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1.
Eur J Med Chem ; 274: 116557, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-38850857

RESUMO

Design and synthesis of novel 4-carboxamidopyrido[3,2-b]pyridine derivatives as novel rigid analogues of sorafenib are reported herein. The target compounds showed potent antiproliferative activities against a panel of NCI-60 cancer cell lines as well as hepatocellular carcinoma cell line. Compounds 8g and 9f were among the most promising derivatives in terms of effectiveness and safety. Therefore, they were further examined to demonstrate their ability to induce apoptosis and alter cell cycle progression in hepatocellular carcinoma cells. The most potent compounds were tested against a panel of kinases that indicated their selectivity against FMS kinase. Compounds 8g and 8h showed the most potent activities against FMS kinase with IC50 values of 21.5 and 73.9 nM, respectively. The two compounds were also tested in NanoBRET assay to investigate their ability to inhibit FMS kinase in cells (IC50 = 563 nM (8g) and 1347 nM (8h) vs. IC50 = 1654 nM for sorafenib). Furthermore, compounds 8g and 8h possess potent inhibitory activities against macrophages when investigated in bone marrow-derived macrophages (BMDM) assay (IC50 = 56 nM and 167 nM, respectively, 164 nM for sorafenib). The safety and selectivity of these compounds were confirmed when tested against normal cell lines. Their safety profile was further confirmed using hERG assay. In silico studies were carried out to investigate their binding modes in the active site of FMS kinase, and to develop a QSAR model for these new motifs.


Assuntos
Antineoplásicos , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Proteínas Quinases , Piridinas , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/farmacologia , Piridinas/química , Piridinas/síntese química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Animais , Simulação de Acoplamento Molecular , Camundongos
2.
Biochem Pharmacol ; 225: 116307, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38797269

RESUMO

Mitochondria play a crucial role in cellular metabolism and bioenergetics, orchestrating various cellular processes, including energy production, metabolism, adaptation to stress, and redox balance. Besides, mitochondria regulate cellular metabolic homeostasis through coordination with multiple signaling pathways. Importantly, the p38 mitogen-activated protein kinase (MAPK) signaling pathway is a key player in the intricate communication with mitochondria, influencing various functions. This review explores the multifaced interaction between the mitochondria and p38 MAPK signaling and the consequent impact on metabolic alterations. Overall, the p38 MAPK pathway governs the activities of key mitochondrial proteins, which are involved in mitochondrial biogenesis, oxidative phosphorylation, thermogenesis, and iron homeostasis. Additionally, p38 MAPK contributes to the regulation of mitochondrial responses to oxidative stress and apoptosis induced by cancer therapies or natural substances by coordinating with other pathways responsible for energy homeostasis. Therefore, dysregulation of these interconnected pathways can lead to various pathologies characterized by aberrant metabolism. Consequently, gaining a deeper understanding of the interaction between mitochondria and the p38 MAPK pathway and their implications presents exciting forecasts for novel therapeutic interventions in cancer and other disorders characterized by metabolic dysregulation.


Assuntos
Mitocôndrias , Neoplasias , Proteínas Quinases p38 Ativadas por Mitógeno , Humanos , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Mitocôndrias/metabolismo , Animais , Sistema de Sinalização das MAP Quinases/fisiologia , Metabolismo Energético/fisiologia
3.
IUBMB Life ; 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38497226

RESUMO

Hepatocellular carcinoma (HCC) significantly contributes to cancer-related mortality due to the limited response of HCC to current anticancer therapies, thereby necessitating more effective treatment approaches. Energy restriction mimetic agents (ERMAs) have emerged as potential therapies in targeting the Warburg effect, a unique metabolic process in cancer cells. However, ERMAs exhibit limited efficacy when used as monotherapy. Additionally, ERMAs have been found to induce autophagy in cancer cells. The role of autophagy in cancer survival remains a subject of debate. Thus, it is crucial to ascertain whether ERMA-induced autophagy is a mechanism for cell survival or cell death in HCC. Our study aims to investigate the effect of autophagy inhibition on the survival of HCC cells treated with ERMAs while also examining the potential of combining an autophagy inhibitor such as spautin-1 with ERMAs to enhance HCC cell death. Our results suggest a cytoprotective role for ERMA-induced autophagy in HCC cells, as combining the autophagy inhibitor spautin-1 with ERMAs effectively suppressed ERMA-induced autophagy and synergistically enhanced their antitumor activity. The treatment combination promoted HCC death through apoptosis, cell cycle arrest, and inhibition of AKT and ERK activation, which are known to play a key role in cellular proliferation. Collectively, our findings highlight a potential strategy to combat HCC by combining energy restriction with autophagy inhibition.

4.
Infection ; 49(5): 855-876, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34339040

RESUMO

PURPOSE: COVID-19 pandemic has emerged as a result of infection by the deadly pathogenic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), causing enormous threats to humans. Coronaviruses are distinguished by a clove-like spike (S) protein, which plays a key role in viral pathogenesis, evolutions, and transmission. The objectives of this study are to investigate the distinctive structural features of SARS-CoV-2 S protein, its essential role in pathogenesis, and its use in the development of potential therapies and vaccines. METHODOLOGY: A literature review was conducted to summarize, analyze, and interpret the available scientific data related to SARS-CoV-2 S protein in terms of characteristics, vaccines development and potential therapies. RESULTS: The data indicate that S protein subunits and their variable conformational states significantly affect the virus pathogenesis, infectivity, and evolutionary mutation. A considerable number of potential natural and synthetic therapies were proposed based on S protein. Additionally, neutralizing antibodies were recently approved for emergency use. Furthermore, several vaccines utilizing the S protein were developed. CONCLUSION: A better understanding of S protein features, structure and mutations facilitate the recognition of the importance of SARS-CoV-2 S protein in viral infection, as well as the development of therapies and vaccines. The efficacy and safety of these therapeutic compounds and vaccines are still controversial. However, they may potentially reduce or prevent SARS-CoV-2 infection, leading to a significant reduction of the global health burden of this pandemic.


Assuntos
COVID-19 , Vacinas , Humanos , Pandemias , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genética
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