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1.
Eur J Med Chem ; 269: 116344, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38522113

RESUMO

Liver fibrosis is commonly occurred in chronic liver diseases, but there is no approved drug for clinical use. The nuclear receptor peroxisome proliferator-activated receptors (PPARs) could not only regulate metabolic homeostasis but also possess anti-inflammatory and antifibrotic effects, and pan-PPARs agonist was considered as a potential anti-liver fibrosis agent. In this study, a series of novel piperazine pan-PPARs agonists were developed, and the preferred compound 12 displayed potent and well-balanced pan-PPARs agonistic activity. Moreover, compound 12 could dose-dependently stimulate the PPARs target genes expression and showed high selectivity over other related nuclear receptors. Importantly, compound 12 exhibited excellent pharmacokinetic profiles and good anti-liver fibrosis effects in vivo. Collectively, compound 12 holds promise for developing an anti-liver fibrosis agent.


Assuntos
Compostos Heterocíclicos , Receptores Ativados por Proliferador de Peroxissomo , Humanos , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Cirrose Hepática/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares , Hipoglicemiantes , Piperazinas
2.
J Med Chem ; 67(6): 4977-4997, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38465588

RESUMO

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.


Assuntos
Neoplasias do Colo , Inibidores de Checkpoint Imunológico , Animais , Camundongos , Inibidores de Checkpoint Imunológico/farmacologia , Linfócitos T CD8-Positivos , Antígeno B7-H1 , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo
3.
J Med Chem ; 67(7): 5502-5537, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38552183

RESUMO

Patients with arterial embolic disease have benefited greatly from antiplatelet therapy. However, hemorrhage risk of antiplatelet agents cannot be ignored. Herein, we describe the discovery of 2,3-dihydro[1,4]dioxino[2,3-g]benzofuran compounds as novel PAR4 antagonists. Notably, the isomers 36 and 37 with the chemotype of phenoxyl methylene substituted on the 2,3-dihydro-1,4-dioxine ring exhibited potent in vitro antiplatelet activity (IC50 = 26.13 nM for 36 and 14.26 nM for 37) and significantly improved metabolic stability in human liver microsomes (T1/2 = 97.6 min for 36 and 11.1 min for BMS-986120). 36 also displayed good oral PK profiles (mice: T1/2 = 7.32 h and F = 45.11%). Both of them showed overall potent ex vivo antiplatelet activity at concentrations of 6 and 12 mg/kg, with no impact on the coagulation system and low bleeding liability. Our work will facilitate development of novel PAR4 antagonists as a safer therapeutic option for arterial embolism.


Assuntos
Benzofuranos , Trombose , Humanos , Camundongos , Animais , Receptores de Trombina , Inibidores da Agregação Plaquetária/metabolismo , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Hemorragia/metabolismo , Coagulação Sanguínea , Trombose/tratamento farmacológico , Benzofuranos/uso terapêutico , Agregação Plaquetária , Receptor PAR-1/metabolismo , Receptor PAR-1/uso terapêutico , Plaquetas/metabolismo
4.
J Org Chem ; 89(2): 1083-1090, 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38173188

RESUMO

A metal-free and thiol-free organophosphorus-catalyzed method for forming thioethers was disclosed, driven by PIII/PV═O 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.

5.
BMC Genomics ; 24(1): 424, 2023 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-37501127

RESUMO

Non-coding RNAs (ncRNAs) draw much attention from studies widely in recent years because they play vital roles in life activities. As a good complement to wet experiment methods, computational prediction methods can greatly save experimental costs. However, high false-negative data and insufficient use of multi-source information can affect the performance of computational prediction methods. Furthermore, many computational methods do not have good robustness and generalization on different datasets. In this work, we propose an effective end-to-end computing framework, called GDCL-NcDA, of deep graph learning and deep matrix factorization (DMF) with contrastive learning, which identifies the latent ncRNA-disease association on diverse multi-source heterogeneous networks (MHNs). The diverse MHNs include different similarity networks and proven associations among ncRNAs (miRNAs, circRNAs, and lncRNAs), genes, and diseases. Firstly, GDCL-NcDA employs deep graph convolutional network and multiple attention mechanisms to adaptively integrate multi-source of MHNs and reconstruct the ncRNA-disease association graph. Then, GDCL-NcDA utilizes DMF to predict the latent disease-associated ncRNAs based on the reconstructed graphs to reduce the impact of the false-negatives from the original associations. Finally, GDCL-NcDA uses contrastive learning (CL) to generate a contrastive loss on the reconstructed graphs and the predicted graphs to improve the generalization and robustness of our GDCL-NcDA framework. The experimental results show that GDCL-NcDA outperforms highly related computational methods. Moreover, case studies demonstrate the effectiveness of GDCL-NcDA in identifying the associations among diversiform ncRNAs and diseases.


Assuntos
MicroRNAs , RNA Longo não Codificante , Aprendizagem , RNA não Traduzido/genética , MicroRNAs/genética , RNA Circular , Biologia Computacional
6.
J Med Chem ; 66(13): 8858-8875, 2023 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-37335602

RESUMO

Aberrant activation of fibroblast growth factor receptors (FGFRs) has been identified as an oncogenic driver force for multiple cancer types, making FGFRs a compelling target for anticancer therapy. Because of the renewed interest in irreversible inhibitors, considerable efforts have been made to find irreversible FGFR inhibitors. Herein, we discovered a series of novel quinolone-based covalent pan-FGFR inhibitors by further optimizing the lead compound (lenvatinib) under the guidance of molecular docking. The representative pan-FGFR inhibitor I-5 exhibited significant inhibitory potency against FGFR1-4 with nanomolar activity and effectively suppressed the proliferation of Huh-7 and Hep3B HCC cells. I-5 displayed high selectivity against a panel of 369 kinases at 1 µM. The irreversible binding to target proteins was characterized by liquid chromatography and tandem mass spectrometry (LC-MS/MS). Moreover, I-5 exhibited favorable PK properties in vivo and induced significant TGI in the Huh-7 and NCI-H1581 xenograft mouse models.


Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Quinolonas , Humanos , Camundongos , Animais , Receptores de Fatores de Crescimento de Fibroblastos , Simulação de Acoplamento Molecular , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Cromatografia Líquida , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Espectrometria de Massas em Tandem , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/química , Linhagem Celular Tumoral
7.
J Med Chem ; 66(11): 7331-7354, 2023 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-37243609

RESUMO

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.


Assuntos
Colestase , PPAR delta , Humanos , PPAR alfa/agonistas , PPAR delta/agonistas , Colestase/tratamento farmacológico , Inflamação
8.
IEEE Trans Cybern ; 53(9): 5605-5617, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35404827

RESUMO

Unsupervised feature selection is a vital yet challenging topic for effective data learning. Recently, 2-D feature selection methods show good performance on image analysis by utilizing the structure information of image. Current 2-D methods usually adopt a sparse regularization to spotlight the key features. However, such scheme introduces additional hyperparameter needed for pruning, limiting the applicability of unsupervised algorithms. To overcome these challenges, we design a feature filter to estimate the weight of image features for unsupervised feature selection. Theoretical analysis shows that a sparse regularization can be derived from the feature filter by transformation, indicating that the filter plays the same role as the popular sparse regularization does. We deploy two distinct strategies in terms of feature selection, called multiple feature filters and single common feature filter. The former divides the optimization problem into multiple independent subproblems and selects features that meet the respective interests of each subproblem. The latter selects features that are in the interest of the overall optimization problem. Extensive experiments on seven benchmark datasets show that our unsupervised 2-D weight-based feature selection methods achieve superior performance over the state-of-the-art methods.

9.
J Org Chem ; 88(8): 5052-5058, 2023 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35880952

RESUMO

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.

10.
J Med Chem ; 65(24): 16622-16639, 2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36454192

RESUMO

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.


Assuntos
Neoplasias do Colo , Camundongos , Ratos , Animais , Peptidase 7 Específica de Ubiquitina , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico
11.
Eur J Med Chem ; 244: 114800, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36215862

RESUMO

Nonalcoholic steatohepatitis (NASH) is a rising public health burden, and there is a lack of effective therapeutic drugs in clinical practice. Sustained hepatic inflammation is considered as the key histopathological feature and dangerous fact for NASH. Different causes vary from one NASH patient to another, while sustained hepatic inflammation affects all NASH patients. AdipoRon is the first small-molecule AdipoR agonist, exerting antidiabetic and anti-inflammatory effect. In order to find novel AdipoRon analogues with more potent anti-inflammatory activity, we designed, synthesized and biologically evaluated 32 analogues. Among them, Q7 exerted potent anti-inflammatory activity and less cytotoxicity. Q7 could dose-dependently stimulate the increasing of AMPK phosphorylation, the widely recognized downstream effector of AdipoR1 activation. In NASH model mice, Q7 showed significant anti-inflammatory, anti-fibrotic and lipid-lowering effect in mice liver, and was superior to AdipoRon. Together, Q7 holds promise for developing anti-inflammatory and anti-NASH agents.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Piperidinas/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Fígado , Camundongos Endogâmicos C57BL
12.
J Chem Inf Model ; 62(12): 3123-3132, 2022 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-35679529

RESUMO

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.


Assuntos
ATP Citrato (pro-S)-Liase , Neoplasias , ATP Citrato (pro-S)-Liase/química , ATP Citrato (pro-S)-Liase/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Neoplasias/metabolismo
13.
J Med Chem ; 65(3): 2571-2592, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35060744

RESUMO

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.


Assuntos
Anti-Inflamatórios/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , PPAR alfa/agonistas , PPAR delta/agonistas , Triazóis/uso terapêutico , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacocinética , Tetracloreto de Carbono , Desenho de Fármacos , Inflamação/tratamento farmacológico , Inflamação/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Hepatopatia Gordurosa não Alcoólica/patologia , PPAR alfa/metabolismo , PPAR delta/metabolismo , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/metabolismo , Triazóis/farmacocinética
14.
Front Pharmacol ; 13: 1042756, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36793921

RESUMO

Introduction: Cytochrome P450 (CYP) 3A4 is a major drug metabolizing enzyme for corticosteroids (CS). Epimedium has been used for asthma and variety of inflammatory conditions with or without CS. It is unknown whether epimedium has an effect on CYP 3A4 and how it interacts with CS. We sought to determine the effects of epimedium on CYP3A4 and whether it affects the anti-inflammatory function of CS and identify the active compound responsible for this effect. Methods: The effect of epimedium on CYP3A4 activity was evaluated using the Vivid CYP high-throughput screening kit. CYP3A4 mRNA expression was determined in human hepatocyte carcinoma (HepG2) cells with or without epimedium, dexamethasone, rifampin, and ketoconazole. TNF-α levels were determined following co-culture of epimedium with dexamethasone in a murine macrophage cell line (Raw 264.7). Active compound (s) derived from epimedium were tested on IL-8 and TNF-α production with or without corticosteroid, on CYP3A4 function and binding affinity. Results: Epimedium inhibited CYP3A4 activity in a dose-dependent manner. Dexamethasone enhanced the expression of CYP3A4 mRNA, while epimedium inhibited the expression of CYP3A4 mRNA and further suppressed dexamethasone enhancement of CYP3A4 mRNA expression in HepG2 cells (p < 0.05). Epimedium and dexamethasone synergistically suppressed TNF-α production by RAW cells (p < 0.001). Eleven epimedium compounds were screened by TCMSP. Among the compounds identified and tested only kaempferol significantly inhibited IL-8 production in a dose dependent manner without any cell cytotoxicity (p < 0.01). Kaempferol in combination with dexamethasone showed complete elimination of TNF-α production (p < 0.001). Furthermore, kaempferol showed a dose dependent inhibition of CYP3A4 activity. Computer docking analysis showed that kaempferol significantly inhibited the catalytic activity of CYP3A4 with a binding affinity of -44.73kJ/mol. Discussion: Inhibition of CYP3A4 function by epimedium and its active compound kaempferol leads to enhancement of CS anti-inflammatory effect.

15.
J Chem Inf Model ; 61(10): 5269-5279, 2021 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-34553597

RESUMO

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.


Assuntos
Simulação de Dinâmica Molecular , Pró-Proteína Convertase 9 , Células Hep G2 , Humanos , Pró-Proteína Convertase 9/metabolismo
16.
Br J Pharmacol ; 178(24): 4907-4922, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34460100

RESUMO

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.


Assuntos
NF-kappa B , Psoríase , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Imiquimode/efeitos adversos , Inflamação/patologia , Queratinócitos , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Psoríase/tratamento farmacológico , Psoríase/patologia , Pele/metabolismo
17.
J Med Chem ; 64(12): 8391-8409, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34115499

RESUMO

A series of novel benzo[c][1,2,5]oxadiazole derivatives were designed, synthesized, and biologically evaluated as inhibitors of PD-L1. Among them, compound L7 exhibited 1.8 nM IC50 value in a homogeneous time-resolved fluorescence (HTRF) assay, which was 20-fold more potent than the lead compound BMS-1016. In the surface plasmon resonance (SPR) assay, L7 bound to human PD-L1 (hPD-L1) with a KD value of 3.34 nM, without showing any binding to hPD-1. In the cell-based coculture assay, L7 blocked PD-1/PD-L1 interaction with an EC50 value of 375 nM, while BMS-1016 had an EC50 value of 2075 nM. Moreover, compound L24, an ester prodrug of L7, was orally bioavailable and displayed significant antitumor effects in tumor models of syngeneic and PD-L1 humanized mice. Mechanistically, L24 exhibited significant in vivo antitumor effects probably through promoting antitumor immunity. Together, this series of benzoxadiazole PD-L1 inhibitors holds promise for tumor immunotherapy. Preclinical trials with selected compounds are ongoing in our laboratory.


Assuntos
Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Oxidiazóis/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antígeno B7-H1/metabolismo , Células CHO , Linhagem Celular Tumoral , Cricetulus , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Inibidores de Checkpoint Imunológico/síntese química , Inibidores de Checkpoint Imunológico/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/metabolismo , Ligação Proteica , Ratos Sprague-Dawley , Relação Estrutura-Atividade
18.
Sci Total Environ ; 787: 147596, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-33991922

RESUMO

PAHs and their derivatives are the main sources of mutagenicity and carcinogenicity in airborne particular matter and cause serious public health and environmental problems. Risk assessment is challenging due to the mixed nature and deficiency of toxicity data of most PAHs and their derivatives. Cytochrome P450 enzymes (CYPs) play important roles in PAH-induced carcinogenicity via metabolic activation, and CYP conformations with compound I structures strongly influence metabolic sites and metabolite species. In this study, complexes of BaP with CYP1A1, CYP1B1 or CYP2C19 compound I were successfully simulated by QM/MM methods and verified by metabolic clearance, and the mutagenicity of chemicals was then predicted by the BaP-7,8-epoxide-related metabolic conformation fitness (MCF) approach, which was validated by Ames tests, showing satisfying accuracy (R2 = 0.46-0.66). Furthermore, a prediction model of the mutagenicity risk of PAH and derivative mixtures was established based on the relative potential factor (RPF) approach and the RPF calculated from the mathematical relationship between the minimum MCF (MCFmin) and RPF, which was successfully validated by the mutagenesis of PAH and derivative mixture mimic-simulating PM2.5 samples collected in eastern China. This study provides fast reliable tools for assessing risk of the complex components of environmental PAHs and their derivatives.


Assuntos
Mutagênicos , Hidrocarbonetos Policíclicos Aromáticos , Ativação Metabólica , China , Simulação por Computador , Mutagênese , Mutagênicos/toxicidade , Hidrocarbonetos Policíclicos Aromáticos/toxicidade
19.
Sci Total Environ ; 758: 143997, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33333309

RESUMO

Cytochrome P450 1A1 (CYP1A1) has served as a known metabolic enzyme that mediates the carcinogenesis of polycyclic aromatic hydrocarbons (PAHs). However, the structural mechanism involved in the metabolic capacity remains unclear. In this study, thirty-three calculated properties representing the physicochemical and electronic properties of PAH and PAH-CYP1A1 interactions were utilized to identify the key structural properties that affect metabolic processes, including binding ability, metabolic clearance, and mutagenicity, using a quantitative structure-activity relationship (QSAR) strategy combined with docking methods, QM/MM calculations and ab initio calculations. van der Waals interactions (glide vdw) appeared to be important for PAH binding to CYP1A1 and were mainly affected by the molecular weight and hydrophobic structures of PAHs. Interaction features between PAHs and heme, including the distance between iron and carbons of PAHs (Fe_Cmin) and heme vdw, coordinately influence the metabolic clearance of PAHs. Furthermore, the electronic properties (ESP neg variance) appeared to be critical for the mutagenicity of PAHs by CYP1A1 through influencing epoxide metabolite formation. The QSAR models with these key properties provide a new perspective on the structural mechanism of PAH metabolism and provide a useful in silico tool for screening, classifying and predicting PAHs for their metabolism-related toxicities and risk assessment in the environment.


Assuntos
Citocromo P-450 CYP1A1 , Hidrocarbonetos Policíclicos Aromáticos , Citocromo P-450 CYP1A1/metabolismo , Cinética , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Relação Quantitativa Estrutura-Atividade
20.
Eur J Med Chem ; 209: 112932, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33131725

RESUMO

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.


Assuntos
Anti-Inflamatórios/química , Ácido Oleanólico/química , Triterpenos Pentacíclicos/química , Saponinas/química , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Relação Dose-Resposta a Droga , Ácido Glicirrízico/química , Humanos , Interleucina-6/metabolismo , Fígado , Macrófagos/efeitos dos fármacos , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos BALB C , Triterpenos Pentacíclicos/farmacologia , Fosforilação/efeitos dos fármacos , Sapogeninas/química , Saponinas/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
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