Synthesis and antioxidant properties of some indole ethylamine derivatives as melatonin analogs

The synthesis and lipid peroxidation (LP) inhibition activity of several novel indole melatonin analogues are reported. Compounds have shown variable antioxidant features depending on the substitution pattern. Melatonin and the antioxidant reference compound butyl hydroxy toluen (BHT) were used to compare the antioxidant capability of the compounds synthesized.     

吲哚脲类化合物的设计合成及其体外抗肿瘤活性研究

目的以索拉非尼为先导物,设计并合成一系列吲哚脲类化合物,并对其体外抗肿瘤活性进行初步评价。方法以5-硝基吲哚-2-甲酸为起始原料,采用BOP法合成酰胺,再将硝基还原成胺基,最后与异氰酸酯缩合,共3步反应制备目标化合物;采用MTT法评价目标化合物对4种肿瘤细胞株(MX-1、A375、HepG2、Ketr3)的生长抑制作用。结果与结论合成了28个吲哚脲类新化合物,其结构经1H-NMR和HR-MS确证。体外活性结果表明,与索拉非尼相比多数化合物选择性地作用于MX-1细胞株,显示出较强的抑制肿瘤细胞增殖的活性。其中含甲基哌啶的化合物26、30和31抑制MX-1和A375细胞生长的作用显著强于索拉非尼。尤其是化合物31抑制A375细胞增殖的作用是索拉非尼的10倍,对HepG2的抑制活性与索拉非尼相当,IC50值均达到微摩尔级水平,值得进一步研究。     

多羟基(口山)酮及其衍生物的合成及抗氧化活性

目的合成多羟基(口山)酮及其脂肪胺基烷基衍生物,研究其抗氧化活性和构效关系.方法以邻甲氧基苯甲酸衍生物为起始原料,经酰氯化、Friedel-Crafts酰化、环合、脱甲基化及脂肪胺基烷基取代等反应合成目标化合物.以体外抑制Cu2 诱导的低密度脂蛋白(LDL)氧化和清除二苯代苦味肼自由基(DPPH)的EC50值检测目标化合物的抗氧化活性.结果共得到11个化合物(其中3个脂肪胺基烷基衍生物为新化合物),经IR、1H-NMR等确证其结构.初步药理试验结果表明,含邻二羟基的多羟基(口山)酮具有良好的抗氧化活性.结论邻二羟基的存在与(口山)酮衍生物的抗氧化活性有密切关系;羟基的取代数量对活性没有明显影响;取代位置对活性的影响有待进一步研究.     

Synthesis and antioxidant activity of new tetrahydro-naphthalene-indole derivatives as retinoid and melatonin analogs

A number of retinoid-related compounds represent classes of antioxidative and proapoptotic agents with promising potential in the treatment of neoplastic diseases. Indeed, the synthetic retinoid amide fenretinide [N-(4-hydroxyphenyl)retinamide] induces apoptosis of cancer cells and acts as a chemotherapeutic drug in cancer therapy. In the present work, and as a continuation of our studies on retinoid-type compounds, the synthesis of melatonin retinamide derivatives was studied as a novel series of melatonin retinoids, using the condensation reaction sequence involving tetrahydrotetramethylnaphthalene carboxylic acid and appropriate melatonin-type moieties. Despite of the weak DPPH inhibition activity pattern of the synthesized compounds, some of them showed a strong inhibition on lipid peroxidation (IVa-b, Va, and VIIa-c, 88, 96, 90, 94, 93, and 86%, respectively at 10(-4) M concentration) when melatonin (85% at 10(-4) M concentration) was used as a reference compound.     

New potent indole derivatives as hyaluronidase inhibitors

Because of the physiologic importance of hyaluronidases, the identification of potent and selective inhibitors of hyaluronidases has become increasingly important. A variety of assay methods have been used for such a purpose, i.e. classical turbidimetric, viscometric and colorimetric. In this study, a modified enzymatic assay has been used to obtain a microtiter plate-based sensitive activity screening. All inhibitors were tested in a stains-all assay at pH 7 and in a Morgan-Elson assay at pH 3.5. Among the tested compounds, 1, 2, 3, 6, 7, 8, 16, 17 and 18 showed good inhibition of more than 50%, so the IC(50) values of these derivatives were determined in the range of 25-41 microm. The IC(50) value of the most active hyaluronidase inhibitor Vcpal (6-palmitoyl-L-ascorbic acid) was measured as 8.36 microm. All inhibitors including Vcpal showed twofold less activity at pH 3.5 in a Morgan-Elson assay. Examination of substituent effects on the activity showed that para-positions of benzamide needs to be chlorinated or fluorinated to obtain good inhibitory effect. It was found that the introduction of a p-fluoro benzyl ring in the indole nitrogen has a positive effect for the inhibitory effects of both indole-2- and 3-carboxamide derivatives.     

甘草萜醇类共轭烯衍生物的合成及抗氧化活性

为优化甘草次酸(Ib)的抗氧化活性，对其化学结构进行修饰，通过还原和脱水反应制备了2个甘草萜醇类共轭烯衍生物。各化合物的抗氧化活性由肝微粒体中的细胞色素P450/NADPH氧化系统做体外抗氧化实验模型进行测定。微粒体中的自由基诱发情况由探针DCFH-DA的氧化程度进行检测，维生素E作为阳性对照物。初步的活性测定结果显示，甘草萜醇类两种同环和异环双烯衍生物——18β-olean-11,13(18)-diene-3β,30-diol (IV)和18β-olean-9(11),12-diene-3β,30-diol(V)显示出较强的抗氧化活性，以1.0 mg·mL^-1的浓度，分别抑制自由基活性为45%和41%。相同条件下，先导物Ib和维生素E分别抑制31%和32%的自由基活性。此结果显示，对先导物Ib的C11位羰基的脱去和C30位羧基进行还原修饰，可显著提高其抗氧化活性。     

去甲斑蝥素-半乳糖衍生物的合成与抗癌活性

设计并合成了肝靶向抗癌前药去甲斑蝥素-半乳糖(NCTD-Gal)偶联物。以去甲斑蝥素为原料，经氨基酸修饰后，再通过酰化、氢解、糖苷化和脱乙酰基反应合成去甲斑蝥素-半乳糖衍生物。合成了7个新β-O-糖苷化合物，结构通过IR、 MS、 ¹H NMR和元素分析确证。对产物4a进行了初步小鼠体内抗肿瘤实验，结果显示，4a中、高剂量组抑瘤率明显高于NCTD组，表明半乳糖苷化对NCTD抗癌作用有一定提高。     

Aromatase inhibition by 2-methyl indole hydrazone derivatives evaluated via molecular docking and in vitro activity studies

1. A causal association is reported between prolonged exposures to elevated levels of estrogen and breast cancer. Therefore inhibiting aromatase (CYP19A), which catalyses the conversion of androgens to estrogens, is an important approach in prevention and treatment of estrogen receptor positive (ER+) breast cancer.

2. Melatonin, a natural indolic hormone, is reported to prevent free radical induced carcinogenesis and block local estrogen synthesis in breast tissue via aromatase inhibition. However several features of melatonin limit its therapeutic use.

3. In the present study aromatase inhibiting potential of 2-methyl indole hydrazones are investigated, and compared with melatonin, by two in vitro models; a cell-free assay using a fluorescence substrate and a cell-based assay where cell proliferation was determined in ER?+?human breast cancer cells (MCF-7 BUS) in the absence of estrogen and the presence of testosterone. Aromatase inhibitory effect is also explored by molecular modelling studies.

4. In biological activity assays monochloro substituted indole hydrazones were found to have stronger aromatase inhibitory activity among all tested derivatives and were more active than melatonin. This finding is further confirmed by molecular modelling.

5. These results may be useful in the design and synthesis of novel melatonin analogues with higher inhibitory potency against aromatase.

     

Synthesis and antimicrobial activity of some indole derivatives

Bromination of 2,3-diphenyl-5-methylindole (I) (using 3 mol) with bromine gave the 4,6-dibromo derivative (II) which upon oxidation gave the corresponding 2-benzamido benzophenone derivative (III). Bromination (using 6 mol) with bromine afforded the tetrabromo derivative (IVa) which reated with amines to form the corresponding 5-substituted aminomethyl derivatives (IVb-d). Further bromination ofII using only 1 mol gave the tribromo derivative (Va) which in turn reacted with amines to formVb-g. The antimicrobial activities of compoundsI, IVa, IVc, Va, Ve, Vf andVg were studied.     

紫菜中类菌孢素氨基酸抗氧化活性研究

目的 提取紫菜中类菌孢素氨基酸（Mycosporine-like amino acids, MAAs ),探究MAAs对外源性自由基的清除及对内源性抗氧化酶的活力影响。方法 采用乙醇提取、层析纯化的方法对紫菜MAAs进行提取纯化;利用液质联用法鉴定紫菜MAAs的种类及结构;采用邻苯三酚-鲁米诺、Fenton反应法和DPPH法研究紫菜MAAs对自由基的清除作用,并测定总抗氧化能力;选取正常ICR小鼠,随机分为空白对照组（NC）、阳性对照组（MP）以及MAAs给药组（MAAs）,通过对比各组小鼠血清中超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH-Px）的活力及丙二醛（MDA）的含量,对MAAs化合物体内抗氧化活性进行研究。结果 紫菜中两种主要的MAAs成分为：Porphyra-334和shinorine;MAAs化合物及Porphyra-334组分具有显著的自由基清除作用,其中功能性成分为Porphyra-334。MAAs的总抗氧化能力随浓度的增大呈现增强趋势;与对照组相比,给药组小鼠血清中SOD、GSH-Px的活力显著提升（P<0.05);结论 紫菜MAAs具有显著的抗氧化活性。     

Copper complexes of some amino acid derivatives of substituted coumarilic acid

A series of copper complexes of some amino acid derivatives of 6-methoxy-3-methyl-coumarilic acid were prepared. The infrared, visible spectra and magnetic sus-ceptibility of these compounds were reported. All copper complexes were found to have antimicrobial activity against gram-positive bacteria only.     

3-(3′-甲基-4′-取代苯基-1′,3′-丁二烯基)吲哚类衍生物的合成及其抗癌活性

目的　研究3-(3′-甲基-4′-取代苯基-1′,3′-丁二烯基)吲哚类衍生物的合成及其抗癌活性。方法　通过亲电取代、羟醛缩合、选择性还原、相转移Wittig反应和水解反应合成目的化合物,利用几种药理模型进行抗癌和抗炎活性筛选。结果　设计合成了11个3-(3′-甲基-4′-取代苯基-1′,3′-丁二烯基)吲哚化合物,均为新化合物。生物活性实验结果表明,化合物8对HL-60,HCT-8和Bel7402癌细胞株有效,且在浓度为10^-5mol·L^-1时,其抗炎抑制率可达100％。结论　化合物8显示了抑癌作用和抗炎活性,值得进一步研究。     

Synthesis and anti-HIV activity of sulfonated amino ribofuranans

New sulfonated amino ribofuranans were synthesized to elucidate the relationship between structure and specific biological activities such as anti-HIV and blood anticoagulant activities. The synthesis was performed by sulfonation of copolymers having various proportion of (1 --> 5)-alpha-D-ribofuranosidic unit. The sulfonation with piperidine N-sulfonic acid produced the sulfonated amino ribofuranans in high yield. The anti-HIV activity of sulfonated 3-amino-3-deoxy-(1 --> 5)-alpha-D-ribofuranan showed more potent by increasing the degree of sulfonation and the average molecular weights. This activity was almost equal to the activities of sulfonated ribofuranans and ribopyranans reported before in spite of low molecular weight. The blood anticoagulant activities was observed at 36-48 mg/units, more potent than standard dextran sulfonate, 22.7 mg/units. In addition, the blood anticoagulant activities of sulfamide-copolysaccharide consisting various proportion of (1 --> 5)-alpha-D-ribofuranan units were potentiated by increasing sulfonated amino-ribofuranan units from 13 to 21 mg/units.     

Synthesis and antioxidant properties of novel N-H and N-substituted propanamide derivatives

The interest in the application of antioxidants for medical treatment has been growing recently. A lot of evidence has proven the link between the development of human diseases and oxidative stress. Indole derivatives were found to be very effective in protecting against oxidative stress. Recent exciting findings have demonstrated that several indole derivatives (IDs) are strong inhibitors of superoxide anion (SOD) and lipid peroxidation (LP). In this study, a series of novel N-H and N-substituted indole-3-propanamide derivatives (I3PADs) have been prepared and their efficiencies were investigated towards SOD and LP. Among the synthesized I3PADs, compounds 5 and 7-12 significantly inhibited O2*- in the range of 94-100%. In addition, N-H I3PADs showed a stronger inhibitory effect (compounds 1-5, 56-83%) on lipid peroxidation levels than SOD.     

Synthesis and antioxidant activity of curcumin analogs

Numerous biological activities including antioxidant, antitumor, anti-inflammation, and antivirus of the natural product curcumin were reported. However, the clinical application of it was significantly limited by its instability, poor solubility, less body absorbing, and low bioavailability. This review focuses on the structure modification and antioxidant activity evaluation of curcumin. To study the structure–activity relationship (SAR), five series of curcumin analogs were synthesized and their antioxidant activity were evaluated in vitro. The results showed that electron-donating groups, especially the phenolic hydroxyl group are an essential component to improve the antioxidant activity.     

Novel indole hydrazide derivatives: Synthesis and their antiproliferative activities through inducing apoptosis and DNA damage

A series of novel indole hydrazide derivatives was synthesized and evaluated for their anticancer activities. Compound 12 exhibited the highest antiproliferative activity against the MCF-7 cell line, with an IC₅₀ value of 3.01 µM. Treatment of MCF-7 cells with compound 12 led to cell cycle arrest at the G0/G1 phase and also displayed a significant annexin V binding pattern, indicating that compound 12 is effective in apoptotic cell death. The Western blot analysis showed that compound 12 increased the expression of proapoptotic Bax and decreased the levels of the antiapoptotic Bcl-2 protein. It was also observed that MCF-7 cells treated with compound 12 showed reduced levels of procaspase-3 and -9 proteins. Moreover, compound 12 treatment induced a significant DNA damage in MCF-7 cells by increasing H2AX and ATM phosphorylation.     

Diglycosidic indole alkaloid derivatives from an aqueous extract of Isatis indigotica roots

Six new indole alkaloid diglycosides named isatigotindolediosides A-F (1–6), along with three known analogs (7–9), were isolated from an aqueous extract of the Isatis indigotica roots (ban lan gen). Their structures including the absolute configurations were determined by comprehensive spectroscopic data analysis, combined with enzyme or acid hydrolysis, and comparison of experimental circular dichroism (CD) and calculated electronic circular dichroism (ECD) spectra. In the preliminary assays, compounds 3, 5, and 8 showed antiviral activity against Coxsackie virus B3.     

1,1,2-三甲基-1H-苯并[e]吲哚的制备

目的合成1,1,2-三甲基-1H-苯并[e]吲哚。方法由2-萘胺经重氮化反应、还原反应制得2-萘肼,再与甲基异丙基酮经费歇尔吲哚合成反应制得目标化合物。结果与结论经熔点测定及1H-NMR分析确证目标化合物结构,总收率为26.4%。     

新型含羟基E,E-1-(3′-吲哚基)-5-取代苯基-1，4-戊二烯-3-酮化合物的合成及抗炎活性

目的寻找新的非甾体抗炎药物。方法利用羟醛缩合反应，合成了8个新型含羟基的E,E-1-(3′-吲哚基)-5-取代苯基-1，4-戊二烯-3-酮化合物，通过¹H NMR，ESI-MS和元素分析对其结构进行表征。并测定了体外抗炎活性。结果体外抗炎活性测试结果表明，所有化合物都有一定程度的抗炎活性。结论其中化合物4d和4e具有较强的抗炎活性，其抗炎活性与白藜芦醇接近，值得进一步研究。