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This work reports a method for the catalytic synthesis of C(3) SCF3-substituted pyrrolidinindoline using a small-ring organophosphorus-based catalyst and a hydrosilane reductant, with trifluoromethanesulfonyl chloride as the electrophilic SCF3 reagent. This method can drive the conversion of tryptamine to the C(3) SCF3-substituted pyrrolidine indoline. The readily available, inexpensive trifluoromethanesulfonyl chloride could be activated as an electrophilic SCF3 source by PIII/PV redox catalysis and could efficiently participate in the reaction of tryptamines, thus providing various substituted C(3) SCF3-substituted pyrrolidinoindoline in moderate to excellent yields. This presented strategy features a broad substrate scope, and the structure has value for in-depth research.
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An organophosphorus catalytic method for the synthesis of substituted 2-amidopyridines is reported. The method employs a small-ring organophosphorus-based catalyst and a hydrosilane reductant to drive the conversion of ketoximes and pyridine-N-oxides into 2-amidopyridines through sequential Beckmann rearrangement followed by [2,3]-sigmatropic rearrangement. The readily available ketoximes could be activated to nitrilium ions in PIII/PV redox catalysis and could efficiently participate in the domino reaction of pyridine-N-oxides, thus providing various substituted 2-amidopyridines in moderate to excellent yields. This presented strategy features excellent functional group tolerance and a broad substrate scope.
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Programmed death-ligand 1 (PD-L1) has surfaced as a promising therapeutic target for various cancers due to its pivotal role in facilitating tumor immune evasion. Herein, we report a series of novel small-molecule PD-L1 inhibitors exhibiting remarkable inhibitory activity against the PD-1/PD-L1 interaction (X18: IC50 = 1.3 nM) and reinstating the suppressive effect of PD-L1 on T cells (X18: EC50 = 152.8 nM). Crystallographic studies revealed the binding mode of X18 and PD-L1. Through a rational prodrug design approach, we have successfully optimized the oral pharmacokinetic properties of X22, effectively addressing the poor oral pharmacokinetic profile of PD-L1 small-molecule inhibitors. Notably, X22 demonstrated significant antitumor efficacy in murine models of MC38 and CT26 colon cancer through the upregulation of tumor infiltration and cytotoxicity of CD8+ T cells partially. These findings offer promising prospects for the advancement of PD-L1 inhibitors as innovative agents in cancer immunotherapy.
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Neoplasias del Colon , Inhibidores de Puntos de Control Inmunológico , Animales , Ratones , Inhibidores de Puntos de Control Inmunológico/farmacología , Linfocitos T CD8-positivos , Antígeno B7-H1 , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismoRESUMEN
A metal-free and thiol-free organophosphorus-catalyzed method for forming thioethers was disclosed, driven by PIII/PVâO redox cycling. In this work, one-step dehydroxylative thioetherification of alcohols was fulfilled with various hypervalent organosulfur compounds. This established strategy features an excellent functional group tolerance and broad substrate scope, especially inactivated alcohols. The scale-up reaction and further transformation of the product were also successful. Additionally, this method offers a protecting-group-free and step-efficient approach for synthesizing peroxisome proliferator-activated receptor agonists which exhibited promising potential for treating osteoporosis in mammals.
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A green method to construct C-S bonds using sulfonyl chlorides and alcohols/acids via a PIII/PVâO catalytic system is reported. The organophosphorus-catalyzed umpolung reaction promotes us to propose the "dual-substrate deoxygenation" strategy. Herein, we adopt the "dual-substrate deoxygenation" strategy, which achieves the deoxygenation of sulfonyl chlorides and alcohols/acids to synthesize thioethers/thioesters driven by PIII/PVâO redox cycling. The catalytic method represents an operationally simple approach using stable phosphine oxide as a precatalyst and shows broad functional group tolerance. The potential application of this protocol is demonstrated by the late-stage diversification of drug analogues.
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Compuestos Organofosforados , Catálisis , Oxígeno/química , Alcoholes/química , Ácidos/química , Compuestos Organofosforados/químicaRESUMEN
Peroxisome proliferator-activator receptors α/δ (PPARα/δ) are considered as potential drug targets for cholestatic liver diseases (CLD) via ameliorating hepatic cholestasis, inflammation, and fibrosis. In this work, we developed a series of hydantoin derivatives as potent PPARα/δ dual agonists. Representative compound V1 exhibited PPARα/δ dual agonistic activity at the subnanomolar level (PPARα EC50 = 0.7 nM; PPARδ EC50 = 0.4 nM) and showed excellent selectivity over other related nuclear receptors. The crystal structure revealed the binding mode of V1 and PPARδ at 2.1 Å resolution. Importantly, V1 demonstrated excellent pharmacokinetic (PK) properties and a good safety profile. Notably, V1 showed potent anti-CLD and antifibrotic effects in preclinical models at very low doses (0.03 and 0.1 mg/kg). Collectively, this work provides a promising drug candidate for treating CLD and other hepatic fibrosis diseases.
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Colestasis , PPAR delta , Humanos , PPAR alfa/agonistas , PPAR delta/agonistas , Colestasis/tratamiento farmacológico , InflamaciónRESUMEN
In order to discover more effective and less toxic drugs in the field of anti-tumor, the backbone structure of 17ß-estradiol was modified, and 11 target compounds were synthesized. Compounds 5 and 10, which exhibited better anti-tumor activity and higher selectivity (more than 10-fold), were chosen for further biological investigation. Flow cytometry results indicated that 5 and 10 could arrest MCF-7 cells in the G2 phase and induce apoptosis. Immunohistochemical analysis revealed that 5 and 10 could bind to the estradiol receptor alpha in MCF-7 cells. Western blotting and real-time PCR assays were performed to detect the effects of compounds on apoptosis-related targets at the protein and gene levels. These results showed that both 5 and 10 could dosed-dependently increase the expression of Apaf-1, Bax, caspase-3,8,9 and reduce the expression levels of the anti-apoptotic factors Bcl-2 and Bcl-xL. Besides, the Human apoptosis array assay demonstrated the expression level of death receptor Trail R2/DR5 was upregulated obviously while the expression of TNF R1, IAPs and Hsp27/60/70 were downregulated. On the whole, 5 induced MCF-7 cell death through the endogenous pathway in mitochondria and the exogenous pathway with death receptor Trail R2/DR5.
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Proteínas Reguladoras de la Apoptosis , Apoptosis , Humanos , Células MCF-7 , Western Blotting , Estradiol/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Línea Celular TumoralRESUMEN
An efficient and environmentally friendly synthetic approach to prepare thiazolidine-2-imine and oxazolidine-2-one derivatives has been developed. Thiazolidine-2-imines are synthesized in good to excellent yields by [3 + 2] annulation of p-quinamines with isothiocyanates under catalyst- and solvent-free conditions. Oxazolidine-2-ones are produced in good to excellent yields via [3 + 2] annulation of p-quinamines with CO2 using triethylenediamine (DABCO) as an organocatalyst. Furthermore, this strategy can be performed on a gram scale and tolerate a wide range of functional groups.
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USP7 emerges as a potential therapeutic target for cancers, as it plays an important role in the development of tumorigenesis by stabilizing multiple cancer-relevant proteins. Nevertheless, the discovery of drug-like USP7 inhibitors remains challenging. Herein, we report a series of N-benzylpiperidinol derivatives as potent and selective USP7 inhibitors (e.g., X20 and X26: IC50 = 7.6 and 8.2 nM), whose binding modes were revealed by crystallographic studies to be distinct from the known N-acylpiperidinol USP7 inhibitors. Among them, X36 with good oral PK profiles (rat: F = 40.8% and T1/2 = 3.5 h) exhibited significant antitumor efficacy in the MC38 colon cancer syngeneic mouse model, at least partly through upregulating the tumor infiltration of CD8+ T, NK, and NKT cells and downregulating that of Tregs and MDSCs. These findings may further pave the way for the development of USP7 inhibitors as novel cancer immunotherapy drugs.
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Neoplasias del Colon , Ratones , Ratas , Animales , Peptidasa Específica de Ubiquitina 7 , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológicoRESUMEN
ATP citrate lyase (ACLY) is an important metabolic enzyme involved in the synthesis of fatty acid and cholesterol. The inhibition of ACLY is considered as a promising therapeutic strategy for various metabolic diseases and numerous malignancies. In this study, a novel macrocyclic compound 2 has been identified as a potent ACLY inhibitor with the "ring closing" strategy for conformational restriction based on NDI-091143. It showed potent ACLY inhibitory activity and binding affinity comparable to the positive control. Furthermore, compared with the positive control (T1/2 = 3.36 min), the metabolic stability of 2 in HLMs (T1/2 = 531.22 min) was significantly improved. All of these results characterized 2 as a promising lead compound worthy of further study.
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ATP Citrato (pro-S)-Liasa , Neoplasias , ATP Citrato (pro-S)-Liasa/química , ATP Citrato (pro-S)-Liasa/metabolismo , Inhibidores Enzimáticos/farmacología , Humanos , Neoplasias/metabolismoRESUMEN
Extensive research effort has been put in pentacyclic triterpenoids due to their numerous biological activities. However, their poor water solubility and low oral bioavailability limit their antitumor effects in vivo. To address these issues, 37 triterpenoid acid derivatives linked to l-phenylalanine or l-proline were designed and synthesized in this study. Structure-activity relationship (SAR) studies found two promising glycyrrhetinic acid (GA) derivatives 11 and 16. Compound 11 was obtained by C3-OH esterification and C30-COOH modification with l-phenylalanine while 16 was obtained by attaching C3-OH with l-phenylalanine. Compounds 11 and 16 exhibit up to 48- and 120-fold improvement respectively compared with the IC50 values of naturally occurring GA in the cellular assay. Fluorescence microscope and flow cytometric analysis suggested that both compounds 11 and 16 increased the content of ROS and Ca2+ in cancer cells, decreased mitochondrial membrane potential (JC-1), and activated the regulator caspase-3/8/9 to trigger cell apoptosis. RNA-seq analysis and western blot analysis indicated that compounds 11 and 16 may promote apoptosis by upregulating the functions of pro-apoptotic factors while inhibiting the proteasome activity.
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Antineoplásicos , Ácido Glicirretínico , Triterpenos , Antineoplásicos/farmacología , Apoptosis , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Fenilalanina/farmacología , Prolina , Relación Estructura-Actividad , Triterpenos/farmacologíaRESUMEN
A series of indole-fused scaffolds and derivatives was synthesized via the cyclization reaction of 2-indolylmethanols with azonaphthalene. These reactions were realized under mild reaction conditions through catalyst control, providing structurally diverse indole derivatives with moderate to excellent yields. This protocol also shows good substrate adaptability, especially in six-membered ring products.
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Indoles , Catálisis , CiclizaciónRESUMEN
Peroxisome proliferator-activator receptors α/δ (PPARα/δ) are regarded as potential therapeutic targets for nonalcoholic steatohepatitis (NASH). However, PPARα/δ dual agonist GFT-505 exhibited poor anti-NASH effects in a phase III clinical trial, probably due to its weak PPARα/δ agonistic activity and poor metabolic stability. Other reported PPARα/δ dual agonists either exhibited limited potency or had unbalanced PPARα/δ agonistic activity. Herein, we report a series of novel triazolone derivatives as PPARα/δ dual agonists. Among them, compound H11 exhibited potent and well-balanced PPARα/δ agonistic activity (PPARα EC50 = 7.0 nM; PPARδ EC50 = 8.4 nM) and a high selectivity over PPARγ (PPARγ EC50 = 1316.1 nM) in PPAR transactivation assays. The crystal structure of PPARδ in complex with H11 revealed a unique PPARδ-agonist interaction. H11, which had excellent PK properties and a good safety profile, showed potent in vivo anti-NASH effects in preclinical models. Together, H11 holds a great promise for treating NASH or other inflammatory and fibrotic diseases.
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Antiinflamatorios/uso terapéutico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , PPAR alfa/agonistas , PPAR delta/agonistas , Triazoles/uso terapéutico , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacocinética , Tetracloruro de Carbono , Diseño de Fármacos , Inflamación/tratamiento farmacológico , Inflamación/patología , Hígado/efectos de los fármacos , Hígado/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Masculino , Ratones Endogámicos C57BL , Microsomas Hepáticos/efectos de los fármacos , Estructura Molecular , Enfermedad del Hígado Graso no Alcohólico/patología , PPAR alfa/metabolismo , PPAR delta/metabolismo , Ratas Sprague-Dawley , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/metabolismo , Triazoles/farmacocinéticaRESUMEN
Insulin degrading enzyme (IDE) is a zinc metalloprotease that cleaves numerous substrates among which amyloid-ß and insulin. It has been linked through genetic studies to the risk of type-2 diabetes (T2D) or Alzheimer's disease (AD). Pharmacological activation of IDE is an attractive therapeutic strategy in AD. While IDE inhibition gave paradoxal activity in glucose homeostasis, recent studies, in particular in the liver suggest that IDE activators could be also of interest in diabetes. Here we describe the discovery of an original series of IDE activators by screening and structure-activity relationships. Early cellular studies show that hit 1 decreases glucose-stimulating insulin secretion. Docking studies revealed it has an unprecedented extended binding to the polyanion-binding site of IDE. These indole-based pharmacological tools are activators of both Aß and insulin hydrolysis by IDE and could be helpful to explore the multiple roles of IDE.
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Indoles/farmacología , Insulisina/metabolismo , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Indoles/química , Ratones , Modelos Moleculares , Estructura Molecular , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
The development of enantioselective desymmetrization of para-quinamines with isocyanates catalyzed by chiral phosphoric acid is reported. The strategy provides concise access to functionalized imidazolidin-2-one derivatives in high yields and enantioselectivities under mild reaction conditions. Remarkably, this reaction could be performed on a gram scale using 5 mol % catalyst loading and the chiral imidazolidin-2-one derivatives could be easily transformed into valuable scaffolds without disturbing the enantiopurity, demonstrating the synthetic utility of this protocol.
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Proprotein convertase subtilisin kexin 9 (PCSK9) has been identified as a reliable therapeutic target for hypercholesterolemia and coronary artery heart diseases since the monoclonal antibodies of PCSK9 have launched. Disrupting the protein-protein interaction (PPI) between PCSK9 and the low-density lipoprotein receptor (LDLR) has been considered as a promising approach for developing PCSK9 inhibitors. However, PPIs have been traditionally considered difficult to target by small molecules since the PPI surface is usually large, flat, featureless, and without a "pocket" or "groove" for ligand binding. The PCSK9-LDLR PPI interface is such a typical case. In this study, a potential binding pocket was generated on the PCSK9-LDLR PPI surface of PCSK9 through induced-fit docking. On the basis of this induced binding pocket, virtual screening, molecular dynamics (MD) simulation, and biological evaluations have been applied for the identification of novel small molecule inhibitors of PCSK9-LDLR PPI. Among the selected compounds, compound 13 exhibited certain PCSK9-LDLR PPI inhibitory activity (IC50: 7.57 ± 1.40 µM). The direct binding affinity between 13 and PCSK9 was determined with a KD value of 2.50 ± 0.73 µM. The LDLR uptake function could be also restored to a certain extent by 13 in HepG2 cells. This well-characterized hit compound will facilitate the further development of novel small molecule inhibitors of PCSK9-LDLR PPI.
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Simulación de Dinámica Molecular , Proproteína Convertasa 9 , Células Hep G2 , Humanos , Proproteína Convertasa 9/metabolismoRESUMEN
BACKGROUND AND PURPOSE: Psoriasis is a chronic inflammatory skin disease associated with both innate and adaptive immune responses. The stimulator of interferon genes (STING) protein engages in sensing of cytosolic DNA to initiate dsDNA-driven immune responses. In vitro and in vivo anti-psoriasis effects of STING antagonist H-151 were explored. EXPERIMENTAL APPROACH: We analysed the gene expression profile of STING and related downstream targets in the skin samples of healthy people and psoriasis patients from the GEO database. Cellular inhibitory activity of H-151 on STING pathway was confirmed via qPCR and western blotting. The preventive effect of topical application of H-151 on imiquimod-induced psoriatic mice was examined through histological, immunohistochemical, immunofluorescent, flow cytometric analysis, ELISA Kits and other approaches. Preliminary mechanistic studies were also performed. KEY RESULTS: Gene expressions of STING and its downstream target were up-regulated in lesional skin samples from psoriasis patients. Topical administration of H-151 attenuated the skin lesions in imiquimod-induced psoriatic mouse model, while the secretion of pro-inflammatory cytokines (IL-17, IL-23 and IL-6), infiltration of M1 macrophages and differentiation of Th17 cells were significantly suppressed by H-151 treatment. Mechanistically, H-151 inhibited STING/NF-κB signalling in both keratinocytes and immune cells. CONCLUSION AND IMPLICATIONS: H-151 displayed anti-inflammatory activity in both keratinocytes and immune cells, and decreased the severity of psoriatic response in vivo. Inhibition of STING signalling pathway may represent a novel therapeutic approach to psoriasis and related complications.
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FN-kappa B , Psoriasis , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Imiquimod/efectos adversos , Inflamación/patología , Queratinocitos , Ratones , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Psoriasis/tratamiento farmacológico , Psoriasis/patología , Piel/metabolismoRESUMEN
A copper-mediated cyclization and dimerization of indole derived oxime acetate was developed to generate a series of biimidazo[1,2-a]indole scaffolds with two contiguous stereogenic quaternary carbons in one step.
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Cobre , Indoles , Acetatos , Catálisis , Ciclización , Dimerización , Estructura Molecular , OximasRESUMEN
Pentacyclic triterpenes (PTs) are the active ingredients of many medicinal herbs and pharmaceutical formulations, and are well-known for their anti-inflammatory activity. On the other hand, anti-inflammatory effects of AMP-activated protein kinase (AMPK) have recently drawn much attention. In this study, we found that a variety of naturally occurring PTs sapogenins and saponins could stimulate the phosphorylation of AMPK, and identified δ-oleanolic acid (10) as a potent AMPK activator. Based on these findings, 23 saponin derivatives of δ-oleanolic acid were synthesized in order to find more potent anti-inflammatory agents with improved pharmacokinetic properties. The results of cellular assays showed that saponin 29 significantly inhibited LPS-induced secretion of pro-inflammatory factors TNF-α and IL-6 in THP1-derived macrophages. Preliminary mechanistic studies showed that 29 stimulated the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC). The bioavailability of 29 was significantly improved in comparison with its aglycon. More importantly, 29 showed significant anti-inflammatory and liver-protective effects in LPS/D-GalN-induced fulminant hepatic failure mice. Taken together, PTs saponins hold promise as therapeutic agents for inflammatory diseases.
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Antiinflamatorios/química , Ácido Oleanólico/química , Triterpenos Pentacíclicos/química , Saponinas/química , Proteínas Quinasas Activadas por AMP/metabolismo , Acetil-CoA Carboxilasa/metabolismo , Animales , Antiinflamatorios/farmacología , Relación Dosis-Respuesta a Droga , Ácido Glicirrínico/química , Humanos , Interleucina-6/metabolismo , Hígado , Macrófagos/efectos de los fármacos , Masculino , Medicina Tradicional China , Ratones , Ratones Endogámicos BALB C , Triterpenos Pentacíclicos/farmacología , Fosforilación/efectos de los fármacos , Sapogeninas/química , Saponinas/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
On the one hand, to obtain a novel next-generation anticancer metal agent; on the other hand, to improve the targeting ability and decrease side effects of metal agent, we proposed to design active-targeting human serum albumin (HSA) nanoparticles (NPs) to achieve the end. Thus, we not only designed and synthesized two ruthenium (Ru) thiosemicarbazone compounds (C1 and C2) but also succeeded in constructing active Biotin-HSA NPs for Ru(III) compounds. Importantly, Biotin-HSA-C2 NPs not only possessed a stronger capacity for killing MCF-7 cells and inhibiting their migration versusC2 alone but also increased accumulation compared to non-malignant WI-38 cells. Additionally, C2 and Biotin-HSA-C2 NPs act against MCF-7 cells by the following potential mechanism: 1) arresting the cell cycle in the S phase by regulating cyclin and cyclin-dependent kinases; 2) inducing apoptosis by releasing cytochrome c to activate caspase-9/3; 3) inhibiting the expression of p-EGFR and regulating its neighboring cellular pathways, followed by the inactivation of PI3K/Akt and activation of p38 MAPK signaling pathways.