RESUMEN
Histone deacetylases (HDACs) are zinc-dependent deacetylases that remove acetyl groups from lysine residues of histones or form protein complexes with other proteins for transcriptional repression, changing chromatin structure tightness, and inhibiting gene expression. Recent in vivo and in vitro studies have amply demonstrated the critical role of HDACs in the cell biology of the nervous system during both physiological and pathological processes and have provided new insights into the conduct of research on neurological disease targets. In addition, in vitro and in vivo studies on HDAC inhibitors show promise for the treatment of various diseases. This review summarizes the regulatory mechanisms of HDAC and the important role of its downstream targets in nervous system diseases, and summarizes the therapeutic mechanisms and efficacy of HDAC inhibitors in various nervous system diseases. Additionally, the current pharmacological situation, problems, and developmental prospects of HDAC inhibitors are described. A better understanding of the pathogenic mechanisms of HDACs in the nervous system may reveal new targets for therapeutic interventions in diseases and help to relieve healthcare pressure through preventive measures.
RESUMEN
Obesity-related chronic kidney disease (CKD) poses a significant risk to individuals' health and wellbeing, but the pathological mechanisms and treatment strategies are currently limited. Trans-cinnamic acid (CA) is a key active monomer found in cinnamon bark and is known for its diverse pharmacological activities. However, its effect on obesity-related renal injury remains unknown. In the current study, the in vitro and in vivo experiments were combined to investigate the beneficial effect of CA on renal injury induced by HFD or PA. We found that CA significantly reduced the obesity of zebrafish body and the accumulation of fat in kidney tissues. The histopathological changes and dysfunction induced by HFD were effectively mitigated by CA administration, as evidenced by the detection of Hematoxylin-Eosin straining, NAG activity, creatinine level, and expression of functional-related genes, respectively. Additionally, the in vitro and in vivo findings demonstrated that CA dramatically reduced the oxidative stress, inflammatory, and apoptosis in HFD-induced kidney tissues or PA-treated HEK293T and HK-2 cells. Finally, the results regarding ERK, JNK, and P38 proteins phosphorylation confirmed that CA may alleviate HFD-induced renal injury by inhibiting the phosphorylation of ERK, JNK, and P38 MAPK proteins. This theory was further supported by the results of co-treatment with anisomycin (a JNK activator) or lipopolysaccharide and CA in HEK293T cells. This study proves that CA alleviates the obesity-related CKD probably through inhibition of MAPK signaling pathway.
RESUMEN
Cinnamic acid and geraniol are two well-known antifungal natural products and widely applied in food and cosmetics industries. To discover novel natural product-based fungicide candidates with more potent activity and good ecological compatibility for the management of plant diseases, a series of cinnamic acid-geraniol hybrids were prepared by means of molecular hybridization and their chemical structures were well confirmed by spectral analysis. The antifungal activities of the target compounds against three phytopathogenic fungi Fusarium graminearum, Gaeumannomycesgraminis (Sacc.) Arx et Oliver var. tritici (Sacc.) Walker, and Valsa mali were evaluated. Among them, compounds 5e and 5f showed the remarkable antifungal activity against G. graminis with the EC50 values of 82.719 and 91.828 µg/mL, respectively; while compounds 5f and 6b exhibited the obvious antifungal activity against V. mali. It suggested that compound 5f can be further optimized for the design of novel broad-spectrum fungicide molecules as the secondary lead compound. In addition, some interesting structure-antifungal activity relationships were obtained. This work will provide some reference and guidance for the further discovery of novel fungicide candidates based on cinnamic acid and geraniol.
RESUMEN
To find potential α-glucosidase inhibitors, a series of 2ß-acetoxyferuginol derivatives containing cinnamic acid (WXC-1 â¼ 25) were synthesized and investigated their biological activity. All derivatives (WXC-1 â¼ 25) displayed better inhibitory activity (IC50 values: 7.56 ± 1.35 â¼ 25.63 ± 1.72 µM) compared to acarbose (IC50 vaule: 564.28 ± 48.68 µM). In particularly, WXC-25 with 4-hydroxycinnamic acid section showed the best inhibitory activity (IC50 vaule: 2.02 ± 0.14 µM), â¼75-fold stronger than acarbose. Kinetics results suggested WXC-25 being one reversible non-competition inhibitors. Fluorescence quenching results indicated that WXC-25 quenched the fluorescence of α-glucosidase in a static manner. 3D fluorescence spectra results indicated that WXC-25 treatment could cause the conformation changes of α-glucosidase. Moreover, molecular docking simulated the detailed interaction of WXC25 with α-glucosidase.
Asunto(s)
Inhibidores de Glicósido Hidrolasas , Simulación del Acoplamiento Molecular , alfa-Glucosidasas , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/síntesis química , Inhibidores de Glicósido Hidrolasas/química , alfa-Glucosidasas/metabolismo , Relación Estructura-Actividad , Estructura Molecular , Relación Dosis-Respuesta a Droga , Cinamatos/química , Cinamatos/farmacología , Cinamatos/síntesis química , CinéticaRESUMEN
Phenolic acids derived from plants have beneficial effects on cardiovascular diseases (CVD). Cinnamic acid (CA) is a crucial phenolic acid that can form numerous hydroxycinnamic derivate found in many food groups. We review current data on the cardiovascular pharmacology of CA with a focus on CVD and their risk factors including hyperlipidaemia, obesity, hyperglycaemia, cardiomyopathy and myocardial ischaemia, vascular dysfunction, oxidative stress and inflammation. Both in vivo and in vitro laboratory studies demonstrate the lipid-lowering, anti-obesity, anti-hyperglycemic, cardio-protective and vasorelaxant activities of CA. The protective impacts of CA against CVD occur by inhibiting inflammatory, oxidative, and apoptotic pathways, regulating the genes and enzymes involved in glucose and lipid metabolisms, and promoting vasodilation. This review showed that the most studied and prominent effects of CA are anti-hyperlipidemic and anti-diabetic properties. In conclusion, intake of plant foods rich in CA may reduce CVD risk especially through regulating blood glucose and lipids levels.
RESUMEN
CONTEXT: The increase in bacterial resistance to currently available medications, which increases mortality rates, treatment costs is a global problem, and highlights the need for novel classes of antibacterial agents or new molecules that interact synergistically with antimicrobials. OBJECTIVE: The current work explores the potential synergistic effects of certain natural phenylpropanoids and flavonoids on ciprofloxacin (CIP), ampicillin (AMP), gentamicin (GEN), and tetracycline (TET). MATERIALS AND METHODS: The adjuvant role of cinnamic acid, p-coumaric acid, caffeic acid, ferulic acid, ferulic acid methyl ester, sinapic acid, apigenin, and luteolin was evaluated by determining the MIC (minimal inhibitory concentration) values of antibiotics in the presence of subinhibitory concentrations (200, 100, and/or 50 µM) of the compounds in Gram-positive and Gram-negative bacterial strains using a 2-fold broth microdilution method. The 96-well plates were incubated at 37 °C for 18 h, and dimethyl sulfoxide was used as a solvent control. RESULTS: The combination of luteolin with CIP, reduced the MIC values of the antibiotic from 0.625 to 0.3125 µM and to 0.078 µM in 100 and 200 µM concentration, respectively, in sensitive Staphylococcus aureus. Sinapic acid decreased the MIC value of CIP from 0.625 to 0.3125 µM in S. aureus, from 1.56 to 0.78 µM in Klebsiella pneumoniae, and the MIC of GEN from 0.39 to 0.095 µM in Pseudomonas aeruginosa strains. DISCUSSION AND CONCLUSIONS: These findings are useful in delaying the development of resistance, as the required antibacterial effect can be achieved with the use of lower concentrations of antibiotics.
Asunto(s)
Antibacterianos , Sinergismo Farmacológico , Flavonoides , Bacterias Gramnegativas , Bacterias Grampositivas , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Flavonoides/farmacología , Bacterias Grampositivas/efectos de los fármacos , Relación Dosis-Respuesta a DrogaRESUMEN
INTRODUCTION: Cinnamic acid is a privileged scaffold for the design of biologically active compounds with putative anticancer potential, following different synthetic methodologies and procedures. Since there is a need for the production of potent anticancer, cinnamate moiety can significantly contribute in the design of new and more active anticancer agents. AREAS COVERED: In this review, the authors provide a review on the synthetic approaches for the discovery of cinnamic acid derivatives with anticancer potential. Results from molecular simulations, hybridization, and chemical derivatization along with biological experiments in vitro and structural activity relationships are given, described, and discussed by the authors. Information for the mechanism of action is taken from original literature sources. EXPERT OPINION: The authors suggest that (i) numerous areas of biology-pharmacology need to be considered: selectivity, in vivo studies, toxicity and drug-likeness, the mechanism of action in animals and humans, development of more efficient assays for various cancer types; (ii) hybridization techniques outbalance in the discovery and production of compounds with higher activity and greater selectivity; (iii) repositioning offers new anticancer cinnamic agents.
RESUMEN
The phenylpropanoid pathway is one of the plant metabolic pathways most prominently linked to the transition to terrestrial life, but its evolution and early functions remain elusive. Here, we show that activity of the t-cinnamic acid 4-hydroxylase (C4H), the first plant-specific step in the pathway, emerged concomitantly with the CYP73 gene family in a common ancestor of embryophytes. Through structural studies, we identify conserved CYP73 residues, including a crucial arginine, that have supported C4H activity since the early stages of its evolution. We further demonstrate that impairing C4H function via CYP73 gene inactivation or inhibitor treatment in three bryophyte species-the moss Physcomitrium patens, the liverwort Marchantia polymorpha and the hornwort Anthoceros agrestis-consistently resulted in a shortage of phenylpropanoids and abnormal plant development. The latter could be rescued in the moss by exogenous supply of p-coumaric acid, the product of C4H. Our findings establish the emergence of the CYP73 gene family as a foundational event in the development of the plant phenylpropanoid pathway, and underscore the deep-rooted function of the C4H enzyme in embryophyte biology.
Asunto(s)
Proteínas de Plantas , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Marchantia/genética , Marchantia/metabolismo , Ácidos Cumáricos/metabolismo , Transcinamato 4-Monooxigenasa/metabolismo , Transcinamato 4-Monooxigenasa/genética , Anthocerotophyta/genética , Anthocerotophyta/metabolismo , Bryopsida/genética , Bryopsida/metabolismo , Bryopsida/crecimiento & desarrollo , Bryopsida/enzimología , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Filogenia , Embryophyta/genética , Embryophyta/metabolismo , Propionatos/metabolismo , Propanoles/metabolismo , Evolución Molecular , Regulación de la Expresión Génica de las PlantasRESUMEN
Antimicrobial resistance has emerged as a significant danger to global health, and the need for more effective antimicrobial resistance (AMR) control has been highlighted. Cinnamic acid is abundant in plant products and is a potential starting material for further modification, focusing on the development of new antimicrobial compounds. In the following review, we describe the classification of critical antibacterial-guided reactions applied to the main skeleton structure of cinnamic acid derivatives over the last decade. Of all of the main parts of cinnamic acids, the phenyl ring and the carboxylic group significantly affect antibacterial activity. The results presented in the following review can provide valuable insights into considerable features in the organic modification of cinnamic acids related to antibacterial medication development and the food industry.
Asunto(s)
Antibacterianos , Cinamatos , Cinamatos/química , Cinamatos/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Estructura Molecular , Bacterias/efectos de los fármacos , HumanosRESUMEN
The current research endeavour aimed to synthesize ferulic acid grafted tamarind gum/guar gum (FA-g-TG/GG) based powders as wound dressings, which could form in situ gels upon contact with wound exudates. In this context, variable amounts of FA were initially grafted with TG via the Steglich esterification reaction protocol and the resulting conjugates were subsequently amalgamated with GG and lyophilized to produce dry powders (F-1 - -F-3) with average particle size within 5.10-5.54 µm and average angle of repose â¼30°. These powders were structurally characterized with 1H NMR, FTIR, DSC, TGA, XRD and SEM analyses. Pristine TG, FA-g-TG and FA-g-TG/GG powders (F-2) revealed their distinct morphological structures and variable negative zeta potential values (-11.06 mV-25.50 mV). Among various formulation (F-1-F-3), F-2 demonstrated an acceptable powder-to-gel conversion time (within 20 min), suitable water vapour transmission rates (WVTR, 2564.94 ± 32.47 g/m2/day) and excellent water retention abilities and swelling profiles (4559.00 ± 41.57 %) in wound fluid. The powders were cytocompatible and conferred antioxidant activities. The powders also displayed fibroblast cell proliferation, migration and adhesion properties, implying their wound-healing potentials. Thus, the developed in situ gel-forming powders could be employed as promising dressings for wound management.
Asunto(s)
Vendajes , Ácidos Cumáricos , Geles , Gomas de Plantas , Polvos , Cicatrización de Heridas , Ácidos Cumáricos/química , Gomas de Plantas/química , Geles/química , Cicatrización de Heridas/efectos de los fármacos , Animales , Mananos/química , Ratones , Tamarindus/química , Galactanos/química , Antioxidantes/química , Antioxidantes/farmacología , Fibroblastos/efectos de los fármacosRESUMEN
Staphylococcus epidermidis, a component of human microbiota, may also cause life-threatening opportunistic infections. These are becoming increasingly common infections associated with the implantation of various implants. Due to the exhaustion of antibiotic resources, new substances with antimicrobial activity are being sought. The present study examined the antibacterial effect of cinnamic acid and its derivatives and their combinations with ß-lactam antibiotics on the growth of Staphylococcus epidermidis strains isolated from vascular infections. The data obtained during the research indicated that cinnamic acid and its derivatives, sinapic acid, ferulic acid, and p-coumaric acid, have weak antibacterial activity (MIC values at the level of 2048 and 4096 mg/L). The combination of cinnamic acid and its derivatives with ß-lactam antibiotics increases the effectiveness of their action and may demonstrate various pharmacological effects depending on the established cutoff.
RESUMEN
A new total synthesis of the natural δ-lactone cleistenolide (1) and its (6S)-stereoisomer 2 was achieved starting from d-glucose. Key steps in the synthesis of 1 involved: oxidative cleavage of the C1-C2 bond in partially protected d-glucose derivative (20), and chain extension of resulting aldehyde 20a with a single C2 fragment using (Z)-selective Wittig olefination. Synthesis of 2 involves the following key steps: periodate cleavage of the C5-C6 bond in the commercially available monoacetone d-glucose (24), followed by C2 chain elongation by using the (Z)-selective Wittig olefination. This new approach is also applied to prepare a few new 4-substituted cleistenolide analogues (3 - 18). Compounds 3 - 7 were designed using molecular hybridization, while the remaining eleven analogues were designed using the bioisosterism method. MTT assay showed that most analogues were more active than lead 1 against several malignant cells, but were completely inactive in the culture of normal foetal lung fibroblasts (MRC-5). The K562 cells appeared to be the most sensitive to the synthesized analogues. The strongest antiproliferative activity against this cell line was shown by 4-O-cinnamoyl derivative 3 and 4,6-di-O-benzyl derivative 17, with submicromolar IC50 values (0.76 and 0.67 µM, respectively). Structural features important for the activity of this class of compounds were identified by SAR analysis.
Asunto(s)
Antineoplásicos , Proliferación Celular , Humanos , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Estereoisomerismo , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular Tumoral , Estructura Molecular , Relación Dosis-Respuesta a Droga , Furanos/química , Furanos/farmacología , Furanos/síntesis química , PironasRESUMEN
Candida spp., causes invasive fungal infections, especially in immune-compromised patients and the propensity of antifungal resistance against azole-based drugs need to be addressed. This study is thus aimed to characterize the anticandidal effect of the cinnamic acid extracted from the barks of Cinnamomum cassia. Five species of Fluconazole-resistant Candida sp. were retrieved from the department repertoire. The extraction of CA was performed by three different methods followed by silica gel column chromatography. Eluant was subjected to FTIR and XRD analysis for confirmation. The anticandidal activity of the CA was checked by the agar disc diffusion method and the MIC and MFC were determined. The anti-biofilm effect of CA was assessed using the CLSM technique followed by the biocompatibility check using MTT assay in normal HGF cell lines. CA was best extracted with the hot maceration method using ethanol with a maximum yield of 6.73 mg. Purification by column chromatography was achieved using benzene, acetic acid, and water (6:7:3) mobile phase. CA was confirmed by FTIR with absorption peaks and by XDR based on strong intensity. CA was found to possess promising anticandidal activity at 8 µg/mL with MIC and MFC values determined as 0.8 µg/mL and 0.08 µg/mL respectively. Antibiofilm activity by CLSM analysis revealed biofilm inhibition and was biocompatible at 8.5 µg/ml concentrations in HGF cell lines until 24 h. The study findings conclude that CA is the best alternative to treat candidal infection warranting further experimental preclinical studies.
RESUMEN
Nanoparticles (NPs) are important in regulating plant tolerance to salt stress. Peppermint is one of the most widely used aromatic plants, with a high sensitivity to salt stress. The present study investigated physiological and biochemical factors to understand better the behavior of cinnamic acid (CA) and cinnamic acid nanocomposite in salinity control in peppermint plants. The first factor was salt stress with different salt concentrations, including 0, 50, 100, and 150 mg/L, the second factor was 50 µM CA, and the third factor was 50 µM CA nanocomposite based on carboxymethyl cellulose (CMC-CA NC). Results showed that stress markers increased with increasing salinity levels. On the contrary, plants treated with salinity showed a decrease in physiological and photosynthetic parameters, while the application of CA and CMC CA NC increased these critical parameters. Under salinity, compared to the control, malondialdehyde and hydrogen peroxide contents decreased by 11.3% and 70.4%, respectively. Furthermore, CA and CMC-CA NC enhanced peppermint tolerance to salinity by increasing compatible solute content such as proline, free amino acids, protein content, and soluble carbohydrates, increasing antioxidant enzymes, and decreasing stress markers in plant tissues. Compared to the control, chlorophyll fluorescence and proline content increased by 1.1% and 172.1%, respectively. Salinity stress negatively affected all physiological and biochemical parameters, but CA and CMC-CA NC treatments improved them. We concluded that the nanocomposite, a biostimulant, significantly enhances mint tolerance under salinity conditions.
Asunto(s)
Cinamatos , Mentha piperita , Nanocompuestos , Estrés Salino , Cinamatos/farmacología , Cinamatos/química , Estrés Salino/efectos de los fármacosRESUMEN
Prenylated cinnamic acid derivatives are the bioactive components of Brazilian green propolis (BGP). The effect of other botanical components on the pharmacokinetic profiles of these derivatives remains relatively unexplored. In the present study, we investigated the influence of several herbal extracts (turmeric, ginkgo leaf, coffee fruit, soybean, and gotu kola) on the plasma concentrations of cinnamic acid derivatives after BGP consumption. When the herbal extracts were co-administered with BGP in the clinical study, the area under the curve (AUC) values of artepillin C and drupanin, the major BGP components in plasma, were significantly increased by 1.7- and 1.5-fold, respectively, compared to those after BGP administration alone. Among the herbal extracts administered to rats, turmeric extract increased the AUC. Furthermore, a bidirectional transport assay suggested that artepillin C and drupanin are substrates of breast cancer resistance protein (BCRP), a drug elimination transporter. These results suggest that curcumin-containing turmeric extract may increase the plasma concentrations of artepillin C and drupanin via BCRP. Our findings enabled us to estimate the food-herb and herb-herb interactions in vivo in foods and herbal medicines containing cinnamic acid derivatives and prenylated compounds.
RESUMEN
Aim: To synthesize new hybrid cinnamic acids (10a, 10b and 11) and ester derivatives (7, 8 and 9) and investigate their anti-breast cancer activities.Materials & methods: Compounds 7-11 were evaluated (in vitro) for their cytotoxic activities against the MCF-7 cell line. A flow cytometry examination was performed. Protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2), topoisomerase II and caspase-9 were measured by qRT-PCR. Molecular docking studies were conducted.Results: Several components were discovered to be active, mainly component 11, which induced arrest in the cell cycle at phase S, greatly decreased the expression of Nrf2 and topoisomerase II; and upregulated the expression of caspase-9.Conclusion: The newly thiohydantoin-cinnamic acid hybrids can contribute to creating promising candidates for cancer drugs.
[Box: see text].
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Cinamatos , Simulación del Acoplamiento Molecular , Humanos , Cinamatos/química , Cinamatos/farmacología , Cinamatos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Femenino , Células MCF-7 , Tiohidantoínas/farmacología , Tiohidantoínas/química , Tiohidantoínas/síntesis química , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Relación Estructura-Actividad , Estructura Molecular , ADN-Topoisomerasas de Tipo II/metabolismo , Apoptosis/efectos de los fármacos , Caspasa 9/metabolismoRESUMEN
Dual-specificity tyrosine phosphorylation-regulated kinase A (DYRK1A) is a potential drug target for diabetes. The DYRK1A inhibitor can promote ß cells proliferation, increase insulin secretion and reduce blood sugar in diabetes. In this paper, a series ß-carboline-cinnamic acid skeletal derivatives were designed, synthesized and evaluated to inhibit the activity of DYRK1A and promote pancreatic islet ß cell proliferation. Pharmacological activity showed that all of the compounds could effectively promote pancreatic islet ß cell proliferation at a concentration of 1 µM, and the cell viability of compound A1, A4 and B4 reached to 381.5 %, 380.2 % and 378.5 %, respectively. Compound A1, A4 and B4 could also inhibit the expression of DYRK1A better than positive drug harmine. Further mechanistic studies showed that compound A1, A4 and B4 could inhibit DYRK1A protein expression via promoting its degradation and thus enhancing the expression of proliferative proteins PCNA and Ki67. Molecular docking showed that ß-carboline scaffold of these three compounds was fully inserted into the ATP binding site and formed hydrophobic interactions with the active pocket. Besides, these three compounds were predicted to possess better drug-likeness properties using SwissADME. In conclusion, compounds A1, A4 and B4 were potent pancreatic ß cell proliferative agents as DYRK1A inhibitors and might serve as promising candidates for the treatment of diabetes.
Asunto(s)
Carbolinas , Proliferación Celular , Cinamatos , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Quinasas DyrK , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas , Proteínas Serina-Treonina Quinasas , Proteínas Tirosina Quinasas , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Carbolinas/farmacología , Carbolinas/química , Carbolinas/síntesis química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Estructura Molecular , Cinamatos/farmacología , Cinamatos/química , Cinamatos/síntesis química , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Hipoglucemiantes/farmacología , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Humanos , Animales , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/metabolismo , Supervivencia Celular/efectos de los fármacosRESUMEN
Molecular hybridization between structural fragments from the structures of curcumin (1) and resveratrol (2) was used as a designing tool to generate a new N-acyl-cinnamoyl-hydrazone hybrid molecular architecture. Twenty-eight new compounds were synthesized and evaluated for multifunctional activities related to Parkinson's disease (PD), including neuroprotection, antioxidant, metal chelating ability, and Keap1/Nrf2 pathway activation. Compounds 3b (PQM-161) and 3e (PQM-164) were highlighted for their significant antioxidant profile, acting directly as induced free radical stabilizers by DPPH and indirectly by modulating intracellular inhibition of t-BOOH-induced ROS formation in neuronal cells. The mechanism of action was determined as a result of Keap1/Nrf2 pathway activation by both compounds and confirmed by different experiments. Furthermore, compound 3e (PQM-164) exhibited a significant effect on the accumulation of α-synuclein and anti-inflammatory activity, leading to an expressive decrease in gene expression of iNOS, IL-1ß, and TNF-α. Overall, these results highlighted compound 3e as a promising and innovative multifunctional drug prototype candidate for PD treatment.
Asunto(s)
Hidrazonas , Fármacos Neuroprotectores , Enfermedad de Parkinson , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/síntesis química , Hidrazonas/farmacología , Hidrazonas/química , Hidrazonas/síntesis química , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Humanos , Estructura Molecular , Relación Estructura-Actividad , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Antioxidantes/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Animales , Cinamatos/farmacología , Cinamatos/química , Cinamatos/síntesis químicaRESUMEN
Hyperpigmentation disorders may result from inappropriate melanin deposition and/or excessive melanin synthesis. They are classified mainly as aesthetic problems, but they can significantly affect human health by decreasing self-esteem. There are available only limited treatment options for hyperpigmentation disorder, among others, cosmetic products applied topically. Depigmenting ingredients were found to be ineffective and characterized by various side effects. As a result, many efforts are made to discover novel, potent, and safe melanogenesis inhibitors for possible use in topical cosmetic depigmenting formulations. Cinnamic acid derivatives constitute a widely tested group for that purpose. This article reports research in the group of N-alkyl cinnamamide derivatives (un)substituted in phenyl ring. Among tested series, (E)-3-(4-chlorophenyl)-N-(5-hydroxypentyl)acrylamide (compound 21) showed the most promising inhibitory properties in mushroom tyrosinase assay (IC50 = 36.98 ± 1.07 µM for monophenolase activity, IC50 = 146.71 ± 16.82 µM for diphenolase activity) and melanin production inhibition in B16F10 mouse melanoma cell line at concentration 6.25 µM resulting probably from decreasing of Tyr, Mitf, Tyrp-1, and Tyrp-2 genes expression. This compound also showed melanin production inhibitory properties in pigmented reconstructed human epidermis when used in 1 % and 2 % solutions in 50 % PEG400. In vitro evaluation of its safety profile showed no cytotoxicity to human keratinocytes HaCaT, human skin fibroblasts BJ, and human primary epidermal melanocytes HEMa, no mutagenicity in the Ames test, no genotoxicity in micronucleus test, no phototoxicity, as well as no skin irritation potential tested in PEG400 solution. This compound was also shown to penetrate across the epidermis to reach the possible site of action. The performed research led to classify (E)-3-(4-chlorophenyl)-N-(5-hydroxypentyl)acrylamide as a novel potential depigmenting cosmetic ingredient.
Asunto(s)
Cinamatos , Cosméticos , Hiperpigmentación , Melaninas , Monofenol Monooxigenasa , Humanos , Animales , Hiperpigmentación/tratamiento farmacológico , Ratones , Monofenol Monooxigenasa/antagonistas & inhibidores , Monofenol Monooxigenasa/metabolismo , Cinamatos/química , Cinamatos/farmacología , Cinamatos/síntesis química , Relación Estructura-Actividad , Estructura Molecular , Cosméticos/química , Cosméticos/farmacología , Melaninas/metabolismo , Relación Dosis-Respuesta a Droga , Acrilamida/química , Acrilamida/farmacología , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , AgaricalesRESUMEN
AIM: This study aimed to overproduce industrially relevant and safe bio-compound trans-cinnamic acid (tCA) from Photorhabdus luminescens with deletion strategies and homologous expression strategies that had not been applied before for tCA production. METHODS AND RESULTS: The overproduction of the industrially relevant compound tCA was successfully performed in P. luminescens by deleting stlB (TTO1ΔstlB) encoding a cinnamic acid CoA ligase in the isopropylstilbene pathway and the hcaE insertion (knockout) mutation (hcaE::cat) in the phenylpropionate catabolic pathway, responsible for tCA degradation. A double mutant of both stlB deletion and hcaE insertion mutation (TTO1DM ΔstlB-hcaE::cat) was also generated. These deletion strategies and the phenylalanine ammonium lyase-producing (PI-PAL from Photorhabdus luminescens) plasmid, pBAD30C, carrying stlA (homologous expression mutants) are utilized together in the same strain using different media, a variety of cultivation conditions, and efficient anion exchange resin (Amberlite IRA402) for enhanced tCA synthesis. At the end of the 120-h shake flask cultivation, the maximum tCA production was recorded as 1281 mg l-1 in the TTO1pBAD30C mutant cultivated in TB medium, with the IRA402 resin keeping 793 mg l-1 and the remaining 488 mg l-1 found in the supernatant. CONCLUSION: TCA production was successfully achieved with homologous expression, coupled with deletion and insertion strategies. 1281 mg l-1is the highest tCA concentration that achieved by bacterial tCA production in flask cultivation, according to our knowledge.