姜黄素类似物抑制酪氨酸酶活性 3D-QSAR 模型研究

三维定量构效关系（3D-QSAR）是一种合理的药物设计方法,是目前使用最多的方法之一。本文根据前期合成的 28 个姜黄素类似物其结构与抑制酪氨酸酶活性关系,建立了统计学意义显著的 3D-QSAR 模型,交叉验证系数 q2为 0.609,模型相关系数R2为 0.997,F 统计量的值为 77.070。对该模型的可靠性和预测能力进行了分析。应用该模型设计了 6 个结构对称的姜黄素类似物 A1、A2、B1、B2、B3 和 B4,对 6 个化合物进行合成、分离提纯以及结构表征。其中,化合物 A2 和 B3 经 SCI Finder 检索为未见合成报道的新型化合物。以左旋多巴（L-DOPA）为底物,测试合成物对酪氨酸酶的抑制活性,其中化合物 B1 的活性最强,所有合成物的活性均比姜黄素好,并且实验值与预测值十分接近,说明 3D-QSAR 模型具有良好的外部预测能力。     

2-茚酮基姜黄素类似物对酪氨酸酶的抑制作用

酪氨酸酶抑制剂可作为食品添加剂用作果蔬保鲜和防腐,芳香醛在适宜的条件下与2-茚酮进行缩合反应,合成5种含2-茚酮基的对称姜黄素类似物(A1～A5)。利用紫外分光光度法测定其对酪氨酸酶的抑制作用。结果表明:合成的对称性姜黄素类似物均对酪氨酸酶有较强的抑制作用,其中A2～A4的半数抑制浓度(IC50)分别为25.42、13.51、10.71μmol/L,比广泛使用的食品添加剂曲酸(IC50为28.59μmol/L)的抑制作用强。     

苯乙酮基姜黄素类似物的合成及其抗氧化活性检测

以4-硝基苯乙酮为基础原料,分别与邻香草醛、对甲氧基苯甲醛、2-萘甲醛、5-甲基呋喃醛合成出4种苯乙酮基姜黄素类似物,其中一种苯乙酮基姜黄素类似物经文献检索为未见报道的全新化合物。测定产物熔点及红外光谱,核磁共振氢谱等对产物结构进行表征。用DPPH自由基清除法对4种化合物的抗氧化活性进行测定,其中有2种化合物的抗氧化活性比姜黄素强。     

茶花粉提取物对酪氨酸酶的抑制作用

为研究茶花粉不同溶剂提取液对酪氨酸酶的抑制作用,以提取液对酪氨酸酶的抑制作用(IC50值)为指标,探讨溶剂体积分数、料液比、提取时间3个因素对茶花粉提取物酪氨酸酶抑制作用的影响,并对茶花粉各提取物中多酚及黄酮类化合物的含量与酪氨酸酶抑制活性进行相关性分析。试验结果表明:与甲醇和蒸馏水提取液相比,茶花粉乙醇提取液对酪氨酸酶的抑制作用最大(IC50值为2.07 mg/m L);茶花粉3种因素最优的提取条件是:乙醇体积分数80%,料液比1∶10 g/m L,提取时间5 min。相关性分析结果表明:茶花粉提取物的酪氨酸酶抑制活性和多酚、黄酮类化合物的含量呈中度正相关关系,相关系数分别为0.404,0.400,且均不显著(P0.05)。     

鸡爪皮胶原多肽对蘑菇酪氨酸酶及B16黑色素瘤细胞的作用

研究分子质量低于3 kDa鸡爪皮胶原多肽对蘑菇蘑菇酪氨酸酶的抑制及对小鼠B16黑色素瘤细胞黑色素合成的影响。以L-多巴为底物,研究胶原肽对蘑菇酪氨酸酶抑制作用及抑制动力学。然后采用B16黑色素瘤细胞验证提取鸡爪皮胶原多肽的安全性及对黑色素合成影响的效果。结果表明,分子质量低于3 kDa的鸡爪皮胶原多肽抑制蘑菇酪氨酸酶的IC50值为0.570 mg/mL,抑制属于非竞争性抑制,米氏常数Km和抑制常数Ki分别为24.68μmol/mL和10.76 mg/mL。鸡爪皮胶原多肽在0²00μg/mL的质量浓度范围内对细胞的增殖活性没有影响,而且能够有效地抑制细胞黑色素的生成。     

苯甲酸及其类似物与酪氨酸酶分子对接研究

以AutoDock 4.2和iGEMDOCK 2.1分子对接软件对13 种苯甲酸类似物与酪氨酸酶进行模拟对接研究,探讨苯甲酸类似物对接结合自由能与实验测得的酶抑制活性的关系,并对分子对接结果进行分析。结果表明：AutoDock 4.2程序中Cu电荷数的设置对结合自由能有显著影响,铜电荷数为2.0时,苯甲酸类似物结合自由能和pIC50（－lgIC50）线性相关系数可达0.803 6。iGEMDOCK 2.1预测苯甲酸类似物的结果线性较差,即AutoDock 4.2较iGEMDOCK 2.1预测酪氨酸酶抑制剂的可靠性更高。     

齐墩果酸-1-脱氧野尻霉素衍生物的合成及其对α-葡萄糖苷酶活性的抑制

根据拼合原理,以齐墩果酸(OA)为先导物,对C-28号位的羧基进行修饰,通过溴代、氮代,引入1-脱氧野尻霉素(1-DNJ)设计合成了不同碳链长度的齐墩果酸-1-DNJ衍生物(OADs),其中5个目标化合物其结构均以高分辨质谱、核磁共振谱进行结构表征。利用微量α-葡萄糖苷酶-PNPG检测模型对这一系列化合物的活性进行了筛选,并通过分子对接初步分析了其构效关系。结果表明:所合成的系列化合物的抑制活性较齐墩果酸有较大提高,且当碳链长度为3时(化合物2b)抑制活性最好,其IC₅₀=0.786 mmol/L(OA的IC₅₀=2.387 mmol/L);酶抑制动力学分析表明其为α-葡萄糖甘酶混合型抑制剂;分子对接和热力学参数结果显示,化合物与酶的结合主要是通过氢键和范德华力,形成的氢键个数越多,抑制活性越强;2b与酶之间形成了7个氢键,结合自由能为-17.19 kJ/mol,接近于阳性对照阿卡波糖。因此,所合成的齐墩果酸-1-DNJ衍生物(2b)对α-葡萄糖苷酶具有较好的抑制活性。     

香水莲花提取物的美白功效研究

天然提取物由于其安全性高,近年来成为化妆品功效研究的热点。通过体外法测定香水莲花提取物所含活性成分及其对酪氨酸酶活性的抑制效果,再采用细胞模型探究其对B16小鼠黑素瘤细胞形态、增殖、黑素含量以及细胞内酪氨酸酶活性的影响。结果显示,黄色、蓝色香莲整花提取物均能有效抑制体外酪氨酸酶活性,其中体积分数60%醇提物能有效减缓B16黑素瘤细胞增殖、抑制黑素合成及胞内酪氨酸酶活性,添加100μg/m L的黄、蓝色整花体积分数60%醇提物的细胞增殖率分别为(84.44±1.77)%、(48.24±3.14)%,黑素质量分数为(69.69±1.40)%、(66.98±2.44)%,具有较好的美白功效。     

类黄酮化合物抑制NDM-1活性的构效关系

选择食物来源相对丰富且分子结构具有一定差异的3种类黄酮化合物(槲皮素、木犀草素、染料木黄酮),通过碘量法比较它们对新德里金属β内酰胺酶-1(NDM-1)的抑制活性。通过分子对接软件分析化合物对NDM-1的理论结合能力,建立类黄酮化合物抑制NDM-1活性的构效关系。碘量法分析结果表明,3种类黄酮化合物对NDM-1抑制活性差异表现为染料木黄酮木犀草素槲皮素,这一结果与分子对接理论分析结果一致。由此,3种化合物抑制NDM-1的构效关系为:B环处于C环3位(染料木黄酮),是抑制NDM-1的相对优势结构;而C环3位羟基(槲皮素)对抑制NDM-1活性具有一定削弱作用。     

3种Dawson型杂多酸对酪氨酸酶的抑制作用

合成3种Dawson型杂多酸H_8[P_2Mo_(17)Zn(OH_2)O_(61)]、H_8[P_2Mo_(17)Cu(OH_2)O_(61)]和H_7[P_2Mo_(17)Fe(OH_2)O_(61)](分别简写为P_2Mo_(17)Zn、P_2Mo_(17)Cu和P_2Mo_(17)Fe),并用红外和紫外光谱进行结构表征。进而用酶动力学方法研究3种化合物对酪氨酸酶二酚酶的抑制作用(包括抑制效果、抑制机理、抑制类型)。结果表明:P_2Mo_(17)Zn、P_2Mo_(17(Cu和P_2Mo_(17)Fe_3种化合物对酪氨酸酶二酚酶均有明显的抑制效果,对应的IC_(50)值分别为0.346 2、0.361 5、0.383 1 mmol/L。3种化合物均属于可逆竞争型,抑制常数KI分别为0.106 8、0.068 2、0.057 2 mmol/L。综合比较,3种化合物的抑酶效果依次是P_2Mo_(17)ZnP_2Mo_(17)CuP_2Mo_(17)Fe。     

Biological evaluation of coumarin derivatives as mushroom tyrosinase inhibitors

A series of coumarin derivatives were synthesised and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. The results showed that some of the synthesised compounds exhibited significant inhibitory activities. Especially, 2-(1-(coumarin-3-yl)ethylidene)hydrazinecarbothioamide bearing thiose-micarbazide group exhibited the most potent tyrosinase inhibitory activity with IC₅₀ value of 3.44 μM. The inhibition mechanism analysis of 2-(1-(coumarin-3-yl)-ethylidene)hydrazinecarbothioamide and 2-(1-(6-chlorocoumarin-3-yl)ethylidene)-hydrazinecarbothioamide demonstrated that the inhibitory effects of the compounds on the tyrosinase were irreversible. Preliminary structure activity relationships’ (SARs) analysis suggested that further development of such compounds might be of interest.     

在线抗氧化分析和超滤亲和液质联用技术快速筛选桂花抗氧化及抑制酪氨酸酶的活性成分

目的:研究桂花水提物的抗氧化活性及酪氨酸酶抑制活性,并初步研究其活性化学成分.方法:以DPPH·清除能力、ABTS+·清除能力和FRAP这3种抗氧化活性评价指标来衡量桂花水提物及其化合物的抗氧化能力;采用超高效液相-ABTS+·-质谱(UPLC-PDA-QDa-ABTS+·)在线法对桂花中的抗氧化活性成分进行定性鉴别,...     

三叶青茎部不同溶剂提取物的功能成分、抗氧化及酪氨酸酶抑制活性研究

目的 以三叶青茎部为原料,探究三叶青不同溶剂提取物的功能成分、抗氧化及酪氨酸酶抑制活性。方法 采用乙醇超声法提取三叶青,获得醇提液及残渣。醇提液依次用石油醚、乙酸乙酯、正丁醇对其进行分步萃取,残渣则采用蒸馏水多次提取,最终得到4种提取物。对该4种提取物分别测定其总酚、总黄酮、总皂苷、总多糖、抗氧化及酪氨酸酶抑制活性,并进行相关性分析。结果 4种提取物中乙酸乙酯萃取物总酚、总黄酮、总皂苷含量最高,分别为40.22%±1.01%、38.56%±0.64%、6.15%±0.21%,正丁醇萃取物总多糖含量最高,为9.29%±0.25%。各萃取物均具有抗氧化和酪氨酸酶抑制活性,其中乙酸乙酯萃取物清除1,1-二苯基-三硝基苯肼(1,1-diphenyl-2-picrylhydrazyl, DPPH)自由基、超氧阴离子、2-苯基-4,4,5,5-四甲基咪唑啉-3-氧代-1-氧(2-phenyl-4,4,5,5-tetramethylimidazoline-3-oxide-1-oxyl, PTIO)自由基、羟自由基能力和铁离子还原能力(ferric reducing antioxidant power, FRAP)最强,其半抑制浓度(half maximal inhibitory concentration, IC50)分别为0.016、0.014、0.355、0.0.265、0.352 mg/mL。同时,在酪氨酸酶抑制活性上,乙酸乙酯萃取物明显强于各萃取物。相关性分析表明,三叶青提取物中总酚、总黄酮、总皂苷物质与抗氧化和酪氨酸酶抑制活性呈极显著正相关性(P<0.01)。结论 三叶青茎部乙酸乙酯萃取物具有较强的抗氧化性及抑制酪氨酸酶活性,主要作用成分为总酚、总黄酮和总皂苷。本研究为进一步开发利用三叶青茎部资源提供相关技术支持。     

白附子酪氨酸酶活性抑制成分的提取与分离

研究了不同溶剂及提取方式对白附子中酪氨酸酶抑制成分的影响,并应用活性追踪法对白附子中酪氨酸酶活性抑制成分进行考察。结果表明,以20%乙醇水溶液为溶剂从白附子中提取的粗提物对酪氨酸酶活性的抑制作用最强,抑制率可达到96.35%,与恒温水浴振荡提取法相比,超声波辅助提取法对活性成分的提取效果更好。在此提取条件下所得白附子粗提物对酪氨酸酶的半抑制浓度IC50为24.69mg/mL。该粗提物依次经乙醚和正丁醇萃取,所得正丁醇萃取组分对酪氨酸酶的抑制率达71.94%。对高活性的正丁醇萃取组分进行分离,获得了一种酪氨酸酶抑制率高达98.82%的组分,是一种潜在的酪氨酸酶抑制剂。研究结果对白附子及其活性组分在医药和食品领域的应用有指导意义。     

对羟基苯甲酸酯类化合物抗菌活性的定量构效关系探讨

基于定量结构-活性关系(QSAR)研究对羟基苯甲酸酯类化合物性质具有重要意义。本文采用量子化学密度泛函理论(DFT)和逐步回归分析法研究了具有抗菌活性的11种对羟基苯甲酸酯类化合物的定量构效关系。在B3LYP/6-31G*水平上计算了对羟基苯甲酸酯类化合物的相关量子化学参数,得到在最稳定构型下分子结构参数,通过多元逐步回归分析筛选出对羟基苯甲酸酯类化合物影响抗大肠杆菌活性的主要因素并建立定量构效关系方程,采用留一法分析模型的稳定性及预测能力。结果表明对羟基苯甲酸酯类化合物抗大肠杆菌活性与最低空轨道能量(ELUMO)及偶极距(μ)呈正相关关系,QSAR模型表明化合物的最低空轨道能量、偶极距和极化率是影响对羟基苯甲酸酯类化合物抗菌活性的主要因素,ELUMO和μ越大,抗菌活性越大,所得QSAR模型对该类化合物抗菌活性有较好的预测效果。     

Curcumin in cancer management: recent results of analogue design and clinical studies and desirable future research

The ability of the curry constituent curcumin to delay the onset of cancer has been the topic of extensive research for many years. Abundant literature is devoted to mechanisms by which curcumin may mediate this activity. These insights have prompted investigations in which curcumin as lead molecule serves as a scaffold for synthetic chemical attempts to optimize pharmacological potency. Among the published analogues with notable efficacy are dimethylcurcumin, 1,5-bis(3-pyridyl)-1,4-pentadien-3-one and 3,5-bis-(2-fluorobenzylidene)-piperidinium-4-one acetate. Results of a small number of clinical pilot studies conducted with curcumin at doses of up to 12 g suggest tentatively that it is safe in humans. Prevention of adenoma recurrence constitutes a clinical paradigm worthy of further investigation for curcumin. Future clinical study should include measurement of mechanism-based pharmacodynamic parameters.     

Isolation of tyrosinase inhibitors from Artocarpus heterophyllus and use of its extract as antibrowning agent

A new furanoflavone, 7-(2,4-dihydroxyphenyl)-4-hydroxy-2-(2-hydroxy propan-2-yl)-2, 3-dihydrofuro(3, 2-g)chromen-5-one (artocarpfuranol, 1), together with 14 known compounds, dihydromorin (2), steppogenin (3), norartocarpetin (4), artocarpanone (5), artocarpesin (6), artocarpin (7), cycloartocarpin (8), cycloartocarpesin (9), artocarpetin (10), brosimone I (11), cudraflavone B (12), carpachromene (13), isoartocarpesin (14), and cyanomaclurin (15) were isolated from the wood of Artocarpus heterophyllus. Their structures were identified by interpretation of MS,( 1)H-NMR,( 13)C-NMR, HMQC, and HMBC spectroscopic data. Among them, compounds 1-6 and 14 showed strong mushroom tyrosinase inhibitory activity with IC(50) values lower than 50 microM, more potent than kojic acid (IC(50) = 71.6 microM), a well-known tyrosinase inhibitor. In addition, extract of A. heterophyllus was evaluated for its antibrowning effect on fresh-cut apple slices. It was discovered that fresh-cut apple slices treated by dipping in solution of 0.03 or 0.05% of A. heterophyllus extract with 0.5% ascorbic acid did not undergo any substantial browning reaction after storage at room temperature for 24 h. The antibrowning effect was significantly better than samples treated with the extract (0.03 or 0.05%) or ascorbic acid (0.5%) alone. The results provide preliminary evidence supporting the potential of this natural extract as antibrowning agent in food systems.     

Thiomethylstilbenes as inhibitors of CYP1A1, CYP1A2 and CYP1B1 activities

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a natural stilbene derivative occurring in grapes, peanuts and red wine. Its chemopreventive action has been established in studies on animal models. Recently, numerous classes of compounds with stilbene backbone have been investigated for their biological activity concerning cancer prevention; e. g. resveratrol methyl ethers appeared to be specific and potent inhibitors of cytochromes P450 (CYP) family 1 involved in the activation of procarcinogens. Since the replacement of the 4'-hydroxyl with a thiomethyl group is supposed to reduce toxicity of stilbene derivatives, the purpose of this study was the synthesis and evaluation of a series of 4-thiomethyl-trans-stilbene derivatives differing in a number and position of additional methoxy groups. Their inhibitory potency toward human recombinant CYPs: CYP1A1, CYP1A2 and CYP1B1 have been studied and compared with the effect of resveratrol and its analogues. Among compounds tested, 2-methoxy-4'-thiomethyl-trans-stilbene and 3-methoxy-4'-thiomethyl-trans-stilbene demonstrated the most potent and selective inhibitory effect on CYP1A1 and CYP1B1 activities. The results of our study indicate that modification of stilbene derivatives with thiomethyl group may influence the selectivity and inhibitory potency of these compounds toward P450 isozymes. Thus, it should be considered in developing new chemopreventive agents based on their mechanism of action.     

Antioxidant, tyrosinase inhibitory, and acetylcholinesterase inhibitory activities of green tea (Camellia sinensis L.) seed and its pericarp

The present study evaluates antioxidant, tyrosinase inhibitory, and acetylcholinesterase (AChE) inhibitory activities of seed and its pericarp of tea plant (Camellia sinensis L.). Water and methanol extracts of tea seed and pericarp were prepared in a shaking incubator overnight at room temperature. The highest total phenolic contents, DPPH and ABTS radical scavenging activities, reducing power, β-carotene bleaching inhibition activity, highest tyrosinase inhibitory activity, and AChE inhibitiory activity were found in the methanol extracts of pericarp. Caffeine, gallic acid, several phenolic compounds, hydroxymethyl furfural, and fatty acid derived compounds were detected in the extract of tea seed and pericarp. The results indicate that seed and pericarp could be utilized as the potential resources for antioxidant ingredients in food industry. In addition, these compounds may protect Alzheimer’s disease as they had inhibitory activity of acetylcholine esterase.