Dawson结构的多金属氧酸盐对酪氨酸酶的抑制作用

按文献方法合成了两种Dawson结构的多金属氧酸盐,并对其结构进行紫外光谱和红外光谱分析。以H_6[P_2Mo_(18)O_(62)]和H_8[P_2Mo_(17)Cr(OH_2)O_(61)](简写为P_2Mo_(18)和P_2Mo_(17)Cr)为效应物,采用紫外分光光度法和酶动力学方法研究两种Dawson结构的多金属氧酸盐效应物对蘑菇酪氨酸酶二酚酶活性的抑制作用。结果表明,P_2Mo_(18)和P_2Mo_(17)Cr对酪氨酸酶二酚酶均具有显著的抑制效果,测定抑制酪氨酸酶活力下降50%的抑制浓度(IC_(50))分别为(0.482±0.009)mmol/L和(0.503±0.011)mmol/L。动力学分析表明,P_2Mo_(18)和P_2Mo_(17)Cr对酪氨酸酶的抑制作用均表现为可逆的竞争型,抑制常数K_I分别为0.212和0.249 mmol/L。其中,综合考虑IC_(50)值和抑制常数,P_2Mo_(18)对酪氨酸酶二酚酶活性的抑制效果略优于P_2Mo_(17)Cr。     

钒取代的Dawson型磷钼酸对酪氨酸酶的抑制作用

采用酶动力学方法研究了5种钒取代的Dawson型磷钼酸H₇[P₂Mo₁₇VO₆₂]、H₈[P₂Mo₁₆V₂O₆₂]、H₉[P₂Mo₁₅V₃O₆₂]、H₈[P₂Mo₁₄V₄O₆₂H₂]和H₉[P₂Mo₁₃V₅O₆₂H₂](分别简写为P₂Mo₁₇V、P₂Mo₁₆V₂、P₂Mo₁₅V₃、P₂Mo₁₄V₄和P₂Mo₁₃V₅)对蘑菇酪氨酸酶二酚酶的抑制作用,结果表明,效应物P₂Mo₁₇V、P₂Mo₁₆V₂和P₂Mo₁₅V₃能够明显地抑制酪氨酸酶的活性,其半抑制浓度(IC₅₀)值分别为0.409、0.386和0.386 mmol/L,且均表现为可逆的竞争型抑制,效应物P₂Mo₁₇V、P₂Mo₁₆V₂和P₂Mo₁₅V₃对游离酶的抑制常数K_I分别为0.234、0.391和0.249 mmol/L。 而效应物P₂Mo₁₄V₄在0~1.0 mmol/L浓度范围内,对酪氨酸酶二酚酶无明显抑制作用,效应物P₂Mo₁₃V₅对酪氨酸酶二酚酶表现为激活作用。     

Newly Designed Quinazolinone Derivatives as Novel Tyrosinase Inhibitor: Synthesis,Inhibitory Activity,and Mechanism

We synthesized a series of quinazolinone derivates as tyrosinase inhibitors and evaluated their inhibition constants. We synthesized 2-(2,6-dimethylhepta-1,5-dien-1-yl)quinazolin-4(3H)-one (Q1) from the natural citral. The concentration, which led to 50% activity loss of Q1, was 103 ± 2 μM (IC₅₀ = 103 ± 2 μM). Furthermore, we considered Q1 to be a mixed-type and reversible tyrosinase inhibitor, and determined the K_I and K_IS inhibition constants to be 117.07 μM and 423.63 μM, respectively. Our fluorescence experiment revealed that Q1 could interact with the substrates of tyrosine and L-DOPA in addition to tyrosinase. Molecular docking studies showed that the binding of Q1 to tyrosinase was driven by hydrogen bonding and hydrophobicity. Briefly, the current study confirmed a new tyrosinase inhibitor, which is expected to be developed into a novel pigmentation drug.     

Insights on the Inhibitory Power of Flavonoids on Tyrosinase Activity: A Survey from 2016 to 2021

Tyrosinase is a multifunctional copper-containing oxidase enzyme that initiates melanin synthesis in humans. Excessive accumulation of melanin pigments or the overexpression of tyrosinase may result in skin-related disorders such as aging spots, wrinkles, melasma, freckles, lentigo, ephelides, nevus, browning and melanoma. Nature expresses itself through the plants as a source of phytochemicals with diverse biological properties. Among these bioactive compounds, flavonoids represent a huge natural class with different categories such as flavones, flavonols, isoflavones, flavan-3-ols, flavanones and chalcones that display antioxidant and tyrosinase inhibitor activities with a diversity of mechanistic approaches. In this review, we explore the role of novel or known flavonoids isolated from different plant species and their participation as tyrosinase inhibitors reported in the last five years from 2016 to 2021. We also discuss the mechanistic approaches through the different studies carried out on these compounds, including in vitro, in vivo and in silico computational research. Information was obtained from Google Scholar, PubMed, and Science Direct. We hope that the updated comprehensive data presented in this review will help researchers to develop new safe, efficacious, and effective drug or skin care products for the prevention of and/or protection against skin-aging disorders.     

The Luteolinidin and Petunidin 3-O-Glucoside: A Competitive Inhibitor of Tyrosinase

The enzyme tyrosinase plays a key role in the early stages of melanin biosynthesis. This study evaluated the inhibitory activity of anthocyanidin (1) and anthocyanins (2–6) on the catalytic reaction. Of the six derivatives examined, 1–3 showed inhibitory activity with IC₅₀ values of 3.7 ± 0.1, 10.3 ± 1.0, and 41.3 ± 3.2 μM, respectively. Based on enzyme kinetics, 1–3 were confirmed to be competitive inhibitors with K_i values of 2.8, 9.0, and 51.9 μM, respectively. Molecular docking analysis revealed the formation of a binary encounter complex between 1–3 and the tyrosinase catalytic site. Luteolinidin (1) and petunidin 3-O-glucoside (2) may serve as tyrosinase inhibitors to block melanin production.     

Conversion of 3-Carbethoxy-4-methyl Coumarin Derivatives into Several New Annelated Coumarin Derivatives

The reaction of ethyl esters of 4-methyl-2-oxo-2H-l-benzo(naphtho) pyran.3-carboxylic acids (1) with aromatic aldehy-des in the presence of piperidine yielded 4-styryl-3-carboxami-dopiperidyl connmrin derivatives 4. The reaction of hydrazlne hydrate with 1 gave acetophenone hydrozone derivatives 5 and acetophenone azine derivatives 6. The reaction of 1 with prima-ry amines afforded compomlds 7—9. And the treatment of la with Grignard reagents afforded 3-aroyl-4-methyl coumarin derivatives 10.     

Methoxy-Substituted Tyramine Derivatives Synthesis,Computational Studies and Tyrosinase Inhibitory Kinetics

Targeting tyrosinase for melanogenesis disorders is an established strategy. Hydroxyl-substituted benzoic and cinnamic acid scaffolds were incorporated into new chemotypes that displayed in vitro inhibitory effects against mushroom and human tyrosinase for the purpose of identifying anti-melanogenic ingredients. The most active compound 2-((4-methoxyphenethyl)amino)-2-oxoethyl (E)-3-(2,4-dihydroxyphenyl) acrylate (Ph9), inhibited mushroom tyrosinase with an IC₅₀ of 0.059 nM, while 2-((4-methoxyphenethyl)amino)-2-oxoethyl cinnamate (Ph6) had an IC₅₀ of 2.1 nM compared to the positive control, kojic acid IC₅₀ 16700 nM. Results of human tyrosinase inhibitory activity in A375 human melanoma cells showed that compound (Ph9) and Ph6 exhibited 94.6% and 92.2% inhibitory activity respectively while the positive control kojic acid showed 72.9% inhibition. Enzyme kinetics reflected a mixed type of inhibition for inhibitor Ph9 (K_i 0.093 nM) and non-competitive inhibition for Ph6 (K_i 2.3 nM) revealed from Lineweaver–Burk plots. In silico docking studies with mushroom tyrosinase (PDB ID:2Y9X) predicted possible binding modes in the catalytic site for these active compounds. Ph9 displayed no PAINS (pan-assay interference compounds) alerts. Our results showed that compound Ph9 is a potential candidate for further development of tyrosinase inhibitors.     

香豆素衍生物对阴离子的识别特性

用紫外光谱滴定法研究了3种香豆素衍生物与阴离子间存在的特殊识别行为,比较了受体分子结构对阴离子配合物稳定性的影响,以及阴离子浓度对配合物光谱的影响.实验结果表明:受体分子对F^- 、Cl^-、Br^-、Ac^-、H₂PO₄^-、HSO₄^-等不同种阴离子客体的识别能力存在一定差异,受体分子与阴离子通过氢键结合,由于氢键良好的方向性和选择性,对F^-、Ac^-、H₂PO₄^-等有较好的选择性和识别能力,而与其他的阴离子几乎没有作用.     

新型4-羟基香豆素衍生物的合成

以DMSO为溶剂,碳酸二乙酯为酰化试剂,4-取代-2-羟基苯乙酮在氢化钠的催化下,经一步反应合成了7个新型的7-取代-4-羟基香豆素,产率49%~90%,其结构经1H NMR表征。     

香豆素基Schiff碱类化合物的合成及抗氧化性能

以2,3,4-三甲氧基苯甲醛为原料,经脱甲基、Knoevenagel缩合、亲核加成等反应合成了2个香豆素基Schiff碱类化合物,其结构经核磁共振谱(¹H NMR))和质谱(MS)确证。 并采用淬灭二苯代苦味肼基自由基(DPPH)、2,2'-联氮双(3-乙基苯并噻唑啉-6-磺酸)二铵盐(ABTS)和羟自由基等方法对其体外抗氧化性能进行了表征。 结果表明,目标化合物对3种自由基均具有一定的淬灭活性,其中对DPPH和羟自由基的淬灭活性高于母体化合物7,8-二甲氧基-3-氨基香豆素,具有较高的抗氧化活性。     

4-羟基香豆素衍生物的荧光性能

4-羟基香豆素衍生物的荧光性能;水杨酸; 羟基香豆素衍生物; 荧光     

香豆素衍生物的合成及结构表征

合成了11个香豆素衍生物,产率53%—79%,利用元素分析、MS和¹HNMR对其结构进行了表征.同时,由2-氨基苯并噻唑(ABT)和8-甲氧基香豆素-3-甲酸乙酯(MCC)合成了给体-受体加合物ABT-MCC,通过X射线单晶衍射法测定了其晶体结构,晶体属三斜晶系,P1空间群,晶胞参数为:a=9.5978(19)Å,b=10.686(2)Å,c=10.693(2)Å,α=71.30(3)°,β=70.43(3)°,γ=88.99(3)°,V=973.9(3)ų,Z=2,D_x=1.359 mg/m³,μ=0.200 mm^-1,F(000)=416,R=0.0463,wR=0.0992.结果表明,在ABT-MCC晶体中,分子间通过N—H…N和N—H…O氢键作用形成对称的A…D…D′…A′氢键四聚体,并通过弱的C—H…O氢键连接成为一维超分子链状结构,进而分子间通过π-π堆积作用形成层状结构.     

Elucidating the Role of Santalol as a Potent Inhibitor of Tyrosinase: In Vitro and In Silico Approaches

This research work focuses on the potential application of an organic compound, santalol, obtained from santalum album, in the inhibition of the enzyme tyrosinase, which is actively involved in the biosynthesis of melanin pigment. Over-production of melanin causes undesirable pigmentation in humans as well as other organisms and significantly downgrades their aesthetic value. The study is designed to explain the purification of tyrosinase from the mushroom Agaricus bisporus, followed by activity assays and enzyme kinetics to give insight into the santalol-modulated tyrosinase inhibition in a dose-dependent manner. The multi-spectroscopic techniques such as UV-vis, fluorescence, and isothermal calorimetry are employed to deduce the efficiency of santalol as a potential candidate against tyrosinase enzyme activity. Experimental results are further verified by molecular docking. Santalol, derived from the essential oils of santalum album, has been widely used as a remedy for skin disorders and a potion for a fair complexion since ancient times. Based on enzyme kinetics and biophysical characterization, this is the first scientific evidence where santalol inhibits tyrosinase, and santalol may be employed in the agriculture, food, and cosmetic industries to prevent excess melanin formation or browning.     

Coumarin Derivatives Inhibit ADP-Induced Platelet Activation and Aggregation

Coumarin was first discovered in Tonka bean and then widely in other plants. Coumarin has an anticoagulant effect, and its derivative, warfarin, is a vitamin K analogue that inhibits the synthesis of clotting factors and is more widely used in the clinical treatment of endovascular embolism. At present, many artificial chemical synthesis methods can be used to modify the structure of coumarin to develop many effective drugs with low toxicity. In this study, we investigated the effects of six coumarin derivatives on the platelet aggregation induced by adenosine diphosphate (ADP). We found that the six coumarin derivatives inhibited the active form of GPIIb/IIIa on platelets and hence inhibit platelet aggregation. We found that 7-hydroxy-3-phenyl 4H-chromen-4-one (7-hydroxyflavone) had the most severe effect. In addition, we further analyzed the downstream signal transduction of the ADP receptor, including the release of calcium ions and the regulation of cAMP, which were inhibited by the six coumarin derivatives selected in this study. These results suggest that coumarin derivatives inhibit coagulation by inhibiting the synthesis of coagulation factors and they may also inhibit platelet aggregation.     

Synthesis and Cytotoxic Activity of Coumarin Derivatives Containing Benzotriazole Moieties

Three coumarin derivatives containing benzotriazole moieties, 3-(1-benzotriazolyl)-4-methyl-coumarin (BMC), 3-(1-benzotriazolyl)-4-methyl-benzo[7,8]coumarin (BMBC), and 3-(4-methyl-1-benzotriazolyl)-4-methyl-benzo[7,8]coumarin (MBMBC), were synthesized. Among them, 3-(4-methyl-1-benzotriazolyl)-4-methyl-benzo[7,8]coumarin has been structurally characterized by X-ray crystallography. The cytotoxic effect by Sulforhodamine B (SRB) assay with these compounds against the human hepatocellular carcinoma cell lines (HepG-2) was carried out in vitro. The preliminary results showed that all compounds inhibit HepG-2 growth effectively.     

Coumarin Sulfonamides and Amides Derivatives: Design,Synthesis, and Antitumor Activity In Vitro

Coumarins possesses immeasurable antitumor potential with minimum side effects depending on the substitutions on the basic nucleus, which exhibits great prospects for antitumor drug development. In an attempt to develop novel antitumor candidates, a series of coumarin sulfonamides and amides derivatives were designed and synthetized. The majority of these derivatives showed good cytotoxic activity against MDA-MB-231 and KB cell lines, among which compound 9c was the most potent against MDA-MB-231 cells, with IC₅₀ value of 9.33 μM, comparable to 5-fluorouracil. Further investigation revealed that compound 9c had versatile properties against tumors, including inhibition of cell migration and invasion as well as inducing apoptosis. Reactive oxygen species (ROS) assay and western blotting analysis suggested that compound 9c promoted cancer cell apoptosis by increasing ROS levels and upregulating the expression of caspase-3 in MDA-MB-231 cells. These results indicated that compound 9c could be promising lead compound for further antitumor drug research.     

Identification of Mushroom and Murine Tyrosinase Inhibitors from Achillea biebersteinii Afan. Extract

Growing scientific evidence indicates that Achillea biebersteinii is a valuable source of active ingredients with potential cosmetic applications. However, the data on its composition and pharmacological properties are still insufficient. This study aims to optimize the extraction procedure of the plant material, evaluate its phytochemical composition, and compare anti-tyrosinase potential of A. biebersteinii extracts obtained by various methods. In order to identify compounds responsible for the tyrosinase inhibitory activity of A. biebersteinii, the most active anti-tyrosinase extract was fractionated by column chromatography. The fractions were examined for their skin lightening potential by mushroom and murine tyrosinase inhibitory assays and melanin release assay. HPLC-ESI-Q-TOF-MS/MS analysis of the total extract revealed the presence of several phenolic acids, flavonoids, flavonoid glucosides, and carboxylic acid. Among them, fraxetin-8-O-glucoside, quercetin-O-glucopyranose, schaftoside/isoschaftoside, gmelinin B, 1,3-dicaffeoylquinic acid (1,3-DCQA), and ferulic acid were found in the fractions with the highest skin lightening potential. Based on obtained qualitative and quantitative analysis of the fractions, it was assumed that the caffeoylquinic acid derivatives and dicaffeoylquinic acid derivatives are more likely responsible for mushroom tyrosinase inhibitory activity of A. biebersteinii extracts and fractions. Ferulic acid was proposed as the most active murine tyrosinase inhibitor, responsible also for the reduced melanin release from B16F10 murine melanoma cells.     

内酯开环塔斯品碱香豆素酯衍生荧光化合物的合成及其抗癌活性

以异香草醛为原料,经溴代、苄基保护、氧化、Ulmman反应和还原等6步反应合成了塔斯品碱内酯开环衍生物（化合物8）。 通过在其结构中分别引入含有2种不同取代基的香豆素衍生物,设计、合成了2个新型荧光性的内酯开环塔斯品碱香豆素酯衍生物（化合物9a和9b）。 产物结构经IR、1H NMR和MS进行了表征。 同时,对产物的荧光特性及其对乳腺肿瘤细胞增殖的抑制活性进行了初步测定。     

Alternative Approach for Specific Tyrosinase Inhibitor Screening: Uncompetitive Inhibition of Tyrosinase by Moringa oleifera

Tyrosinase (TYR) is a type III copper oxidase present in fungi, plants and animals. The inhibitor of human TYR plays a vital role in pharmaceutical and cosmetic fields by preventing synthesis of melanin in the skin. To search for an effective TYR inhibitor from various plant extracts, a kinetic study of TYR inhibition was performed with mushroom TYR. Among Panax ginseng, Alpinia galanga, Vitis vinifera and Moringa oleifera, the extracts of V. vinifera seed, A. galanga rhizome and M. oleifera leaf reversibly inhibited TYR diphenolase activity with IC₅₀ values of 94.8 ± 0.2 µg/mL, 105.4 ± 0.2 µg/mL and 121.3 ± 0.4 µg/mL, respectively. Under the same conditions, the IC₅₀ values of the representative TYR inhibitors of ascorbic acid and kojic acid were found at 235.7 ± 1.0 and 192.3 ± 0.4 µg/mL, respectively. An inhibition kinetics study demonstrated mixed-type inhibition of TYR diphenolase by A. galanga and V. vinifera, whereas a rare uncompetitive inhibition pattern was found from M. oleifera with an inhibition constant of K_ii 73 µg/mL. Phytochemical investigation by HPLC-MS proposed luteolin as a specific TYR diphenolase ES complex inhibitor, which was confirmed by the inhibition kinetics of luteolin. The results clearly showed that studying TYR inhibition kinetics with plant extract mixtures can be utilized for the screening of specific TYR inhibitors.