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1.
Mol Phylogenet Evol ; 186: 107870, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37406952

RESUMEN

The deciduous broad-leaved forests (DBLFs) cover large temperate and subtropical high-altitude regions in the Northern Hemisphere. They are home to rich biodiversity, especially to numerous endemic and relict species. However, we know little about how this vegetation in the Northern Hemisphere has developed through time. Here, we used Actaea (Ranunculaceae), an herbaceous genus almost exclusively growing in the understory of the Northern Hemisphere DBLFs, to shed light on the historical assembly of this biome in the Northern Hemisphere. We present a complete species-level phylogenetic analysis of Actaea based on five plastid and nuclear loci. Using the phylogenetic framework, we estimated divergence times, ancestral ranges, and diversification rates. Phylogenetic analyses strongly support Actaea as monophyletic. Sections Podocarpae and Oligocarpae compose a clade, sister to all other Actaea. The sister relationship between sections Chloranthae and Souliea is strongly supported. Section Dichanthera is not monophyletic unless section Cimicifuga is included. Actaea originated in East Asia, likely the Qinghai-Tibet Plateau, in the late Paleocene (c. 57 Ma), and subsequently dispersed into North America in the middle Eocene (c. 43 Ma) via the Thulean bridge. Actaea reached Europe twice, Japan twice, and Taiwan once, and all these five colonization events occurred in the late Miocene-early Pliocene, a period when sea level dropped. Actaea began to diversify at c. 43 Ma. The section-level diversification took place at c. 27-37 Ma and the species-level diversification experienced accelerations twice, which occurred at c. 15 Ma and c. 5 Ma, respectively. Our findings suggest that the Northern Hemisphere DBLFs might have risen in the middle Eocene and further diversified in the late Eocene-Oligocene, middle Miocene and early Pliocene, in association with climatic deterioration during these four periods.


Asunto(s)
Actaea , Ranunculaceae , Filogenia , Filogeografía , Bosques
2.
3.
Bioorg Med Chem Lett ; 21(6): 1719-23, 2011 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-21316221

RESUMEN

Quinazoline 3 was discovered as a novel c-jun N-terminal kinase (JNK) inhibitor with good brain penetration and pharmacokinetic (PK) properties. A number of analogs which were potent both in the biochemical and cellular assays were discovered. Quinazoline 13a was found to be a potent JNK3 inhibitor (IC(50)=40 nM), with >500-fold selectivity over p38, and had good PK and brain penetration properties. With these properties, 13a is considered a potential candidate for in vivo evaluation.


Asunto(s)
Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/síntesis química , Quinazolinas/farmacología , Encéfalo/metabolismo , Concentración 50 Inhibidora , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Quinazolinas/química , Quinazolinas/farmacocinética , Relación Estructura-Actividad
5.
Bioorg Med Chem Lett ; 19(12): 3344-7, 2009 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-19433357

RESUMEN

A novel series of c-jun N-terminal kinase (JNK) inhibitors were designed and developed from a high-throughput-screening hit. Through the optimization of the piperazine amide 1, several potent compounds were discovered. The X-ray crystal structure of 4g showed a unique binding mode different from other well known JNK3 inhibitors.


Asunto(s)
Amidas/síntesis química , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Piperazinas/síntesis química , Amidas/farmacología , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Piperazinas/farmacología , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-Actividad
6.
EBioMedicine ; 36: 18-28, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-30279143

RESUMEN

BACKGROUND: Senescence is a tumor suppressor mechanism activated in stressed cells to prevent replication of damaged DNA. Senescent cells have been demonstrated to play a causal role in driving aging and age-related diseases using genetic and pharmacologic approaches. We previously demonstrated that the combination of dasatinib and the flavonoid quercetin is a potent senolytic improving numerous age-related conditions including frailty, osteoporosis and cardiovascular disease. The goal of this study was to identify flavonoids with more potent senolytic activity. METHODS: A panel of flavonoid polyphenols was screened for senolytic activity using senescent murine and human fibroblasts, driven by oxidative and genotoxic stress, respectively. The top senotherapeutic flavonoid was tested in mice modeling a progeroid syndrome carrying a p16INK4a-luciferase reporter and aged wild-type mice to determine the effects of fisetin on senescence markers, age-related histopathology, disease markers, health span and lifespan. Human adipose tissue explants were used to determine if results translated. FINDINGS: Of the 10 flavonoids tested, fisetin was the most potent senolytic. Acute or intermittent treatment of progeroid and old mice with fisetin reduced senescence markers in multiple tissues, consistent with a hit-and-run senolytic mechanism. Fisetin reduced senescence in a subset of cells in murine and human adipose tissue, demonstrating cell-type specificity. Administration of fisetin to wild-type mice late in life restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan. INTERPRETATION: The natural product fisetin has senotherapeutic activity in mice and in human tissues. Late life intervention was sufficient to yield a potent health benefit. These characteristics suggest the feasibility to translation to human clinical studies. FUND: NIH grants P01 AG043376 (PDR, LJN), U19 AG056278 (PDR, LJN, WLL), R24 AG047115 (WLL), R37 AG013925 (JLK), R21 AG047984 (JLK), P30 DK050456 (Adipocyte Subcore, JLK), a Glenn Foundation/American Federation for Aging Research (AFAR) BIG Award (JLK), Glenn/AFAR (LJN, CEB), the Ted Nash Long Life and Noaber Foundations (JLK), the Connor Group (JLK), Robert J. and Theresa W. Ryan (JLK), and a Minnesota Partnership Grant (AMAY-UMN#99)-P004610401-1 (JLK, EAA).


Asunto(s)
Productos Biológicos/farmacología , Flavonoides/farmacología , Estado de Salud , Longevidad/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Productos Biológicos/uso terapéutico , Biomarcadores , Senescencia Celular/efectos de los fármacos , Senescencia Celular/genética , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Flavonoides/uso terapéutico , Flavonoles , Expresión Génica , Genes Reporteros , Humanos , Peroxidación de Lípido , Masculino , Ratones , Ratones Noqueados
7.
Nat Commun ; 8(1): 422, 2017 09 04.
Artículo en Inglés | MEDLINE | ID: mdl-28871086

RESUMEN

Aging is the main risk factor for many chronic degenerative diseases and cancer. Increased senescent cell burden in various tissues is a major contributor to aging and age-related diseases. Recently, a new class of drugs termed senolytics were demonstrated to extending healthspan, reducing frailty and improving stem cell function in multiple murine models of aging. To identify novel and more optimal senotherapeutic drugs and combinations, we established a senescence associated ß-galactosidase assay as a screening platform to rapidly identify drugs that specifically affect senescent cells. We used primary Ercc1 -/- murine embryonic fibroblasts with reduced DNA repair capacity, which senesce rapidly if grown at atmospheric oxygen. This platform was used to screen a small library of compounds that regulate autophagy, identifying two inhibitors of the HSP90 chaperone family as having significant senolytic activity in mouse and human cells. Treatment of Ercc1 -/∆ mice, a mouse model of a human progeroid syndrome, with the HSP90 inhibitor 17-DMAG extended healthspan, delayed the onset of several age-related symptoms and reduced p16INK4a expression. These results demonstrate the utility of our screening platform to identify senotherapeutic agents as well as identified HSP90 inhibitors as a promising new class of senolytic drugs.The accumulation of senescent cells is thought to contribute to the age-associated decline in tissue function. Here, the authors identify HSP90 inhibitors as a new class of senolytic compounds in an in vitro screening and show that administration of a HSP90 inhibitor reduces age-related symptoms in progeroid mice.


Asunto(s)
Envejecimiento/fisiología , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Benzoquinonas/farmacología , Bioensayo , Biomarcadores/metabolismo , Senescencia Celular/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Endonucleasas/metabolismo , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Lactamas Macrocíclicas/farmacología , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos
8.
Aging Cell ; 14(4): 644-58, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25754370

RESUMEN

The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1(-/Δ) mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1(-/∆) mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.


Asunto(s)
Envejecimiento/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Dasatinib/farmacología , Osteoporosis/prevención & control , Quercetina/farmacología , Transcriptoma , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Adipocitos/patología , Envejecimiento/genética , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/patología , Senescencia Celular/genética , Fosfatidilinositol 3-Quinasa Clase I , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Combinación de Medicamentos , Endonucleasas/genética , Endonucleasas/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Efrinas/genética , Efrinas/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Perfilación de la Expresión Génica , Corazón/efectos de los fármacos , Corazón/fisiopatología , Disco Intervertebral/química , Disco Intervertebral/efectos de los fármacos , Disco Intervertebral/patología , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Ratones , Ratones Noqueados , Osteoporosis/genética , Osteoporosis/metabolismo , Osteoporosis/patología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidor 2 de Activador Plasminogénico/genética , Inhibidor 2 de Activador Plasminogénico/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
9.
ACS Chem Neurosci ; 2(4): 198-206, 2011 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-21666839

RESUMEN

There are currently no drugs to treat neurodegeneration in Parkinson's disease (PD) and all existing medications only treat symptoms, lose efficacy over time, and produce untoward side effects. In the current work, we report the first highly selective, orally bioavailable, c-jun-N-terminal kinase (JNK) inhibitor for protection of dopaminergic neurons in vitro and in vivo. At 300 nM this compound showed statistically significant protection of primary dopaminergic neurons exposed to 1-methyl-4-phenylpyridinium (MPP(+)), had pharmacokinetic properties in rodents consistent with twice daily (b.i.d.) dosing, and was orally efficacious at 30 mg/kg in a mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Moreover, a dose-dependent target modulation of c-jun phosphorylation served as a biomarker for demonstrating on-target inhibition of JNK as the mechanism of action for this compound. Collectively these results suggest that this JNK inhibitor could be a promising therapeutic neuroprotective agent in the treatment of Parkinson's disease.

10.
J Med Chem ; 53(1): 419-31, 2010 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-19947601

RESUMEN

Given the significant body of data supporting an essential role for c-jun-N-terminal kinase (JNK) in neurodegenerative disorders, we set out to develop highly selective JNK inhibitors with good cell potency and good brain penetration properties. The structure-activity relationships (SAR) around a series of aminopyrimidines were evaluated utilizing biochemical and cell-based assays to measure JNK inhibition and brain penetration in mice. Microsomal stability in three species, P450 inhibition, inhibition of generation of reactive oxygen species (ROS), and pharmacokinetics in rats were also measured. Compounds 9g, 9i, 9j, and 9l had greater than 135-fold selectivity over p38, and cell-based IC(50) values < 100 nM. Moreover, compound 9l showed an IC(50) = 0.8 nM for inhibition of ROS and had good pharmacokinetic properties in rats along with a brain-to-plasma ratio of 0.75. These results suggest that biaryl substituted aminopyrimidines represented by compound 9l may serve as the first small molecule inhibitors to test efficacy of JNK inhibitors in neurodegenerative disorders.


Asunto(s)
Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad
11.
J Biol Chem ; 284(19): 12853-61, 2009 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-19261605

RESUMEN

c-Jun N-terminal kinase 3alpha1 (JNK3alpha1) is a mitogen-activated protein kinase family member expressed primarily in the brain that phosphorylates protein transcription factors, including c-Jun and activating transcription factor-2 (ATF-2) upon activation by a variety of stress-based stimuli. In this study, we set out to design JNK3-selective inhibitors that had >1000-fold selectivity over p38, another closely related mitogen-activated protein kinase family member. To do this we employed traditional medicinal chemistry principles coupled with structure-based drug design. Inhibitors from the aminopyrazole class, such as SR-3576, were found to be very potent JNK3 inhibitors (IC(50) = 7 nm) with >2800-fold selectivity over p38 (p38 IC(50) > 20 microm) and had cell-based potency of approximately 1 microm. In contrast, indazole-based inhibitors exemplified by SR-3737 were potent inhibitors of both JNK3 (IC(50) = 12 nm) and p38 (IC(50) = 3 nm). These selectivity differences between the indazole class and the aminopyrazole class came despite nearly identical binding (root mean square deviation = 0.33 A) of these two compound classes to JNK3. The structural features within the compounds giving rise to the selectivity in the aminopyrazole class include the highly planar nature of the pyrazole, N-linked phenyl structures, which better occupied the smaller active site of JNK3 compared with the larger active site of p38.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Proteína Quinasa 10 Activada por Mitógenos/antagonistas & inhibidores , Pirazoles/química , Pirazoles/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Factor de Transcripción Activador 2/metabolismo , Animales , Células Cultivadas , Cristalografía por Rayos X , Humanos , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Modelos Moleculares , Fosforilación/efectos de los fármacos , Conformación Proteica , Ratas , Relación Estructura-Actividad
12.
Bioorg Med Chem Lett ; 17(22): 6378-82, 2007 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-17911023

RESUMEN

The structure-based design and synthesis of a novel series of c-Jun N-terminal kinase (JNK) inhibitors with selectivity against p38 is reported. The unique structure of 3,5-disubstituted quinolines (2) was developed from the previously reported 4-(2,7-phenanthrolin-9-yl)phenol (1). The X-ray crystal structure of 16a in JNK3 reveals an unexpected binding mode for this new scaffold with protein.


Asunto(s)
Diseño de Fármacos , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Quinolinas/química , Quinolinas/farmacología , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Estructura Molecular , Fenantrolinas/síntesis química , Fenantrolinas/química , Fenantrolinas/farmacología , Unión Proteica/efectos de los fármacos , Relación Estructura-Actividad , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores
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