RESUMO
Four new p-terphenyl derivatives, talaroterphenyls A-D (1-4), together with three biosynthetically related known ones (5-7), were obtained from the mangrove sediment-derived Talaromyces sp. SCSIO 41412. Compounds 1-3 are rare p-terphenyls, which are completely substituted on the central benzene ring by oxygen atoms; this is the first report of their isolation from natural sources. Their structures were elucidated through NMR spectroscopy, HRESIMS, and X-ray diffraction. Genome sequence analysis revealed that 1-7 were biosynthesized from tyrosine and phenylalanine, involving four key biosynthetic genes (ttpB-ttpE). These p-terphenyls (1-7) and 36 marine-derived terphenyl analogues (8-43) were screened for phosphodiesterase 4 (PDE4) inhibitory activities, and 1-5, 14, 17, 23, and 26 showed notable activities with IC50 values of 0.40-16 µM. The binding pattern of p-terphenyl inhibitors 1-3 with PDE4 were explored by molecular docking analysis. Talaroterphenyl A (1), with a low cytotoxicity, showed obvious anti-inflammatory activity in LPS-stimulated RAW264.7 cells. Furthermore, in the TGF-ß1-induced medical research council cell strain-5 (MRC-5) pulmonary fibrosis model, 1 could down-regulate the expression levels of FN1, COL1, and α-SMA significantly at concentrations of 5-20 µM. This study suggests that the oxidized p-terphenyl 1, as a marine-derived PDE4 inhibitor, could be used as a promising antifibrotic agent.
Assuntos
Inibidores da Fosfodiesterase 4 , Compostos de Terfenil , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/isolamento & purificação , Camundongos , Animais , Compostos de Terfenil/farmacologia , Compostos de Terfenil/química , Compostos de Terfenil/isolamento & purificação , Estrutura Molecular , Talaromyces/química , Células RAW 264.7 , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Biologia MarinhaRESUMO
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high mortality lung disease. Although the antifibrotic drugs pirfenidone and nintedanib could slow the rate of lung function decline, the usual course of the condition is inexorably to respiratory failure and death. Therefore, new approaches and novel therapeutic drugs for the treatment of IPF are urgently needed. And the selective PDE4 inhibitor has in vivo and in vitro anti-fibrotic effects in IPF models. But the clinical application of most PDE4 inhibitors are limited by their unexpected and severe side effects such as nausea, vomiting, and diarrhea. Herein, structure-based optimizations of the natural product Moracin M resulted in a novel a novel series of 2-arylbenzofurans as potent PDE4 inhibitors. The most potent inhibitor L13 has an IC50 of 36 ± 7 nM with remarkable selectivity across the PDE families and administration of L13·citrate (10.0 mg/kg) exhibited comparable anti-pulmonary fibrosis effects to pirfenidone (300 mg/kg) in a bleomycin-induced IPF mice model, indicate that L13 is a potential lead for the treatment of IPF.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Fibrose Pulmonar Idiopática , Inibidores da Fosfodiesterase 4 , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/induzido quimicamente , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/uso terapêutico , Animais , Relação Estrutura-Atividade , Camundongos , Estrutura Molecular , Humanos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Bleomicina , Relação Dose-Resposta a Droga , Camundongos Endogâmicos C57BL , Masculino , Benzofuranos/farmacologia , Benzofuranos/química , Benzofuranos/síntese químicaRESUMO
BACKGROUND: Ulcerative colitis (UC) is one chronic and relapsing inflammatory bowel disease. Macrophage has been reputed as one trigger for UC. Recently, phosphodiesterase 4 (PDE4) inhibitors, for instance roflumilast, have been regarded as one latent approach to modulating macrophage in UC treatment. Roflumilast can decelerate cyclic adenosine monophosphate (cAMP) degradation, which impedes TNF-α synthesis in macrophage. However, roflumilast is devoid of macrophage-target and consequently causes some unavoidable adverse reactions, which restrict the utilization in UC. RESULTS: Membrane vesicles (MVs) from probiotic Escherichia coli Nissle 1917 (EcN 1917) served as a drug delivery platform for targeting macrophage. As model drugs, roflumilast and MnO2 were encapsulated in MVs (Rof&MnO2@MVs). Roflumilast inhibited cAMP degradation via PDE4 deactivation and MnO2 boosted cAMP generation by activating adenylate cyclase (AC). Compared with roflumilast, co-delivery of roflumilast and MnO2 apparently produced more cAMP and less TNF-α in macrophage. Besides, Rof&MnO2@MVs could ameliorate colitis in mouse model and regulate gut microbe such as mitigating pathogenic Escherichia-Shigella and elevating probiotic Akkermansia. CONCLUSIONS: A probiotic-based nanoparticle was prepared for precise codelivery of roflumilast and MnO2 into macrophage. This biomimetic nanoparticle could synergistically modulate cAMP in macrophage and ameliorate experimental colitis.
Assuntos
Aminopiridinas , Benzamidas , AMP Cíclico , Ciclopropanos , Macrófagos , Compostos de Manganês , Óxidos , Probióticos , Animais , Aminopiridinas/farmacologia , Camundongos , AMP Cíclico/metabolismo , Probióticos/farmacologia , Ciclopropanos/farmacologia , Ciclopropanos/química , Compostos de Manganês/química , Compostos de Manganês/farmacologia , Benzamidas/farmacologia , Benzamidas/química , Óxidos/farmacologia , Óxidos/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/química , Colite/tratamento farmacológico , Colite/induzido quimicamente , Células RAW 264.7 , Escherichia coli/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Camundongos Endogâmicos C57BL , Masculino , Modelos Animais de DoençasRESUMO
Phosphodiesterase 4 (PDE4) enzymes catalyze cyclic adenosine monophosphate (cAMP) hydrolysis and are involved in a variety of physiological processes, including brain function, monocyte and macrophage activation, and neutrophil infiltration. Among different PDE4 isoforms, Phosphodiesterases 4D (PDE4Ds) play a fundamental role in cognitive, learning and memory consolidation processes and cancer development. Selective PDE4D inhibitors (PDE4Dis) could represent an innovative and valid therapeutic strategy for the treatment of various neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's, and Lou Gehrig's diseases, but also for stroke, traumatic brain and spinal cord injury, mild cognitive impairment, and all demyelinating diseases such as multiple sclerosis. In addition, small molecules able to block PDE4D isoforms have been recently studied for the treatment of specific cancer types, particularly hepatocellular carcinoma and breast cancer. This review overviews the PDE4DIsso far identified and provides useful information, from a medicinal chemistry point of view, for the development of a novel series of compounds with improved pharmacological properties.
Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Inibidores da Fosfodiesterase 4 , Humanos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 4/química , Animais , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
Phosphodiesterase-4D (PDE4D) has emerged as a significant target for treating neuropsychiatric disorders, but no PET radioligand currently exists for robustly quantifying human brain PDE4D to assist biomedical research and drug discovery. A prior candidate PDE4D PET radioligand, namely [11C]T1650, failed in humans because of poor time stability of brain PDE4D-specific signal (indexed by total volume of distribution), likely due to radiometabolites accumulating in brain. Its nitro group was considered to be a source of the brain radiometabolites. Methods: We selected 5 high-affinity and selective PDE4D inhibitors, absent of a nitro group, from our prior structure-activity relationship study for evaluation as PET radioligands. Results: All 5 radioligands were labeled with 11C (half-time, 20.4 min) in useful yields and with high molar activity. All displayed sizable PDE4D-specific signals in rhesus monkey brain. Notably, [11C]JMJ-81 and [11C]JMJ-129 exhibited excellent time stability of signal (total volume of distribution). Furthermore, as an example, [11C]JMJ-81 was found to be free of radiometabolites in ex vivo monkey brain, affirming that this radioligand can provide robust quantification of brain PDE4D with PET. Conclusion: Given their high similarity in structures and metabolic profiles, both [11C]JMJ-81 and [11C]JMJ-129 warrant further evaluation in human subjects. [11C]JMJ-129 shows a higher PDE4D specific-to-nonspecific binding ratio and will be the first to be evaluated.
Assuntos
Encéfalo , Radioisótopos de Carbono , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Macaca mulatta , Tomografia por Emissão de Pósitrons , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Ligantes , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/química , Masculino , Marcação por Isótopo , Inibidores da Fosfodiesterase 4/química , HumanosRESUMO
Peptide-drug conjugates (PDCs) are a promising class of drug delivery systems that utilize covalently conjugated carrier peptides with therapeutic agents. PDCs offer several advantages over traditional drug delivery systems including enhanced target engagement, improved bioavailability, and increased cell permeability. However, the development of efficient transcellular peptides capable of effectively transporting drugs across biological barriers remains an unmet need. In this study, physicochemical criteria based on cell-penetrating peptides are employed to design transcellular peptides derived from an antimicrobial peptides library. Among the statistically designed transcellular peptides (SDTs), SDT7 exhibits higher skin permeability, faster kinetics, and improved cell permeability in human keratinocyte cells compared to the control peptide. Subsequently, it is found that 6-Paradol (PAR) exhibits inhibitory activity against phosphodiesterase 4, which can be utilized for an anti-inflammatory PDC. The transcellular PDC (SDT7-conjugated with PAR, named TM5) is evaluated in mouse models of psoriasis, exhibiting superior therapeutic efficacy compared to PAR alone. These findings highlight the potential of transcellular PDCs (TDCs) as a promising approach for the treatment of inflammatory skin disorders.
Assuntos
Psoríase , Psoríase/tratamento farmacológico , Psoríase/metabolismo , Animais , Humanos , Camundongos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Pele/metabolismo , Pele/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/farmacologia , Peptídeos Penetradores de Células/farmacocinética , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/farmacocinéticaRESUMO
Sepsis can quickly result in fatality for critically ill individuals, while liver damage can expedite the progression of sepsis, necessitating the exploration of new strategies for treating hepatic sepsis. PDE4 has been identified as a potential target for the treatment of liver damage. The scaffold hopping of lead compounds FCPR16 and Z19153 led to the discovery of a novel 7-methoxybenzofuran PDE4 inhibitor 4e, demonstrating better PDE4B (IC50 = 10.0 nM) and PDE4D (IC50 = 15.2 nM) inhibitor activity as a potential anti-hepatic sepsis drug in this study. Compared with FCPR16 and Z19153, 4e displayed improved oral bioavailability (F = 66 %) and longer half-life (t1/2 = 2.0 h) in SD rats, which means it can be more easily administered and has a longer-lasting effect. In the D-GalN/LPS-induced liver injury model, 4e exhibited excellent hepatoprotective activity against hepatic sepsis by decreasing ALT and AST levels and inflammatory infiltrating areas.