RESUMO
The biosynthesis of fatty acids constitutes a critical metabolic pathway in bacterial organisms. Prior investigations have highlighted the synthesis of antimicrobial compounds anchored in the benzodioxepin scaffold, noted for their pronounced antibacterial properties. Leveraging this foundational knowledge, the current research endeavors to meticulously engineer and synthesize a series of eight innovative benzodioxepin amide-biphenyl derivatives. This achievement was realized through the sophisticated optimization of synthetic methodologies. The scope of this study extends to a rigorous evaluation of the antibacterial prowess and biocompatibility of the aforementioned novel derivatives. Notably, Compound E4 emerged as a supremely potent antimicrobial agent. A detailed elucidation of the crystalline architecture of Compound E4 was conducted, alongside a thorough docking study to explore its interactions with the FabH enzyme.
Assuntos
Amidas , Antibacterianos , Compostos de Bifenilo , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Amidas/farmacologia , Amidas/química , Amidas/síntese química , Compostos de Bifenilo/química , Simulação de Acoplamento Molecular , Benzodioxóis/farmacologia , Benzodioxóis/síntese química , Benzodioxóis/química , Relação Estrutura-Atividade , Staphylococcus aureus/efeitos dos fármacos , Estrutura MolecularRESUMO
Cystic fibrosis (CF) is caused by the functional expression defect of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Despite the recent success in CFTR modulator development, the available correctors only partially restore the F508del-CFTR channel function, and several rare CF mutations show resistance to available drugs. We previously identified compound 4172 that synergistically rescued the F508del-CFTR folding defect in combination with the existing corrector drugs VX-809 and VX-661. Here, novel CFTR correctors were designed by applying a classical medicinal chemistry approach on the 4172 scaffold. Molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted to propose a plausible binding site and design more potent and effective analogs. We identified three optimized compounds, which, in combination with VX-809 and the investigational corrector 3151, increased the plasma membrane density and function of F508del-CFTR and other rare CFTR mutants resistant to the currently approved therapies.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Pirazóis , Pirimidinonas , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Pirazóis/farmacologia , Pirazóis/síntese química , Pirazóis/química , Humanos , Pirimidinonas/farmacologia , Pirimidinonas/síntese química , Pirimidinonas/química , Fibrose Cística/tratamento farmacológico , Fibrose Cística/metabolismo , Relação Quantitativa Estrutura-Atividade , Simulação de Acoplamento Molecular , Benzodioxóis/farmacologia , Benzodioxóis/síntese química , Benzodioxóis/química , Mutação , Aminopiridinas/farmacologia , Aminopiridinas/síntese química , Aminopiridinas/químicaRESUMO
This study reports the design, synthesis, and comprehensive biological evaluation of 13 benzodioxolane derivatives, derived from the core structure of piperine, a natural product with established antitumor properties. Piperine, primarily found in black pepper, has been noted for its diverse pharmacological activities, including anti-inflammatory, antioxidant, and anticancer effects. Leveraging piperine's antitumor potential, we aimed to enhance its efficacy through structural modifications. Among the synthesized compounds, HJ1 emerged as the most potent, exhibiting a 4-fold and 10-fold increase in inhibitory effects on HeLa and MDA-MB-231 cell lines, respectively, compared to piperine. Furthermore, HJ1 demonstrated a favorable safety profile, characterized by significantly lower cytotoxicity towards the human normal cell line 293T. Mechanistic investigations revealed that HJ1 markedly inhibited clonogenicity, migration, and adhesion of HeLa cells. In vivo studies utilizing the chick embryo chorioallantoic membrane (CAM) model substantiated the robust antitumor activity of HJ1, evidenced by its ability to suppress tumor angiogenesis and reduce tumor weight. These results suggest that HJ1 holds significant promise as a lead compound for the development of novel antitumor therapies.
Assuntos
Antineoplásicos , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Relação Estrutura-Atividade , Animais , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Benzodioxóis/farmacologia , Benzodioxóis/síntese química , Benzodioxóis/química , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Células HeLa , Movimento Celular/efeitos dos fármacos , Embrião de GalinhaRESUMO
A series of piperine derivatives were designed and successfully synthesized. The antitumor activities of these compounds against 293 T human normal cells, as well as MDA-MB-231 (breast) and Hela (cervical) cancer cell lines, were assessed through the MTT assay. Notably, compound H7 exhibited moderate activity, displaying reduced toxicity towards non-tumor 293 T cells while potently enhancing the antiproliferative effects in Hela and MDA-MB-231 cells. The IC50 values were determined to be 147.45 ± 6.05 µM, 11.86 ± 0.32 µM, and 10.50 ± 3.74 µM for the respective cell lines. In subsequent mechanistic investigations, compound H7 demonstrated a dose-dependent inhibition of clone formation, migration, and adhesion in Hela cells. At a concentration of 15 µM, its inhibitory effect on Hela cell function surpassed that of both piperine and 5-Fu. Furthermore, compound H7 exhibited promising antitumor activity in vivo, as evidenced by significant inhibition of tumor angiogenesis and reduction in tumor weight in a chicken embryo model. These findings provide a valuable scientific foundation for the development of novel and efficacious antitumor agents, particularly highlighting the potential of compound H7 as a therapeutic candidate for cervical cancer and breast cancer.
Assuntos
Alcaloides , Benzodioxóis , Piperidinas , Alcamidas Poli-Insaturadas , Humanos , Piperidinas/farmacologia , Piperidinas/síntese química , Piperidinas/química , Benzodioxóis/farmacologia , Benzodioxóis/síntese química , Alcamidas Poli-Insaturadas/farmacologia , Alcamidas Poli-Insaturadas/síntese química , Alcamidas Poli-Insaturadas/química , Alcaloides/farmacologia , Alcaloides/síntese química , Alcaloides/química , Animais , Estrutura Molecular , Linhagem Celular Tumoral , Células HeLa , Embrião de Galinha , Movimento Celular/efeitos dos fármacos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Desenho de Fármacos , Proliferação de Células/efeitos dos fármacosRESUMO
Inhibition of human dihydroorotate dehydrogenase (hDHODH) represents a promising strategy for suppressing the proliferation of cancer cells. To identify novel and potent hDHODH inhibitors, a total of 28 piperine derivatives were designed and synthesized. Their cytotoxicities against three human cancer cell lines (NCI-H226, HCT-116, and MDA-MB-231) and hDHODH inhibitory activities were also evaluated. Among them, compound H19, exhibited the strongest inhibitory activities (NCI-H226 IC50 = 0.95 µM, hDHODH IC50 = 0.21 µM). Further pharmacological investigations revealed that H19 exerted anticancer effects by inducing ferroptosis in NCI-H226 cells, with its cytotoxicity being reversed by ferroptosis inhibitors. This was supported by the intracellular growth or decline of ferroptosis markers, including lipid peroxidation, Fe2+, GSH, and 4-HNE. Overall, H19 emerges as a promising hDHODH inhibitor with potential anticancer properties warranting development.
Assuntos
Alcaloides , Antineoplásicos , Benzodioxóis , Proliferação de Células , Di-Hidro-Orotato Desidrogenase , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos , Ferroptose , Piperidinas , Alcamidas Poli-Insaturadas , Humanos , Alcaloides/farmacologia , Alcaloides/química , Alcaloides/síntese química , Di-Hidro-Orotato Desidrogenase/antagonistas & inibidores , Piperidinas/farmacologia , Piperidinas/química , Piperidinas/síntese química , Benzodioxóis/farmacologia , Benzodioxóis/síntese química , Benzodioxóis/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Relação Estrutura-Atividade , Ferroptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Alcamidas Poli-Insaturadas/farmacologia , Alcamidas Poli-Insaturadas/química , Alcamidas Poli-Insaturadas/síntese química , Estrutura Molecular , Relação Dose-Resposta a Droga , Descoberta de Drogas , Linhagem Celular TumoralRESUMO
The genus Absidia is widely used in the biotransformation of different classes of natural products. This study evaluates the ability of the Absidia coerulea 3A9 marine derived strain isolated from the ascidian Distaplia stilyfera to perform biotransformations by conducting assays with (-)-cubebin, as substrate. The experiment was optimized using the experimental design proposed by Plackett-Burman for seven factors and eight experiments, to establish the biotransformation conditions that would allow maximum production of biotransformed dibenzylbutyrolactone (-)-hinokinin. An analytical method based on Reverse-Phase-High Performance Liquid Chromatography (RP-HPLC) was developed to quantify the fungal biotransformation product. The factor that influenced the (-)-hinokinin peak area the most positively was the percentage of seawater (%seawater) given that its %relative standard deviation (%RSD) showed a 32.92% deviation from the real value.
Assuntos
4-Butirolactona/análogos & derivados , Absidia , Benzodioxóis , Lignanas , 4-Butirolactona/síntese química , Organismos Aquáticos/metabolismo , Benzodioxóis/síntese química , Biotransformação , Lignanas/síntese química , Lignanas/química , Lignanas/metabolismo , Água do Mar/químicaRESUMO
Several synthetic approaches (aminomethylation, alkylation, condensation, etc.) have been used to synthesize derivatives based on the sesamol (1), natural phenol. The set of methods, including the study of antioxidant activity (AOA) by the ability to inhibit the initiated oxidation of animal lipids, radical scavenging activity, Fe2+ -chelation ability, as well as a comparative assessment of membrane-protective activity under the conditions of H2 O2 -induced hemolysis of mice red blood cells (RBCs), was used to analyze the antioxidant potential of the synthesized compounds. The synthesized derivatives have demonstrated different activity in the listed test systems, and we have identified compounds which appear to be most promising for a detailed study of their pharmacological properties.
Assuntos
Antioxidantes/farmacologia , Benzodioxóis/farmacologia , Fenóis/farmacologia , Animais , Antioxidantes/síntese química , Antioxidantes/química , Benzodioxóis/síntese química , Benzodioxóis/química , Eritrócitos/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Camundongos , Modelos Moleculares , Estrutura Molecular , Estresse Oxidativo/efeitos dos fármacos , Fenóis/síntese química , Fenóis/químicaRESUMO
A set of 12 analogues of piperine was designed, replacing the amide functional group of the molecule with different aliphatic and aromatic ester functional groups. Molecular docking studies of these molecules with FDA-approved target proteins for anti-bacterial drugs were done. The binding energy of the proteins and the ligands were low and the analogues were found to be drug-like based on the ADME results; hence, the molecules were synthesized. The synthesized compounds were tested for their anti-bacterial property against six bacterial species via Agar well-diffusion method. Acinetobacter baumannii, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis and Staphylococcus epidermidis were the strains tested. The overall susceptibility is higher in gram-positive. The analogues showed better activity than piperine. The analogues, propyl piperic ester (P3) and 2-fluorophenyl piperic ester (P9) and 4-fluorophenyl piperic ester (P10) showed comparatively bigger inhibition zones for all the strains.
Assuntos
Alcaloides/síntese química , Antibacterianos/síntese química , Benzodioxóis/síntese química , Ácidos Graxos Insaturados/síntese química , Piperidinas/síntese química , Alcamidas Poli-Insaturadas/síntese química , Alcaloides/farmacologia , Antibacterianos/farmacologia , Benzodioxóis/farmacologia , Ácidos Graxos Insaturados/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Relação Estrutura-AtividadeRESUMO
Cancer stem cells (CSCs) are involved in recurrent hepatocellular carcinoma (HCC), yet there is a lack of effective treatment that targets these CSCs. CD44+ and CD133+ CSCs are markedly expressed in HepG2 cells and were isolated and characterized using fluorescence-activated cell sorting (FACS) analysis. Since piperine is known as an effective molecule against metastasis, we thought to investigate the effect of piperine against CD44+/CD133+ CSCs. Herein, piperine was found to be active against these CSCs. Also, it was found appropriate to respite at the 'subG0/G1 and G0/G1' phase of the cell cycle analysis, respectively. TGF-ß activated epithelial-mesenchymal transition (EMT) has been involved in the invasion and metastasis of HepG2 cells in hepatocellular carcinoma. Therefore, we next investigated the effect of piperine on different biomarkers that remarkably takes part in the process of EMT using flow cytometric analysis. Piperine was found able to repress the epithelial marker (E-cadherin) but was unable to restore the level of Vimentin (mesenchymal marker) and SNAIL (EMT-inducing transcription factor). Therefore, the findings of this study revealed that piperine could be an effective treatment strategy for recurrent hepatocarcinogenesis.
Assuntos
Alcaloides/farmacologia , Antineoplásicos/farmacologia , Benzodioxóis/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Hepáticas/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/síntese química , Alcaloides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Benzodioxóis/síntese química , Benzodioxóis/química , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Simulação de Dinâmica Molecular , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Alcamidas Poli-Insaturadas/síntese química , Alcamidas Poli-Insaturadas/química , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Cystic fibrosis (CF) is the most frequent life-limiting autosomal recessive disorder in the Caucasian population. It is due to mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Current symptomatic CF therapies, which treat the downstream consequences of CFTR mutations, have increased survival. Better knowledge of the CFTR protein has enabled pharmacologic therapy aiming to restore mutated CFTR expression and function. These CFTR "modulators" have revolutionised the CF therapeutic landscape, with the potential to transform prognosis for a considerable number of patients. This review provides a brief summary of their mechanism of action and presents a thorough review of the results obtained from clinical trials of CFTR modulators.
Assuntos
Aminofenóis/farmacologia , Aminopiridinas/farmacologia , Benzodioxóis/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Fibrose Cística/tratamento farmacológico , Desenvolvimento de Medicamentos , Indóis/farmacologia , Quinolonas/farmacologia , Aminofenóis/síntese química , Aminofenóis/química , Aminopiridinas/síntese química , Benzodioxóis/síntese química , Ensaios Clínicos como Assunto , Fibrose Cística/diagnóstico , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Indóis/síntese química , Quinolonas/síntese química , Quinolonas/químicaRESUMO
Major lignans of sesame sesamin and sesamolin are benzodioxol--substituted furofurans. Sesamol, sesaminol, its epimers, and episesamin are transformation products found in processed products. Synthetic routes to all lignans are known but only sesamol is synthesized industrially. Biosynthesis of furofuran lignans begins with the dimerization of coniferyl alcohol, followed by the formation of dioxoles, oxidation, and glycosylation. Most genes of the lignan pathway in sesame have been identified but the inheritance of lignan content is poorly understood. Health-promoting properties make lignans attractive components of functional food. Lignans enhance the efficiency of insecticides and possess antifeedant activity, but their biological function in plants remains hypothetical. In this work, extensive literature including historical texts is reviewed, controversial issues are critically examined, and errors perpetuated in literature are corrected. The following aspects are covered: chemical properties and transformations of lignans; analysis, purification, and total synthesis; occurrence in Seseamum indicum and related plants; biosynthesis and genetics; biological activities; health-promoting properties; and biological functions. Finally, the improvement of lignan content in sesame seeds by breeding and biotechnology and the potential of hairy roots for manufacturing lignans in vitro are outlined.
Assuntos
Benzodioxóis/química , Furanos/química , Lignanas/química , Fenóis/química , Sesamum/química , Benzodioxóis/síntese química , Dioxóis/química , Lignanas/síntese química , Oxirredução , Fenóis/síntese química , Sementes/química , Sesamum/genéticaRESUMO
We report an asymmetric homocoupling of ortho-(iodo)arylphosphine oxides and ortho-(iodo)arylphosphonates resulting in highly enantioenriched axially chiral bisphosphine oxides and bisphosphonates. These products are readily converted to enantioenriched biaryl bisphosphines without need for chiral auxiliaries or optical resolution. This provides a practical route for the development of previously uninvestigated atroposelective biaryl bisphosphine ligands. The conditions have also proven effective for asymmetric dimerization of other, non-phosphorus-containing aryl halides.
Assuntos
Benzodioxóis/síntese química , Compostos de Bifenilo/síntese química , Complexos de Coordenação/química , Ácidos Fosforosos/síntese química , Catálise , Dimerização , Ligantes , Níquel/química , Oxazóis/química , Oxirredução , Piridinas/química , EstereoisomerismoRESUMO
Piper species is one of the most widely consumed spices for culinary purposes. Piperine (PIP) present in Piper species has a wide range of therapeutic activity including hepatoprotection. However, the major biological limitation of PIP is its low bioavailability after oral administration. Purpose of the study was to prepare an optimized and adequately characterized PIP-phospholipid complex (PPC) as a delivery system to overcome these limitations and to investigate the pharmacokinetics and hepato-protectivity of the formulation in the animal model. Response surface methodology was adopted to optimize the process parameters for PPC preparation. FT-IR, DTA, PXRD, SEM, molecular docking etc. were used for characterization. Solubility, log P, dissolution efficiency and in vivo pharmacokinetics were also investigated. PPC showed enhanced hepatoprotective potential as compared to pure PIP at the same dose level (25 and 50 mg/kg). PPC restored the levels of serum marker and antioxidant enzymes. PPC also increased the bioavailability of PIP in rat serum by 10.40-fold in comparison with pure PIP at the same dose level and enhanced the elimination half-life (t1/2 el) from 0.477 ± 1.76 to 9.80 ± 1.98 h. Results concluded that PPC enhanced the hepatoprotection of PIP which may be due to the improved bioavailability and pharmacokinetics of PIP in rats.
Assuntos
Alcaloides/administração & dosagem , Alcaloides/metabolismo , Benzodioxóis/administração & dosagem , Benzodioxóis/metabolismo , Fígado/metabolismo , Fosfolipídeos/administração & dosagem , Fosfolipídeos/metabolismo , Piperidinas/administração & dosagem , Piperidinas/metabolismo , Alcamidas Poli-Insaturadas/administração & dosagem , Alcamidas Poli-Insaturadas/metabolismo , Alcaloides/síntese química , Animais , Benzodioxóis/síntese química , Disponibilidade Biológica , Fígado/efeitos dos fármacos , Masculino , Simulação de Acoplamento Molecular/métodos , Fosfolipídeos/síntese química , Piperidinas/síntese química , Alcamidas Poli-Insaturadas/síntese química , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/síntese química , Substâncias Protetoras/metabolismo , Ratos , Ratos WistarRESUMO
Antioxidants is a kind of substances that can effectively inhibit the oxidation reaction of free radicals. There are many chemical components with antioxidant activity in natural products. Sesamol is one of the natural products with antioxidant activity, and it is often used as an antioxidant in food, medicine and other fields. In the present study, sesame was used as the extraction raw material for the extraction and separated of sesamol with antioxidant activity. On this basis, a total 10 of sesamol derivatives were synthesized by two steps reaction with sesamol as starting material. The antioxidant activity of these sesamol derivatives were tested, and the test results showed that these sesamol derivatives had a good antioxidant activity, among them, compound 4d had the best antioxidant activity. Sesamol derivatives can be used as an antioxidant in food, medicine and other fields and it needs a further study.
Assuntos
Antioxidantes/farmacologia , Benzodioxóis/farmacologia , Produtos Biológicos/farmacologia , Radical Hidroxila/antagonistas & inibidores , Fenóis/farmacologia , Superóxidos/antagonistas & inibidores , Antioxidantes/síntese química , Antioxidantes/química , Benzodioxóis/síntese química , Benzodioxóis/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Fenóis/síntese química , Fenóis/química , Relação Estrutura-AtividadeRESUMO
The natural products piperlongumine and piperine have been shown to inhibit cancer cell proliferation through elevation of reactive oxidative species (ROS) and eventually cell death, but only have modest cytotoxic potencies. A series of 14 novel phenylallylidenecyclohexenone analogues based on piperlongumine and piperine therefore were designed and synthesized, and their pharmacological properties were evaluated. Most of the compounds produced antiproliferative activities against five human cancer cells with IC50 values lower than those of piperlongumine and piperine. Among these, compound 9m exerted the most potent antiproliferative activity against drug-resistant Bel-7402/5-FU human liver cancer 5-FU resistant cells (IC50 = 0.8 µM), which was approximately 10-fold lower than piperlongumine (IC50 = 8.4 µM). Further, 9m showed considerably lower cytotoxicity against LO2 human normal liver epithelial cells compared to Bel-7402/5-FU. Mechanistically, compound 9m inhibited thioredoxin reductase (TrxR) activity, increased ROS levels, reduced mitochondrial transmembrane potential (MTP), and induced autophagy in Bel-7402/5-FU cells via regulation of autophagy-related proteins LC3, p62, and beclin-1. Finally, 9m activated significantly the p38 signaling pathways and suppressed the Akt/mTOR signaling pathways. In conclusion, 9m could be a promising candidate for the treatment of drug-resistant cancer cells and, as such, warrants further investigation.
Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Autofagia/efeitos dos fármacos , Benzodioxóis/farmacologia , Dioxolanos/farmacologia , Proteína Oncogênica v-akt/efeitos dos fármacos , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/efeitos dos fármacos , Tiorredoxina Redutase 1/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Alcaloides/síntese química , Alcaloides/química , Antimetabólitos Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Benzodioxóis/síntese química , Benzodioxóis/química , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dioxolanos/síntese química , Dioxolanos/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluoruracila/farmacologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Alcamidas Poli-Insaturadas/síntese química , Alcamidas Poli-Insaturadas/química , Espécies Reativas de OxigênioRESUMO
Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. It is caused by different mutations in the cystic fibrosis transmembrane regulator protein (CFTR) gene, with F508del being the most common. During the last years, small-molecule therapy chosen to contrast CF relied on compounds that correct CFTR misfolding and ER retention (correctors such as VX-809), or defective channel gating (potentiators such as VX-770). Combination therapy with the two series of drugs has been applied, leading to the approval of several multi-drugs such as Orkambi. Despite this, this treatment proved to be only partially effective making the search for novel modulators an urgent need to contrast CF. Recently, we reported compound 2a as reference compound of a series of aminoarylthiazole-VX-809 hybrid derivatives exhibiting promising F508del-CFTR corrector ability. Herein, we report exploring the docking mode of the prototype VX-809 and of 2a in order to derive useful guidelines for the rational design of novel optimized analogues. To demonstrate experimentally their effective F508del-CFTR-binding and rescuing potential, the most promising derivatives had been synthesized and evaluated in biological assays including YFP functional assay on F508del-CFTR CFBE41o-cells, trans epithelial electrical resistance (TEER) and surface plasmon resonance (SPR). This multidisciplinary strategy led to the discovery of a second series of hybrids including 7j and 7m endowed with higher potency than the prototype.
Assuntos
Aminopiridinas/metabolismo , Aminopiridinas/farmacologia , Benzodioxóis/metabolismo , Benzodioxóis/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Aminopiridinas/síntese química , Benzodioxóis/síntese química , Linhagem Celular , Regulador de Condutância Transmembrana em Fibrose Cística/química , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Desenho de Fármacos , Humanos , Simulação de Acoplamento Molecular , Mutação , Ligação Proteica , Domínios ProteicosRESUMO
Exposure to environmental toxins may be responsible for biliary atresia. The focus of this study was to investigate the effect of biliatresone on the development of the hepatobiliary system in mice. We successfully synthesized biliatresone with a purity of 98% and confirmed its biliary toxicity. Exposure to high doses of biliatresone caused abortion or death in pregnant mice. Neonatal mice injected with biliatresone developed clinical signs of biliary obstruction, and dysplasia or the absence of extrahepatic biliary tract lumen, which confirmed the occurrence of biliary atresia. In the portal tract of biliary atresia mice, signs of infiltration of inflammatory cells and liver fibrosis were observed. The signature of extrahepatic biliary gene expression in these mice mainly involved the cell adhesion process, and hepatic RNA-seq was highly linked to transcriptional evidence of oxidative stress. When compared with the control group, hepatic glutathione levels were markedly reduced after biliatresone injection. Taken together, these data confirm that biliatresone causes severe developmental abnormalities of the hepatobiliary system in mice. Furthermore, decreased levels of glutathione may play a mechanistic role in the pathogenesis of liver fibrosis in biliatresone-induced experimental biliary atresia.
Assuntos
Benzodioxóis/toxicidade , Atresia Biliar/induzido quimicamente , Fígado/efeitos dos fármacos , Aborto Induzido , Animais , Animais Recém-Nascidos , Benzodioxóis/síntese química , Feminino , Glutationa/metabolismo , Fígado/imunologia , Fígado/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Gravidez , Transcriptoma , Peixe-ZebraRESUMO
Sesamol is a phenolic derivative. Its antioxidant activity is low than that of Trolox and depends on benzodioxole moiety. Thus, a molecular modification strategy through alkylation, inspired by natural and synthetic antioxidants, was studied by molecular modeling at the DFT/B3LYP level of theory by comparing the 6-31+G(d,p) and 6-311++G(2d,2p) basis sets. All proposed derivatives were compared to classical related antioxidants such as Trolox, t-butylated hydroxytoluene (BHT) and t-butylated hydroxyanisole (BHA). According to our results, molecular orbitals, single electron or hydrogen-atom transfers, spin density distributions, and alkyl substitutions at the ortho positions related to phenol moiety were found to be more effective than any other positions. The trimethylated derivative was more potent than Trolox. t-Butylated derivatives were stronger than all other alkylated derivatives and may be new alternative forms of modified antioxidants from natural products with applications in the chemical, pharmaceutical, and food industries.
Assuntos
Antioxidantes/síntese química , Benzodioxóis/síntese química , Fenóis/síntese química , Alquilação , Benzodioxóis/química , Hidroxianisol Butilado/química , Hidroxitolueno Butilado/química , Cromanos/química , Transporte de Elétrons , Radicais Livres/química , Estrutura Molecular , Fenóis/químicaRESUMO
INTRODUCTION: Peroxisome proliferator-activated receptor γ (PPARγ) plays a key role in glucose, which is a ligand-mediated transcription factor. The lipid homeostasis often serves as a pharmacological target for new drug discovery and development. MATERIALS AND METHODS: In the research, we synthesized a series of piperine derivatives and then used a fluorescence polarization-based PPARγ ligand screening assay to evaluate the agonistic activity of PPARγ. Then, we cultured human normal hepatocytes, which were treated with 100µM compounds 2a, 2t or 3d. Then, the levels of PPARγ gene were determined so as to show whether the compounds could activate or inhibit the expression of PPARγ. RESULTS: A total of 30 piperine derivatives were synthesized and evaluated. Compound 2a was identified as a potential PPARγ agonist with IC50 at 2.43 µM, which is 2 times more potent than the positive control rosiglitazone with IC50 at 5.61µM. The human hepatocytes cells were cultured and treated with compounds 2a, 2t or 3d as described in the "Materials and Methods" section. We found that compounds 2a, 2t and 3d could activate PPARγ by 11.8, 1.9 and 7.0 times compared with the "blank", with compound 2a activation being the most significant. Molecular docking studies indicated that the piperine derivative 2a stably interacts with the amino acid residues of the PPARγ complex active site, which is consistent with the results of the in vitro PPARγ ligand screening assay.
Assuntos
Alcaloides/farmacologia , Benzodioxóis/farmacologia , PPAR gama/agonistas , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Alcaloides/síntese química , Alcaloides/química , Benzodioxóis/síntese química , Benzodioxóis/química , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , PPAR gama/genética , PPAR gama/metabolismo , Piperidinas/síntese química , Piperidinas/química , Alcamidas Poli-Insaturadas/síntese química , Alcamidas Poli-Insaturadas/química , Relação Estrutura-AtividadeRESUMO
Parkinson's disease (PD) is a slowly progressive and complex neurodegenerative disorder. Up to date, there are no approved drugs that could slow or reverse the neurodegenerative process of PD. Here, we reported the synthesis of series of piperine analogues and the evaluation of their neuroprotective effects against hydrogen peroxide (H2O2) induced damage in the neuron-like PC12 cells. Among these analogues, 3b exhibited the most potent protection effect and its underlying mechanism was further investigated. Further results indicated that the ROS scavenging and cytoprotection effect of 3b might be related to the Nrf2 activation and upregulation of related phase II antioxidant enzymes, such as HO-1 and NQO1. In in vivo study, oral administration (100 mg/kg) of 3b significantly attenuated PD-associated behavioral deficits in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD and protected tyrosine hydroxylase-immunopositive dopaminergic neurons. Our results provided evidence that 3b might be a promising candidate for Parkinson's disease treatment.