RESUMEN
The influence of UV radiation on skin discoloration, skin aging and the development of skin cancer is widely known. As a part of this study, the effect of extracts from three varieties of Cornus mas L. (C. mas L.) on skin cells exposed to UVA radiation was assessed. The analyses were performed on both normal and cancer skin cells. For this purpose, the potential photoprotective effects of the obtained extracts (aqueous and ethanolic) was assessed by performing two cytotoxicity tests (Alamar blue and Neutral red). Additionally, the antioxidant capacity was compared using three different assays. The 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) probe was used to evaluate the intracellular level of free radicals in cells exposed to the simultaneous action of UVA radiation and dogwood extracts. Additionally, the ability to inhibit excessive pigmentation was determined by assessing the inhibition of melanin formation and tyrosinase activity. The obtained results confirmed the strong antioxidant properties of dogwood extracts and their photoprotective effect on normal skin cells. The ability to inhibit the viability of melanoma cells was also observed. Additionally, a reduction in oxidative stress in skin cells exposed to UVA radiation and a strong inhibition of melanin formation and tyrosinase activity have been demonstrated. This study shows that dogwood extract could be a valuable cosmetic raw material that can play both a photoprotective and antihyperpigmentation role in cosmetic preparations.
Asunto(s)
Antioxidantes , Cornus , Extractos Vegetales , Rayos Ultravioleta , Rayos Ultravioleta/efectos adversos , Humanos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Cornus/química , Antioxidantes/farmacología , Melaninas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Línea Celular Tumoral , Células HaCaT , Fibroblastos/efectos de los fármacos , Fibroblastos/efectos de la radiación , Fibroblastos/metabolismo , Monofenol Monooxigenasa/metabolismo , Monofenol Monooxigenasa/antagonistas & inhibidoresRESUMEN
In the context of a circular economy, this study explores the valorization of blueberry pomace (BP) as a source of bioactive compounds using sustainable extraction methods. Microwave-assisted extraction (MAE) and microwave-assisted subcritical water extraction (MASWE) were employed to obtain two distinct fractions: MAE 1° and MASWE 2°. The first extract, MAE 1°, obtained at 80 °C, had a high total anthocyanin content (21.96 mgCya-3-glu/gextract), making it suitable as a natural pigment. Additionally, MAE 1° exhibited significant enzyme inhibition, particularly against α-amylase and ß-glucosidase, suggesting potential anti-diabetic and anti-viral applications. The second extract, MASWE 2°, obtained at 150 °C, contained a higher total phenolic content (211.73 mgGAE/gextract) and demonstrated stronger antioxidant activity. MASWE 2° showed greater inhibition of acetylcholinesterase and tyrosinase, indicating its potential for use in Alzheimer's treatment, skincare, or as a food preservative. MASWE 2° exhibited cytotoxicity against HeLa cells and effectively mitigated H2O2-induced oxidative stress in HaCat cells, with MAE 1° showing similar but less pronounced effects. A tested formulation combining MAE 1° and MASWE 2° extracts in a 3:2 ratio effectively enhanced anthocyanin stability, demonstrating its potential as a heat-stable pigment. The extract characteristics were compared with a conventional method (MeOH-HCl in reflux condition), and the protocol's sustainability was assessed using several green metric tools, which provided insights into its environmental impact and efficiency.
Asunto(s)
Antocianinas , Antioxidantes , Arándanos Azules (Planta) , Extractos Vegetales , Polifenoles , Antocianinas/farmacología , Antocianinas/aislamiento & purificación , Antocianinas/química , Humanos , Arándanos Azules (Planta)/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Polifenoles/farmacología , Polifenoles/aislamiento & purificación , Polifenoles/química , Células HeLa , Microondas , Monofenol Monooxigenasa/antagonistas & inhibidores , Monofenol Monooxigenasa/metabolismoRESUMEN
Natural compounds are widely incorporated into cosmetic products for many purposes. Diterpenes often function as fragrances, enhancing the sensory experience of these formulations. However, current trends in cosmetic science aim to develop multifunctional products, where compounds traditionally used for texture or fragrance also possess biological activities that contribute to the product's efficacy. In this context, this study focuses on synthesizing derivatives of phytol-a compound already presents in cosmetic formulations-to enhance its anti-aging properties. The derivatives were synthesized through esterification with substituted benzoic and cinnamic acids, known for their antioxidant and enzyme inhibition properties. Reaction yields ranged from 91.0% to 5.2%, depending on the substituents in acid derivatives. The structures of the synthesized compounds were confirmed through NMR and MS techniques. Both the natural and newly synthesized derivatives were evaluated for their cosmeceutical potential using antioxidant assays and inhibition assays for tyrosinase, elastase, collagenase, and hyaluronidase. This work presents the first report of the synthesis and cosmetic evaluation of several of these derivatives. Comparing with phytol (1), which presented an IC50 of 77.47 µM, four of the derivatives presented improved tyrosinase inhibitory activity, with phytyl 4-methoxybenzoate being the most active (IC50 = 27.9 µM), followed by phytyl benzoate with an IC50 of 34.73 µM. Substitutions at other positions on the aromatic ring were less effective. Molecular docking studies confirmed that the modifications potentiated a stronger interaction between the synthesized compounds and tyrosinase.
Asunto(s)
Antioxidantes , Cosmecéuticos , Simulación del Acoplamiento Molecular , Monofenol Monooxigenasa , Fitol , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/síntesis química , Fitol/química , Fitol/farmacología , Monofenol Monooxigenasa/antagonistas & inhibidores , Monofenol Monooxigenasa/metabolismo , Cosmecéuticos/química , Cosmecéuticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Colagenasas/metabolismo , Elastasa Pancreática/antagonistas & inhibidores , Elastasa Pancreática/metabolismo , Hialuronoglucosaminidasa/antagonistas & inhibidores , Hialuronoglucosaminidasa/metabolismo , Cosméticos/química , Humanos , Estructura Molecular , Relación Estructura-Actividad , Cinamatos/química , Cinamatos/farmacología , Cinamatos/síntesis químicaRESUMEN
BACKGROUND: Koenigia alpina (All.) T.M.Schust. & Reveal (alpine knotweed) is a perennial herb belonging to the Polygonaceae family. Several studies have examined Polygonaceae species' potential applications as cosmeceutical materials; however, the potential of K. alpina as a cosmeceutical has not yet been studied. MATERIALS AND METHODS: Hydrogen peroxide (H2O2) and lipopolysaccharide were used to induce an inflammatory response in RAW 264.7 cells. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radicals and H2O2 were used to evaluate the free-radical scavenging activity of K. alpina extract and its protective effect against reactive oxygen species (ROS)-induced cell damage. The whitening, antiaging, and cell proliferation/migration effects of the extracts were evaluated via tyrosinase inhibition, collagenase/elastase inhibition, and wound healing assays, respectively. The anti-inflammatory effect was confirmed by evaluating nitric oxide (NO) production in RAW 264.7 cells. High-performance liquid chromatography (HPLC), UV, and MS/MS were used to determine the main components of the extract and fractions. RESULTS: The ethyl acetate (EA) fraction and its aglycone fraction showed very high free-radical scavenging activities (47.5 and 47.1 µg/mL, respectively). The extract/fractions also showed significant tyrosinase inhibition (IC50 = 0.38 mg/mL in EA fraction), collagenase inhibition (IC50 = 0.21 mg/mL in EA fraction), and elastase inhibition (IC50 = 0.57 mg/mL in aglycone fraction). NO production in lipopolysaccharide-induced RAW 264.7 cells was inhibited by the extract/fractions. The extract also promoted the closure of scratch wounds in HaCaT cells. The K. alpina extract/fractions contained cardamonin, quercetin, and quercitrin. CONCLUSION: K. alpina extracts/fractions showed antioxidant, antiaging, whitening, and anti-inflammatory activities, suggesting they may have potential as antiaging cosmeceuticals.
Asunto(s)
Antiinflamatorios , Extractos Vegetales , Extractos Vegetales/farmacología , Ratones , Animales , Células RAW 264.7 , Humanos , Antiinflamatorios/farmacología , Polygonaceae/química , Óxido Nítrico/metabolismo , Proliferación Celular/efectos de los fármacos , Antioxidantes/farmacología , Especies Reactivas de Oxígeno/metabolismo , Peróxido de Hidrógeno/farmacología , Depuradores de Radicales Libres/farmacología , Cicatrización de Heridas/efectos de los fármacos , Envejecimiento de la Piel/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Lipopolisacáridos/farmacología , Compuestos de Bifenilo , Preparaciones para Aclaramiento de la Piel/farmacología , Picratos , Monofenol Monooxigenasa/metabolismo , Monofenol Monooxigenasa/antagonistas & inhibidores , Células HaCaTRESUMEN
Ocimum species have a great interest in different traditional medicinal systems. This study examined the chemical composition, antioxidant properties, enzyme inhibitory effects, and antibacterial and antifungal activities of the aerial parts of Ocimum gratissimum, Ocimum americanum, and Ocimum basilicum from the Comoros Islands. The extracts were analyzed using high-performance liquid chromatography-mass spectrometry (HPLC-MS) to determine their chemical composition. Antioxidant activity was assessed using 2,2-Diphenyl-1-picrylhydrazyl (DPPH), 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), cupric reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), chelating ability, and phosphomolybdenum radical scavenging assays. Enzyme inhibitory activities against acetylcholinesterase (AChE), butrylcholinesterase (BChE), tyrosinase, amylase, and glucosidase were evaluated using spectrophotometric methods. Antibacterial and antifungal activities were tested using the broth microdilution method against selected pathogenic microorganisms. The selected enzymes and proteins were evaluated using in silico methods with biomolecules from these plants. In addition, 111 different metabolites were identified in the tested extracts using advanced HPLC/MS techniques. The most significant number of detected compounds were derivatives of hydroxycinnamic acids, followed by flavonoid glycosides and aglycones and derivatives of hydroxybenzoic acids. All three Ocimum species exhibited significant antioxidant activities, O. gratissimum exhibited the best-reducing abilities in CUPRAC and FRAP assays. In addition, enzyme inhibitory assays revealed that O. americanum had the most potent inhibitory effect on tyrosinase (48.01 ± 3.89 mg kojic acid equivalent [KAE]/g), and amylase (1.08 ± 0.02 mmol acarbose equivalent [ACAE]/g). Antibacterial and antifungal tests demonstrated that the extracts possess broad-spectrum activity. Molecular docking results showed that compounds exhibited remarkable binding energies with target enzymes and proteins. The molecular dynamics simulations identified chicoric acid with MurE of Staphylococcus aureus complex as the most promising drug candidate. These findings support their traditional medical and nutraceutical uses and suggest possibilities for natural functional applications.
Asunto(s)
Antibacterianos , Antioxidantes , Ocimum , Extractos Vegetales , Extractos Vegetales/farmacología , Extractos Vegetales/química , Antioxidantes/farmacología , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Ocimum/química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Antifúngicos/farmacología , Antifúngicos/química , Antifúngicos/aislamiento & purificación , Acetilcolinesterasa/metabolismo , Acetilcolinesterasa/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Cromatografía Líquida de Alta Presión , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/aislamiento & purificación , Monofenol Monooxigenasa/antagonistas & inhibidores , Monofenol Monooxigenasa/metabolismoRESUMEN
The genus Lentzea is a prolific source of bioactive and structurally diverse secondary metabolites. We isolated a novel strain, Lentzea sp. JNUCC 0626, from Hwasun Gotjawal on Jeju Island, Korea. Based on 16S rRNA partial gene sequence analysis, strain JNUCC 0626 is closely related to Lentzea isolaginshaensis NX62 (99.41% similarity), Lentzea pudingi DHS C021 (99.31%), and Lentzea cavernae SYSU K10001 (99.26%). From the fermentation broth of JNUCC 0626, we isolated 1-acetyl-ß-carboline, whose structure was established using IR, HR-ESI-MS, and 1D- and 2D-NMR techniques. 1-acetyl-ß-carboline was found to activate melanogenesis in mouse B16F10 cells without cytotoxicity at concentrations up to 50 µM. At this concentration, the compound increased melanin content by 27.44% and tyrosinase activity by 240.64% compared to the control, by upregulating key melanogenic enzymes, including tyrosinase, TRP-1, TRP-2, and microphthalmia-associated transcription factor (MITF), a central regulator of melanogenesis. In addition, 1-acetyl-ß-carboline significantly inhibited ERK phosphorylation, reducing it by 20.79% at a concentration of 12.5 µM and by 25.63% at 25 µM. This inhibition supports the hypothesis that 1-acetyl-ß-carboline enhances melanin synthesis by upregulating MITF and melanogenic enzymes via the ERK signaling pathway. This study aimed to isolate and identify 1-acetyl-ß-carboline from a novel strain of Lentzea sp. JNUCC 0626, discovered in Gotjawal, Jeju Island, and to evaluate its effect on melanin production in B16F10 melanoma cells. Skin irritation tests on 32 subjects confirmed its safety for topical use, and the findings suggest that 1-acetyl-ß-carboline, which enhances melanogenesis without cytotoxicity, holds promise as a therapeutic agent for hypopigmentation-related conditions or as a cosmetic ingredient.
Asunto(s)
Carbolinas , Melaninas , Melanoma Experimental , Animales , Carbolinas/farmacología , Carbolinas/química , Carbolinas/aislamiento & purificación , Ratones , Melaninas/biosíntesis , Melaninas/metabolismo , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Melanoma Experimental/metabolismo , Línea Celular Tumoral , Monofenol Monooxigenasa/metabolismo , Monofenol Monooxigenasa/antagonistas & inhibidores , Monofenol Monooxigenasa/genética , Factor de Transcripción Asociado a Microftalmía/metabolismo , Factor de Transcripción Asociado a Microftalmía/genéticaRESUMEN
The presented study depicts the synthesis of 11 carborane-thiazole conjugates with anticancer activity, as well as an evaluation of their biological activity as inhibitors of two enzymes: tyrosinase and 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1). The overexpression of tyrosinase results in the intracellular accumulation of melanin and can be observed in melanoma. The overexpression of 11ß-HSD1 results in an elevation of glucocorticoid levels and has been associated with the aggravation of metabolic disorders such as type II diabetes mellitus and obesity. Recently, as the comorbidity of melanomas and metabolic disorders is being recognized as an important issue, the search for new therapeutic options has intensified. This study demonstrates that carborane-thiazole derivatives inhibit both enzymes, exerting beneficial effects. The antiproliferative action of all newly synthesized compounds was evaluated using three cancer cell lines, namely A172 (human brain glioblastoma), B16F10 (murine melanoma) and MDA-MB-231 (human breast adenocarcinoma), as well as a healthy control cell line of HUVEC (human umbilical vein endothelial cells). The results show that 9 out of 11 newly synthesized compounds demonstrated similar antiproliferative action against the B16F10 cell line to the reference drug, and three of these compounds surpassed it. To the best of our knowledge, this study is the first to demonstrate dual inhibitory action of carborane-thiazole derivatives against both tyrosinase and 11ß-HSD1. Therefore, it represents the first step towards the simultaneous treatment of melanoma and comorbid diseases such as type II diabetes mellitus.
Asunto(s)
Proliferación Celular , Inhibidores Enzimáticos , Simulación del Acoplamiento Molecular , Monofenol Monooxigenasa , Tiazoles , Humanos , Tiazoles/farmacología , Tiazoles/química , Tiazoles/síntesis química , Monofenol Monooxigenasa/antagonistas & inhibidores , Monofenol Monooxigenasa/metabolismo , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Línea Celular Tumoral , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Animales , Ratones , Boranos/química , Boranos/farmacología , Boranos/síntesis química , Estructura Molecular , Células Endoteliales de la Vena Umbilical HumanaRESUMEN
Undaria pinnatifida is a temperate brown alga known to exert free radical-scavenging and anti-inflammatory effects. In this study, we investigated the skin-whitening effects of U. pinnatifida sporophyll extracts (UPEs) in α-melanocyte-stimulating hormone (α-MSH)-stimulated B16F10 melanoma cells. The crude polysaccharide fraction (UPF) was obtained via ethanol precipitation. Four polysaccharide fractions (UPF1-4) were isolated and purified using ion-exchange column chromatography, and their anti-melanogenic activity was evaluated. UPF3 exhibited the highest anti-melanogenic activity, showing the highest sulfate (39.79%), fucose (143 µg/mg), and galactose (208 µg/mg) contents. UPF3 significantly inhibited intracellular tyrosinase activity in B16F10 cells. We also evaluated the melanogenic signaling pathway to determine the mechanism of action of UPF3 in melanongenesis. UPF3 reduced the expression of tyrosinase-related protein-1 (TRP-1), tyrosinase-related protein-2 (TRP-2), and tyrosinase, which play important roles in melanin production. Therefore, UPF3 has high potential for use in skin-whitening functional pharmaceuticals and cosmetics.
Asunto(s)
Melaninas , Polisacáridos , Undaria , Polisacáridos/farmacología , Polisacáridos/química , Polisacáridos/aislamiento & purificación , Animales , Ratones , Melaninas/biosíntesis , Melaninas/metabolismo , Undaria/química , Línea Celular Tumoral , Melanoma Experimental/patología , Melanoma Experimental/tratamiento farmacológico , Extractos Vegetales/farmacología , Extractos Vegetales/química , Monofenol Monooxigenasa/metabolismo , Monofenol Monooxigenasa/antagonistas & inhibidores , alfa-MSH/farmacología , Oxidorreductasas/metabolismo , Algas ComestiblesRESUMEN
For thousands of years, pearl and nacre powders have been important traditional Chinese medicines known for their skin whitening effects. To prepare the enzymatic hydrolysates of Hyriopsis cumingii nacre powder (NP-HCH), complex enzymatic hydrolysis by pineapple protease and of neutral protease was carried out after the powder was pre-treated with a high-temperature and high-pressure method. The peptides were identified using LC-MS/MS and picked out through molecular docking and molecular dynamics simulations. Subsequently, the tyrosinase inhibitory and antioxidant properties of novel tyrosinase inhibitory peptides were investigated in vitro. In addition, the enzymatic activity of tyrosinase in B16F10 cells as well as melanin content and antioxidant enzyme levels were also examined. The results showed that a tyosinase inhibitory peptide (Tyr-Pro-Asn-Pro-Tyr, YPNPY) with an efficient IC50 value of 0.545 ± 0.028 mM was identified. The in vitro interaction results showed that YPNPY is a reversible competitive inhibitor of tyrosinase, suggesting that it binds to the free enzyme. The B16F10 cell whitening test revealed that YPNPY can reduce the melanin content of B16F10 cells by directly inhibiting the activity of intracellular tyrosinase. Additionally, it indirectly affects melanin production by acting as an antioxidant. These results suggest that YPNPY could be widely used as a tyrosinase inhibitor in whitening foods and drugs.
Asunto(s)
Antioxidantes , Melaninas , Simulación del Acoplamiento Molecular , Monofenol Monooxigenasa , Péptidos , Monofenol Monooxigenasa/antagonistas & inhibidores , Animales , Péptidos/farmacología , Péptidos/química , Péptidos/aislamiento & purificación , Ratones , Antioxidantes/farmacología , Antioxidantes/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Línea Celular Tumoral , Melanoma Experimental/tratamiento farmacológico , Simulación por Computador , Espectrometría de Masas en Tándem , Preparaciones para Aclaramiento de la Piel/farmacología , Preparaciones para Aclaramiento de la Piel/química , Preparaciones para Aclaramiento de la Piel/aislamiento & purificación , Simulación de Dinámica MolecularRESUMEN
Based on the hypothesis that the 2-mercaptoacetamide moiety chelates the copper ions of tyrosinase, 2-mercapto-N-arylacetamide (2-MAA) analogs were designed and synthesized as potential tyrosinase inhibitors. Four 2-MAA analogs showed low IC50 values ranging from 0.95 to 2.0 µM against mushroom tyrosinase, which was 12-26 times lower than that of kojic acid (IC50 value = 24.3 µM). However, according to a copper ion chelation experiment performed, the 2-MAA analogs did not participate in chelation with copper ions. To identify the mode of inhibition of the 2-MAA analogs, kinetic studies were performed, and the results were supported by docking results. In addition, docking simulation results suggested that the 2-MAA analogs strongly inhibited tyrosinase activity because of the hydrogen bonding of the amide NH group and the hydrophobic interaction of the aryl ring instead of chelation with copper ions. In experiments using B16F10 cells, 2-MAA analogs were shown to inhibit melanin production by inhibiting cellular tyrosinase activity. Western blotting showed that in addition to directly inhibiting tyrosinase activity, analog 7 also has an anti-melanogenic effect by inhibiting the expression of microphthalmia-associated transcription factor (MITF) and tyrosinase. The 2-MAA analogs showed no appreciable cytotoxicity against HaCaT and B16F10 cells, making them suitable for dermal applications. In a depigmentation experiment using zebrafish embryos, analogs 1 and 2 showed more potent depigmentation effects than kojic acid even at 1000 times lower concentration than that of kojic acid. These results suggest that the 2-MAA analogs are promising anti-melanogenic agents that can inhibit most tyrosinases in various species.
Asunto(s)
Acetamidas , Inhibidores Enzimáticos , Melaninas , Monofenol Monooxigenasa , Pez Cebra , Animales , Monofenol Monooxigenasa/antagonistas & inhibidores , Monofenol Monooxigenasa/metabolismo , Ratones , Acetamidas/farmacología , Acetamidas/química , Acetamidas/síntesis química , Melaninas/antagonistas & inhibidores , Melaninas/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Agaricales/enzimología , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Línea Celular Tumoral , Estructura Molecular , Relación Dosis-Respuesta a Droga , HumanosRESUMEN
Tyrosinase, a key enzyme in melanin synthesis, represents a crucial therapeutic target for hyperpigmentation disorders due to excessive melanin production. This study aimed to design and evaluate a series of indole-thiourea derivatives by conjugating thiosemicarbazones with strong tyrosinase inhibitory activity to indole. Among these derivatives, compound 4b demonstrated tyrosinase inhibitory activity with an IC50 of 5.9 ± 2.47 µM, outperforming kojic acid (IC50 = 16.4 ± 3.53 µM). Kinetic studies using Lineweaver-Burk plots confirmed competitive inhibition by compound 4b. Its favorable ADMET and drug-likeness properties make compound 4b a promising therapeutic candidate with a reduced risk of toxicity. Molecular docking revealed that the compounds bind strongly to mushroom tyrosinase (mTYR) and human tyrosinase-related protein 1 (TYRP1), with compound 4b showing superior binding energies of -7.0 kcal/mol (mTYR) and -6.5 kcal/mol (TYRP1), surpassing both kojic acid and tropolone. Molecular dynamics simulations demonstrated the stability of the mTYR-4b complex with low RMSD and RMSF and consistent Rg and SASA values. Persistent strong hydrogen bonds with mTYR, along with favorable Gibbs free energy and MM/PBSA calculations (-19.37 kcal/mol), further support stable protein-ligand interactions. Overall, compound 4b demonstrated strong tyrosinase inhibition and favorable pharmacokinetics, highlighting its potential for treating pigmentary disorders.
Asunto(s)
Inhibidores Enzimáticos , Indoles , Simulación del Acoplamiento Molecular , Monofenol Monooxigenasa , Tiourea , Monofenol Monooxigenasa/antagonistas & inhibidores , Monofenol Monooxigenasa/química , Monofenol Monooxigenasa/metabolismo , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Tiourea/química , Tiourea/farmacología , Tiourea/análogos & derivados , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Cinética , Humanos , Simulación de Dinámica Molecular , Agaricales/enzimología , Relación Estructura-ActividadRESUMEN
Coreopsis tinctoria Nutt. is an important medicinal plant in traditional Uyghur medicine. The skin-lightening potential of the flower has been recognized recently; however, the active compounds responsible for that are not clear. In this work, tyrosinase, a target protein for regulating melanin synthesis, was immobilized on the Whatman paper for the first time to screen skin-lightening compounds present in the flower. Quercetagetin-7-O-glucoside (1), marein (2), and okanin (3) were found to be the enzyme inhibitors. The IC50 values of quercetagetin-7-O-glucoside (1) and okanin (3) were 79.06 ± 1.08 µM and 30.25 ± 1.11 µM, respectively, which is smaller than 100.21 ± 0.11 µM of the positive control kojic acid. Enzyme kinetic analysis and molecular docking were carried out to investigate their inhibition mechanism. Although marein (2) showed a weak inhibition effect in vitro, it inhibited the intracellular tyrosinase activity and diminished melanin production in melanoma B16 cells as did the other two inhibitors. The paper-based ligand fishing method developed in this work makes it effective to quickly screen tyrosinase inhibitors from natural products. This is the first report on the tyrosinase inhibitory effect of those three compounds, showing the promising potential of Coreopsis tinctoria for the development of herbal skin-lightening products.
Asunto(s)
Coreopsis , Inhibidores Enzimáticos , Simulación del Acoplamiento Molecular , Monofenol Monooxigenasa , Monofenol Monooxigenasa/antagonistas & inhibidores , Monofenol Monooxigenasa/metabolismo , Coreopsis/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Animales , Melaninas/antagonistas & inhibidores , Melaninas/biosíntesis , Ligandos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Ratones , Enzimas Inmovilizadas/química , Enzimas Inmovilizadas/antagonistas & inhibidores , CinéticaRESUMEN
Tyrosinase is a crucial copper-containing enzyme involved in the production of melanin. Melasma, age spots, and freckles are examples of hyperpigmentation diseases caused by excess production of melanin. Inhibiting tyrosinase activity is a crucial method for treating these disorders along with various applications such as cosmetics, food technology, and medicine. Natural products have proven a rich source of tyrosinase inhibitors, with several molecules from plant, marine, and microbial sources showing potential inhibitory action. This chapter provides a complete overview of natural compounds that have been found as tyrosinase inhibitors, with emphasis on their structures, modes of action, and prospective applications.
Asunto(s)
Productos Biológicos , Inhibidores Enzimáticos , Monofenol Monooxigenasa , Monofenol Monooxigenasa/antagonistas & inhibidores , Productos Biológicos/farmacología , Productos Biológicos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Humanos , Animales , Melaninas/antagonistas & inhibidores , Melaninas/metabolismoRESUMEN
Computational studies have significantly advanced the understanding of tyrosinase (TYR) function, mechanism, and inhibition, accelerating the development of more effective and selective inhibitors. This chapter provides an overview of in silico studies on TYR inhibitors, emphasizing key inhibitory chemotypes and the main residues involved in ligand-target interactions. The chapter discusses tools applied in the context of TYR inhibitor development, e.g., structure-based virtual screening, molecular docking, artificial intelligence, and machine learning algorithms.
Asunto(s)
Inhibidores Enzimáticos , Monofenol Monooxigenasa , Humanos , Inteligencia Artificial , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Aprendizaje Automático , Simulación del Acoplamiento Molecular , Monofenol Monooxigenasa/antagonistas & inhibidores , Monofenol Monooxigenasa/químicaRESUMEN
This copper-containing enzyme catalyzes the rate-limiting step for the melanin skin pigment bioproduction. Tyrosinase inhibitors can be exploited as skin whitening agents and food preservatives, opening new scenarios in food, cosmetics, agriculture and medicine. Despite the availability of natural inhibitors (hydroquinone, α-arbutin, kojic acid, retinoids, azelaic acid, resveratrol, caftaric acid, valonea tannin, chrysosplenetin and phenylethyl resorcinol), several synthetic compounds were proposed to overcome side effects and to improve the efficacy of natural agents. This chapter will gather the recent advances about synthetic tyrosinase inhibitors from the MedChem perspective, providing new suggestions for the scaffold-based design of innovative compounds.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos , Monofenol Monooxigenasa , Monofenol Monooxigenasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Humanos , AnimalesRESUMEN
Tyrosinase, a pivotal enzyme in melanin biosynthesis, orchestrates the pigmentation process in humans, affecting skin, hair, and eye color. This chapter examines the three-dimensional structure and functional aspects of tyrosinases from various sources, highlighting their di-metal ion coordination crucial for catalytic activity. I explore the biochemical pathwayscheme catalyzed by tyrosinase, specifically the oxidation of L-tyrosine to L-dopaquinone, a precursor in melanin synthesis. Detailed structural analyses, including 3D structures obtained from X-ray crystallography and computational modeling, reveal key insights into the enzyme's active site, variations among tyrosinases, and substrate binding mechanisms. Furthermore, the chapter investigates the role of human tyrosinase variants, their inhibitors, essential for developing therapeutic and cosmetic applications targeting hyperpigmentation disorders. Structural characterizations of tyrosinase-inhibitor complexes provide a foundation for designing effective inhibitors, with compounds like kojic acid, L-mimosine, and (S)-3-amino-tyrosine demonstrating significant inhibitory potential. This comprehensive examination of the structure, function, and inhibition mechanisms of tyrosinase offers avenues for innovative treatments in biotechnology, health, and beyond.
Asunto(s)
Monofenol Monooxigenasa , Humanos , Dominio Catalítico , Cristalografía por Rayos X , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Melaninas/metabolismo , Melaninas/biosíntesis , Melaninas/química , Modelos Moleculares , Monofenol Monooxigenasa/antagonistas & inhibidores , Monofenol Monooxigenasa/metabolismo , Monofenol Monooxigenasa/química , Conformación Proteica , Tirosina/química , Tirosina/metabolismoRESUMEN
Melanin, which is produced by melanocytes and spread over keratinocytes, is responsible for human skin browning. There are several processes involved in melanogenesis, mostly prompted by enzymatic activities. Tyrosinase (TYR), a copper containing metalloenzyme, is considered the main actor in melanin production, as it catalyzes two crucial steps that modify tyrosine residues in dopaquinone. For this reason, TYR inhibition has been exploited as a possible mechanism of modulation of hyper melanogenesis. There are various types of molecules used to block TYR activity, principally used as skin whitening agents in cosmetic products, e.g., tretinoin, hydroquinone, azelaic acid, kojic acid, arbutin and peptides. Peptides are highly valued for their versatile nature, making them promising candidates for various functions. Their specificity often leads to excellent safety, tolerability, and efficacy in humans, which can be considered their primary advantage over traditional small molecules. There are several examples of tyrosinase inhibitor peptides (TIPs) operating as possible hypo-pigmenting agents, which can be classified according to their origin: natural, hybrid or synthetically produced. Moreover, the possibility of variating their backbones, introducing non-canonical amino acids or modifying one or more peptide bond(s), to obtain peptidomimetic molecules, is an added value to avoid or delay proteolytic activity, while the possibility of conjugation with other bioactive peptides or organic moieties can bring other specific activity leading to dual-functional peptides.
Asunto(s)
Inhibidores Enzimáticos , Monofenol Monooxigenasa , Péptidos , Peptidomiméticos , Monofenol Monooxigenasa/antagonistas & inhibidores , Monofenol Monooxigenasa/metabolismo , Humanos , Peptidomiméticos/farmacología , Peptidomiméticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Péptidos/química , Péptidos/farmacología , Animales , Melaninas/metabolismo , Melaninas/antagonistas & inhibidoresRESUMEN
Bacterial tyrosinase is a copper-containing metalloenzyme with diverse physio-chemical properties, that have been identified in various bacterial strains, including actinobacteria and proteobacteria. Tyrosinases are responsible for the rate-limiting catalytic steps in melanin biosynthesis and enzymatic browning. The physiological role of bacterial tyrosinases in melanin biosynthesis has been harnessed for the production of coloring and dyeing agents. Additionally, bacterial tyrosinases have the capability of cross-linking activity, demonstrated material functionalization applications, and applications in food processing with varying substrate specificities and stability features. These characteristics make bacterial tyrosinases a valuable alternative to well-studied mushroom tyrosinases. The key feature of substrate specificity of bacterial tyrosinase has been exploited to engineer biosensors that have the ability to detect the minimal amount of different phenolic compounds. Today, the world is facing the challenge of multi-drugs resistance in various diseases, especially antibiotic resistance, skin cancer, enzymatic browning of fruits and vegetables, and melanogenesis. To address these challenges, medicinal scientists are developing novel chemotherapeutic agents by inhibiting bacterial tyrosinases. To serve this purpose, heterocyclic compounds are of particular interest due to their vast spectrum of biological activities and their potential as effective tyrosinase inhibitors. In this chapter, a plethora of research explores applications of bacterial tyrosinases in different fields, such as the production of dyes and pigments, catalytic applications in organic synthesis, bioremediation, food and feed applications, biosensors, wool fiber coating and the rationalized synthesis, and structure-activity relationship of bacterial tyrosinase inhibitors.
Asunto(s)
Bacterias , Inhibidores Enzimáticos , Monofenol Monooxigenasa , Monofenol Monooxigenasa/antagonistas & inhibidores , Monofenol Monooxigenasa/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Bacterias/efectos de los fármacos , Bacterias/enzimología , Especificidad por Sustrato , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/metabolismo , Humanos , Melaninas/biosíntesis , Melaninas/antagonistas & inhibidores , Melaninas/metabolismoRESUMEN
Tyrosinase is involved in several human diseases, among which hypopigmentation and depigmentation conditions (vitiligo, idiopathic guttate hypomelanosis, pityriasis versicolor, pityriasis alba) and hyperpigmentations (melasma, lentigines, post-inflammatory and periorbital hyperpigmentation, cervical idiopathic poikiloderma and acanthosis nigricans). There are increasing evidences that tyrosinase plays a relevant role in the formation and progression of melanoma, a difficult to treat skin tumor. Hydroquinone, azelaic acid and tretinoin (all-trans-retinoic acid) are clinically used in the management of some hyperpigmentations, whereas many novel chemotypes acting as tyrosinase inhibitors with potential antimelanoma action are being investigated. Kojic acid, hydroquinone, its glycosylated derivative arbutin, or the resorcinol derivative rucinol are used in cosmesis in creams as skin whitening agents, whereas no antimelanoma tyrosinase inhibitor reached clinical trials so far, although thiamidol is a recently approved new tyrosinase inhibitor for the treatment of melasma. Kojic acid and vitamin C are used for avoiding vegetable/food oxidative browning due to the tyrosinase-catalyzed reactions, whereas bacterial enzymes show potential in biotechnological applications, for the production of mixed melanins, for protein cross-linking reactions, for producing phenol(s) biosensors, of for the production of L-DOPA, an anti-Parkinson's disease drug.
Asunto(s)
Inhibidores Enzimáticos , Monofenol Monooxigenasa , Monofenol Monooxigenasa/antagonistas & inhibidores , Monofenol Monooxigenasa/metabolismo , Humanos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Animales , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Melanoma/tratamiento farmacológico , PironasRESUMEN
Inspired by the potent tyrosinase inhibitory activity of phenolic compounds with a 2-phenylbenzo[d]thiazole scaffold, we explored phenolic compounds 1-15 with 2-phenylbenzo[d]oxazole, which is isosterically related to 2-phenylbenzo[d]thiazole, as novel tyrosinase inhibitors. Among these, compounds 3, 8, and 13, featuring a resorcinol structure, exhibited significantly stronger mushroom tyrosinase inhibition than kojic acid, with compound 3 showing a nanomolar IC50 value of 0.51 µM. These results suggest that resorcinol plays an important role in tyrosinase inhibition. Kinetic studies using Lineweaver-Burk plots demonstrated the inhibition mechanisms of compounds 3, 8, and 13, while docking simulation results indicated that the resorcinol structure contributed to tyrosinase binding through hydrophobic and hydrogen bonding interactions. Additionally, these compounds effectively inhibited tyrosinase activity and melanin production in B16F10 cells and inhibited B16F10 tyrosinase activity in situ in a concentration-dependent manner. As these compounds showed no cytotoxicity to epidermal cells, melanocytes, or keratinocytes, they are appropriate for skin applications. Compounds 8 and 13 demonstrated substantially higher depigmentation effects on zebrafish larvae than kojic acid, even at 800- and 400-times lower concentrations than kojic acid, respectively. These findings suggest that 2-phenylbenzo[d]oxazole is a promising candidate for tyrosinase inhibition.