RESUMO
Increasing evidence has demonstrated that oxidative phosphorylation (OXPHOS) is closely associated with the progression of pancreatic cancer (PC). Given its central role in mitochondrial transcription, the human mitochondrial RNA polymerase (POLRMT) is a promising target for developing PC treatments. Herein, structure-activity relationship exploration led to the identification of compound S7, which was the first reported POLRMT inhibitor possessing single-digit nanomolar potency of inhibiting PC cells proliferation. Mechanistic studies showed that compound S7 exerted antiproliferative effects without affecting the cell cycle, apoptosis, mitochondrial membrane potential (MMP), or intracellular reactive oxygen species (ROS) levels specifically in MIA PaCa-2 cells. Notably, compound S7 inhibited tumor growth in MIA PaCa-2 xenograft tumor model with a tumor growth inhibition (TGI) rate of 64.52% demonstrating significant improvement compared to the positive control (44.80%). In conclusion, this work enriched SARs of POLRMT inhibitors, and compound S7 deserved further investigations of drug-likeness as a candidate for PC treatment.
Assuntos
Antineoplásicos , Proliferação de Células , Cumarínicos , RNA Polimerases Dirigidas por DNA , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Animais , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Cumarínicos/farmacologia , Cumarínicos/química , Cumarínicos/síntese química , Cumarínicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , RNA Polimerases Dirigidas por DNA/metabolismo , Linhagem Celular Tumoral , Camundongos , Camundongos Nus , Flúor/química , Apoptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
Targeting NLRP3 inflammasome with inhibitors is a novel strategy for NLRP3-driven diseases. Herein, hit compound 5 possessing an attractive skeleton was identified from our in-house database of oridonin, and then a potential lead compound 32 was obtained by optimization of 5, displaying two-digit nanomolar inhibition on NLRP3. Moreover, compound 32 showed enhanced safety index (SI) relative to oridonin (IC50 = 77.2 vs 780.4 nM, SI = 40.5 vs 8.5) and functioned through blocking ASC oligomerization and interaction of NLRP3-ASC/NEK7, thereby suppressing NLRP3 inflammasome assembly and activation. Furthermore, diverse agonists-induced activations of NLRP3 could be impeded by compound 32 without altering NLRC4 or AIM2 inflammasome. Crucially, compound 32 possessed tolerable pharmaceutical properties and significant anti-inflammatory activity in MSU-induced gouty arthritis model. Therefore, this work enriched the SAR of NLRP3 inflammasome inhibitors and provided a potential candidate for the treatment of NLRP3-associated diseases.
Assuntos
Anti-Inflamatórios , Diterpenos do Tipo Caurano , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/uso terapêutico , Diterpenos do Tipo Caurano/síntese química , Inflamassomos/metabolismo , Inflamassomos/antagonistas & inibidores , Animais , Humanos , Camundongos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/síntese química , Relação Estrutura-Atividade , Masculino , Produtos Biológicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/síntese química , Camundongos Endogâmicos C57BL , Quinases Relacionadas a NIMA/antagonistas & inibidores , Quinases Relacionadas a NIMA/metabolismoRESUMO
Alzheimer's disease (AD) is a complex neurodegenerative disease that can lead to the loss of cognitive function. The progression of AD is regulated by multiple signaling pathways and their associated targets. Therefore, multitarget strategies theoretically have greater potential for treating AD. In this work, a series of new hybrids were designed and synthesized by the hybridization of tacrine (4, AChE: IC50 = 0.223 µM) with pyrimidone compound 5 (GSK-3ß: IC50 = 3 µM) using the cysteamine or cystamine group as the connector. The biological evaluation results demonstrated that most of the compounds exhibited moderate to good inhibitory activities against acetylcholinesterase (AChE) and glycogen synthase kinase 3ß (GSK-3ß). The optimal compound 18a possessed potent dual AChE/GSK-3ß inhibition (AChE: IC50 = 0.047 ± 0.002 µM, GSK-3ß: IC50 = 0.930 ± 0.080 µM). Further molecular docking and enzymatic kinetic studies revealed that this compound could occupy both the catalytic anionic site and the peripheral anionic site of AChE. The results also showed a lack of toxicity to SH-SY5Y neuroblastoma cells at concentrations of up to 25 µM. Collectively, this work explored the structure-activity relationships of novel tetrahydroacridin hybrids with sulfur-inserted linkers, providing a reference for the further research and development of new multitarget anti-AD drugs.
Assuntos
Acetilcolinesterase , Doença de Alzheimer , Inibidores da Colinesterase , Desenho de Fármacos , Glicogênio Sintase Quinase 3 beta , Simulação de Acoplamento Molecular , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Humanos , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Linhagem Celular Tumoral , Enxofre/química , Relação Estrutura-Atividade , Acridinas/química , Acridinas/farmacologia , Acridinas/síntese química , Tacrina/química , Tacrina/farmacologia , Tacrina/síntese química , Estrutura MolecularRESUMO
Excessive melanin deposition may lead to a series of skin disorders. The production of melanin is carried out by melanocytes, in which the enzyme tyrosinase performs a key role. In this work, we identified a series of novel tyrosinase inhibitor hybrids with a dihydrochalcone skeleton and resorcinol structure, which can inhibit tyrosinase activity and reduce the melanin content in the skin. Compound 11c possessed the most potent activity against tyrosinase, showing IC50 values at nanomolar concentration ranges, along with significant antioxidant activity and low cytotoxicity. Furthermore, in vitro permeation tests, supported by HPLC analysis and 3D OrbiSIMS imaging visualization, revealed the excellent permeation of 11c. More importantly, compound 11c reduced the melanin content on UV-induced skin pigmentation in a guinea pig model in vivo. These results suggest that compound 11c may serve as a promising potent tyrosinase inhibitor for the development of a potential therapy to treat skin hyperpigmentation.
Assuntos
Hiperpigmentação , Melaninas , Animais , Cobaias , Monofenol Mono-Oxigenase , Hiperpigmentação/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêuticoRESUMO
High oxidative phosphorylation (OXPHOS) happens in some tumors, which depends on OXPHOS for energy supply, particularly in slow-cycling tumor cells. Therefore, targeting human mitochondrial RNA polymerase (POLRMT) to inhibit mitochondrial gene expression emerges as a potential therapeutic strategy to eradicate tumor cells. In this work, exploration and optimization of the first-in-class POLRMT inhibitor IMT1B and its SAR led to the identification of a novel compound D26, which exerted a strong antiproliferative effect on several cancer cells and decreased mitochondrial-related genes expression. In addition, mechanism studies demonstrated that D26 arrested cell cycle at the G1 phase and had no effect on apoptosis, depolarized mitochondria, or reactive oxidative stress generation in A2780 cells. Importantly, D26 exhibited more potent anticancer activity than the lead IMT1B in A2780 xenograft nude mice and had no observable toxic effect. All results suggest that D26 deserves to be further investigated as a potent and safe antitumor candidate.