more selective over HADC2.
Asunto(s)
Benzopiranos/química , Benzopiranos/farmacología , Diseño de Fármacos , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/farmacología , Benzopiranos/síntesis química , Espectroscopía de Resonancia Magnética con Carbono-13 , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores de Histona Desacetilasas/síntesis química , Humanos , Espectroscopía de Protones por Resonancia Magnética , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
BACKGROUND: In rice, five common Wx alleles, wx, Wxt , Wxg1 , Wxg2 and Wxg3 , have been identified according to their apparent amylose content (AAC) phenotypes. Previous studies revealed that this Wx allelic variation may also affect other starch properties. However, so far, to what extent the five Wx alleles influence the crystalline structure, thermal and swelling properties of rice starch is still unclear. For this purpose, a set of single-segment substitution lines (SSSLs) harboring five different Wx alleles, varying widely in AAC, was used for comparative studies. RESULTS: The crystalline structure, thermal properties and swelling behavior of starches from the SSSLs varied widely depending on Wx genotype. Effects of different Wx alleles on relative crystallinity followed the order wx > Wxt > Wxg1 = Wxg2 > Wxg3 . The glutinous and Wxt genotype starches showed higher gelatinization temperatures and enthalpy compared with other Wx genotypes. The order for swelling power was wx > Wxt > Wxg1 > Wxg2 > Wxg3 , while the order for degree of solubility was Wxg3 > Wxg1 > Wxg2 > Wxt = wx. Correlation analysis indicated that AAC was significantly and negatively correlated with relative crystallinity (r = -0.996, P < 0.01) and swelling power (r = -0.982, P < 0.01). CONCLUSION: The present results provide new knowledge about the influence of different Wx alleles on the structural and physicochemical properties of rice starch. © 2016 Society of Chemical Industry.
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Oryza/química , Almidón/química , Alelos , Geles/química , Calor , Oryza/clasificación , Oryza/genética , Solubilidad , TemperaturaRESUMEN
Herein, a novel mutual prodrug BC-A1 was discovered by integrating ubenimex and gemcitabine into one molecule. Biological characterization revealed that compound BC-A1 could maintain both the anti-CD13 activity of ubenimex and the cytotoxic activity of gemcitabine in vitro. Further characterization also demonstrated that compound BC-A1 exhibited significant anti-invasion and anti-angiogenesis effects in vitro. The preliminary stability test of BC-A1 revealed that it could release gemcitabine in vitro. The in vivo anti-tumor results in liver cancer showed that at the same dosage, oral administration of BC-A1 was as potent as intraperitoneal administration of gemcitabine. This warranted the further research and development of the orally active prodrug BC-A1 because gemcitabine can not be orally administrated in clinic.
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Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Desoxicitidina/análogos & derivados , Descubrimiento de Drogas , Leucina/análogos & derivados , Administración Oral , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/química , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Aorta Torácica/efectos de los fármacos , Apoptosis/efectos de los fármacos , Antígenos CD13/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Desoxicitidina/administración & dosificación , Desoxicitidina/química , Desoxicitidina/farmacología , Relación Dosis-Respuesta a Droga , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Humanos , Leucina/administración & dosificación , Leucina/química , Leucina/farmacología , Estructura Molecular , Ratas , Relación Estructura-Actividad , Porcinos , GemcitabinaRESUMEN
Histone deacetylases inhibitors (HDACIs) have captured more and more attention in many diseases therapies, of which cancer is the most intractable. A novel series of N-hydroxybenzamide derivatives containing indole cap group was designed and synthesized. Most compounds exhibited excellent HDACs inhibitory activity, especially 8q-8v with low nanomolar IC50 values (1.5-13.0 nM), which were much more potent than the positive control SAHA. The most potent compound 8r showed slightly higher growth inhibitory activity than SAHA in multiple tumor cell lines, even though, antiproliferative activity of 8r seemed inferior to its HDAC inhibition activity. Poor transcellular permeability obtained from the result of HDAC class I cellular assay could explain the inferior antiproliferative activity. In addition, 8r displayed similar HDAC IIa cellular activity to class I, which indicated 8r might be a potent pan-HDAC inhibitor.
Asunto(s)
Benzamidas/química , Inhibidores de Histona Desacetilasas/química , Histona Desacetilasas/química , Indoles/química , Benzamidas/síntesis química , Benzamidas/toxicidad , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células HeLa , Inhibidores de Histona Desacetilasas/metabolismo , Inhibidores de Histona Desacetilasas/toxicidad , Histona Desacetilasas/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Unión Proteica , Estructura Terciaria de Proteína , Relación Estructura-ActividadRESUMEN
Off-target toxicity is one of the main challenges faced by anticancer chemotherapeutics. For tumor targeted and precision chemotherapy, we take the advantages of the ligand directed tumor active targeting of small molecule drug conjugates (SMDCs) and the passive tumor targeting of nanoparticles via the enhanced penetration and retention (EPR) effects, put forward a branched small molecule drug conjugate (BSMDC) nanomedicine design concept. In a proof of concept, we used pentaerythritol as the branched moiety, galactosamine (GalN) as the hepatocellular carcinoma (HCC) directing ligands, PTX as a payload, and a stearoyl moiety as the amphiphilic property adjusting group, designed and synthesized BSMDC 1 and prepared its NPs. In cellular level, the BSMDC 1 NPs targeted asialoglycoprotein receptor (ASGPR)-overexpressing HepG2 cells, were effectively taken up in the cells and released in tumor microenvironments, inhibited the HepG2 cell proliferation, arrested HepG2 cell in G2/M phase and induced tumor cell apoptosis. In HepG2 xenograft nude mice, the BSMDC 1 NPs were high specific to target the tumor and demonstrated a higher antitumor efficiency than BSMDC 1, having no apparent influences on mice body weights and major organs, supporting our BSMDC nanomedicine design concept. Therefore, this new strategy may find applications for cancer targeted and precision chemotherapy.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Galactosamina/farmacología , Neoplasias Hepáticas/tratamiento farmacológico , Paclitaxel/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Antineoplásicos Fitogénicos/química , Apoptosis/efectos de los fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Galactosamina/química , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/metabolismo , Neoplasias Hepáticas Experimentales/patología , Ratones , Ratones Desnudos , Estructura Molecular , Nanomedicina , Paclitaxel/química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
A series of novel S-DABO analogues of 5-alkyl-2-arylthio-6-((3,4-dihydroquinolin-1(2H)-yl)methyl)pyrimidin-4(3H)-ones were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Among them, the most potent HIV-1 inhibitors were compounds 6c1,6c6, and 6b1 (EC(50)=0.24 ± 0.05, 0.38 ± 0.13, 0.39 ± 0.05 µM, respectively), which possess improved or similar HIV-1 inhibitory activity compared with nevirapine (NVP) (EC(50)=0.21 µM) and delavirdine (DLV) (EC(50)=0.32 µM). None of these compounds were active against HIV-2 replication. Furthermore, enzyme inhibitory assays were performed with selected derivatives against HIV-1 wtRT, confirming that the main target of these compounds is the HIV-1 RT and these new S-DABOs are acting as NNRTIs. The preliminary structure-activity relationship (SAR) of these new congeners is discussed briefly and rationalized by docking studies.
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Fármacos Anti-VIH/farmacología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Pirimidinonas/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Línea Celular Tumoral , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Transcriptasa Inversa del VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-2/efectos de los fármacos , Humanos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Pirimidinonas/síntesis química , Pirimidinonas/química , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Estereoisomerismo , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Histone deacetylase 6 (HDAC6) is a potential target for Alzheimer's disease (AD). In this study, a series of novel phenothiazine-, memantine-, and 1,2,3,4-tetrahydro-γ-carboline-based HDAC6 inhibitors with a variety of linker moieties were designed and synthesized. As a hydrochloride salt, the phenothiazine-based hydroxamic acid W5 with a pyridyl-containing linker motif was identified as a high potent and selective HDAC6 inhibitor. It inhibited HDAC6 with an IC50 of 2.54 nM and was more than 290- to 3300-fold selective over other HDAC isoforms. In SH-SY5Y cells, W5 dose-dependently increased the acetylated α-tubulin levels and reduced the hyperphosphorylated tau proteins at Ser396. As an effective metal chelator, W5 inhibited Cu2+-induced Aß1-42 aggregation and disaggregated Cu2+-Aß1-42 oligomers, and showed protective effects on the SH-SY5Y cells against Aß1-42- as well as Cu2+-Aß1-42 induced cell damages, serving as a potential ligand to target AD metal dyshomeostasis. Moreover, W5 promoted the differentiated neuronal neurite outgrowth, increased the mRNA expression of the recognized neurogenesis markers, GAP43, N-myc, and MAP-2. Therefore, W5 might be a good lead for the development of novel HDAC6 inhibitors targeting multi-facets of AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Histona Desacetilasa 6/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Fármacos Neuroprotectores/farmacología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Supervivencia Celular/efectos de los fármacos , Cobre/metabolismo , Relación Dosis-Respuesta a Droga , Histona Desacetilasa 6/metabolismo , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/química , Humanos , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/metabolismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
A thiazolidine-2,4-dione derivative, 3-(2-aminoethyl)-5-(3-phenyl-propylidene)-thiazolidine-2,4-dione (2), was identified as a dual inhibitor of the Raf/MEK/ extracellular signal-regulated kinase (ERK) and the phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascades. The discovered compound inhibited cell proliferation, induced early apoptosis, and arrested cells in G(0)/G(1) phase in human leukemia U937 cells. These results indicate its potential as a new lead compound to develop novel dual signaling pathway inhibitors and anticancer agents.
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Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Tiazolidinas/química , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-raf/metabolismo , Tiazolidinas/síntesis química , Tiazolidinas/farmacologíaRESUMEN
NLRP3 (Nod-like receptor protein 3) belongs to the NOD-like receptor family, which is activated by pathogen and damage-associated signals to form a multimeric protein complex, known as the NLRP3 inflammasome. NLRP3 inflammasome activation leads to release of proinflammatory cytokines IL-1ß and IL-18, thus inducing pyroptosis, a programmed cell death mechanism. Dysregulation of the NLRP3 inflammasome pathway is closely related to the development of many human diseases, such as neuroinflammation, metabolic inflammation, and immune inflammation. Emerging studies have suggested NLRP3 inflammasome as a potential drug-target for inflammatory diseases. Several small molecules have recently been identified to target the NLRP3 inflammasome pathway directly or indirectly and alleviate related disease pathology. This review summarizes recent evolving landscape of small molecule inhibitor development targeting the NLRP3 inflammasome pathway.
Asunto(s)
Inflamasomas/efectos de los fármacos , Inflamación/tratamiento farmacológico , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Humanos , Inflamasomas/metabolismo , Inflamación/metabolismo , Estructura Molecular , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-ActividadRESUMEN
Taking the previously discovered 1-methyl-1,4-dihydroindeno[1,2c]pyrazol derivative LL01 as a lead, systematic structural modifications were made at the phenolic 6- and 7-positions and the aniline at the 3-position of the indenopyrazole core to investigate the SARs and to improve water solubility. Among the designed indenopyrazoles ID01-ID33, a series of potent MTAs were identified. As the hydrochloride salt(s), ID09 and ID33 showed excellent aqueous solubility and favorable Logâ¯P value and displayed noteworthily low nanomolar potency against a variety of tumor cells, including those taxol-resistant ones. They inhibited tubulin polymerization, disrupted cellular microtubule networks by targeting the colchicine site, and promoted HepG2 cell cycle arrest and cell apoptosis. In the HepG2 xenograft mouse model, ID09 and ID33 effectively inhibited tumor growth at an oral dose of 25 mg/kg. At an intravenous (iv) injection dose of 10 mg/kg every other day, ID09 suppressed tumor growth by 68% without obvious toxicity.