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日本科学技术振兴机构数据库(JST)
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医药导报, 2017, 36(2): 181-185
doi: 10.3870/j.issn.1004-0781.2017.02.016
黄酮类化合物的结构修饰及生物活性研究进展*
周宗宝, 王红, 叶晓川, 胡春玲

摘要:

黄酮类化合物广泛存在于自然界,是一类重要的天然有机化合物,其生物活性多种多样。该文主要对各种黄酮类化合物的结构修饰及其生物活性研究进展进行综述,其中一些新型黄酮类衍生物具有优良的生物活性。

关键词: 黄酮类化合物 ; 结构修饰 ; 生物活性

Abstract:

黄酮类化合物(flavonoids)是一类多酚类抗氧化剂,是葛根、补骨脂、黄芩、银杏、沙棘、槐米等临床常用中药材的主要活性成分[1]。该类化合物不仅数量众多,而且结构复杂,具有许多重要的生理活性,如抗氧化[2]、抗癌[3]、抗炎[4]、抗菌[5]、抗病毒[6]、抗变态反应[7]、抗糖尿病并发症[8]等。天然黄酮类化合物因溶解性差、生物利用度不高等缺点而限制其临床应用[9]。因此对自然界含量较高的天然黄酮进行半合成的结构修饰,使之达到成药要求,是合理开发利用该类化合物的一条重要途径[10]。黄酮类化合物泛指两个具有酚羟基的苯环(A环与B环)通过中央三碳原子相互连接而成的一系列化合物。目前黄酮类化合物的结构修饰主要集中在环上取代基的变化,通过不同基团的替换,以此来丰富其种类和改善其化学性质,以寻求活性良好的化合物。因此,国内外许多课题组都选择天然黄酮为研究对象,通过结构改造和优化研究其针对不同生理活性的构效关系,以求开发出一批具有新颖结构的黄酮类药物的先导化合物。笔者依据黄酮结构分类,综述近年来国内外关于黄酮类化合物构效关系的研究进展,报道如下。

1 二氢黄酮(醇)类

二氢黄酮类(flavanones)为黄酮类C-2,3位的双键氢化后的衍生物,此类植物成分多数带有羟基或甲氧基,当C-3位上带有羟基时,通称为二氢黄酮醇类(flavanonols)。二氢黄酮类化合物作为一类微量黄酮类化合物,在自然界分布相对有限,对其相关研究报道较少,但近期分子生物学的研究结果显示某些化合物有着显著的生物活性[11-12]

β-淀粉样蛋白由39~43个氨基酸组成,是大脑皮质老年斑的主要成分,这种蛋白能在体内聚合为可溶性二聚体,这种二聚体可以有效地削弱突触结构和功能,而这是引起阿尔茨海默病(Alzheimer disease, AD)的重要原因[13]。现代研究表明:二氢黄酮醇类化合物能显著抑制β-淀粉样蛋白42(amyloid-β 42, Aβ42)的聚合,但是对其作用机制不明确[14]。SATO等[15]首次将B环上3',4'位具有邻苯二酚结构的(d)-二氢槲皮素(taxifolin )氧化形成邻醌结构,并在2'位上引入氨基取代加合物。药理活性研究表明:合成的这些(d)-二氢槲皮素加合物能明显抑制Aβ42的聚合,同时发现这类化合物当B环上有邻醌结构时,能与Aβ42中16位与28位赖氨酸发生反应,形成稳定的加合物,从而发挥阻碍Aβ42聚合的作用。这一发现阐明二氢黄酮醇类化合物抑制Aβ42聚合的机制,并且这对于研制新型的抗AD的药物提供思路。

2 黄酮(醇)类

黄酮(flavonoids),即2-苯基色原酮(2-苯基苯并γ吡喃酮)类,绝大多数植物体内都含有黄酮类化合物,在植物的生长、发育、开花、结果以及抗菌防病等方面起着重要的作用。由于黄酮类化合物在植物中含量较高,关于其生理活性研究也十分广泛[16]。刘瑞[17]采用Mannich反应,将芹菜素、山奈酚、槲皮素3种黄酮与不同胺类在甲醛溶液中,温和的反应条件下,合成一系列C-8位取代胺甲基黄酮衍生物,并分别研究其抗菌与抗肿瘤活性。实验结果发现:①C-8位取代的黄酮类衍生物中具有脂环链结构的衍生物的抗细菌活性高于含有脂肪链的衍生物;②在含脂环链结构的衍生物中,含有六元环的化合物相对于含五元环的化合物具有较高活性,且含有较多杂原子衍生物的抗细菌活性较高;③C-8位取代的黄酮衍生物的抗癌细胞增殖活性测试也发现了类似抗菌活性的规律。这一结果表明黄酮醇类化合物连接上胺类化合物时能使其生理活性增强。

3 异黄酮类

异黄酮(isoflavones)是植物苯丙氨酸代谢过程中,由肉桂酰辅酶A侧链延长后环化形成以苯色酮环为基础的酚类化合物,属植物次级代谢产物,主要存在于豆科植物中,具有消除氧自由基、抗氧化、保护心血管等诸多生理活性[18]。SWEIS等[19]研究表明,化合物2-(4-羰基苯基)苯并叮恶唑作为胆固醇酯转运蛋白(cholesteryl ester transfer protei, CETP)抑制剂,其结构中2-芳基苯并叮恶唑是其发挥抑制作用的关键,而异黄酮同样具有类似2-芳基苯并叮恶唑的骨架结构。因此,认为异黄酮具有潜在的调节血脂的生物活性。WANG等[20]合成一系列异黄酮的B环4'位乙酰胺衍生物,通过药理活性表明:①在异黄酮C-7羟基被乙酰基取代的化合物比起相应未乙酰化的化合物活性更好,具有很好的调节血脂能力;②异黄酮B环2,3,4位的甲基化会使活性降低,甚至丧失;因此,A环C-7位的乙酰化可能使异黄酮结构更加契合CETP结构,而B环的取代会使结构差异变大。这一结果验证异黄酮的骨架结构衍生物具有调节血脂的能力。

鹰嘴豆(Cicer arietinum)为豆科草本植物,因其面形奇特,尖如鹰嘴,故称此名。根据最近的研究,鹰嘴豆中提取的异黄酮类化合物表现出良好的降糖活性[21],但活性成分的含量非常有限。LI等[22]以鹰嘴豆为研究对象,提取分离一系列异黄酮类化合物,研究发现,B环4'位甲醚化的异黄酮降低血糖作用最为显著,于是以这类化合物作为先导化合物合成一系列异黄酮衍生物,以胰岛素抵抗HepG2细胞为模型,研究这些衍生物抗血糖作用,结果表明:①这些衍生物都能有效地降低HepG2细胞的血糖活性;②将活性最好的衍生物相互组合时,形成的组合物能发挥成倍的降低血糖活性强度,其半数抑制浓度(IC50)值仅为1.29 μmol·L-1,并且这一组合物能保护被高血糖损伤的人脐静脉血管内皮细胞(human umbilical vein endothelial cells, HUVEC),这一发现表明异黄酮B环4'位可能是异黄酮类化合物发挥降血糖作用的关键位置。

4 查耳酮类

查耳酮(chalcones)作为生物体内合成黄酮类化合物的中间体,广泛存在于甘草、红花等药用植物中,由于其分子结构具有较大的柔性,能与不同的受体结合,因此具有抗炎[23]、抗病毒[24]、抗恶性细胞增殖[25]等多种生物活性。

近年来由于其在抗癌方面的突出活性,对于新型潜在的类查耳酮候选药物一直是国内外研究热点[26]。DYRAGERA等[27]以3,5-二卤代邻羟基苯乙酮为原料,与多种不同苯甲醛衍生物通过羟醛缩合合成一系列查耳酮类化合物,通过细胞实验研究发现:①这些衍生物对于个体的癌细胞株系都表现有细胞毒性,且IC50值低。②这些衍生物都能抑制微管蛋白的聚集,而当查耳酮的B环变为吲哚环时,却能稳定微管蛋白。通过分子对接实验发现,这一化合物能与紫杉醇结合位点发生作用,这表明查耳酮B环修饰为吲哚环时可能作为一种全新的小分子微管蛋白稳定剂的先导化合物。

5 花青素类

花青素苷的糖苷配基称为花青素(anthocyanin),广泛存在于植物界中。花青素与其他黄酮类化合物不同处在于:拥有一个氧鎓离子,即2-苯基苯并呋喃正离子。现代研究表明,花青素具有优良的抗自由基活性和抗氧化活性,在治疗慢性疾病方面具有极大优势。例如:炎症、认知障碍、神经功能障碍、心血管并发症及肝脏损伤等,而这些活性与花青素的结构有密切的关系[28]

ALI等[29]通过简单原料合成一系列花青素衍生物。对比研究这些化合物的自由基清除作用发现:①这些花青素衍生物都能清除各类自由基,且此类作用都比已有的抗氧化剂儿茶酚强。②A环与B环至少有一个邻苯二酚结构的衍生物,活性明显强于其他相应化合物。③仅有5,7和4'三取代酚羟基的衍生物活性很弱,而3-OH能有效增强活性,这可能是由于3-OH衍生物能形成一个二酮的结构,这一结构使其更能作为氢受体。④花青素衍生物与相对应的花青素苷衍生物的活性是相似的。因此,花青素的抗血糖作用跟其母核结构上的羟基数目与取代位置有着密切的关系。

6 橙酮类

橙酮(aurone)又称噢哢类,可视为黄酮类的异构体,也可由查耳酮经氧化而得,是苯骈呋喃的衍生物。现代研究表明,橙酮类化合物具有广泛的生物活性[30]。到目前为止,治疗AD的方法通常是通过抑制乙酰胆碱酯酶来平衡体内乙酰胆碱的水平。LEE等[31]通过化合物库随机筛选发现:橙酮类化合物硫黄菊素(sulfuretin)存在潜在的抑制乙酰胆碱酯酶的作用,但是它的作用很弱(IC50为698.88 μmol·L-1)。于是以硫黄菊素为先导化合物合成一系列衍生物,并研究其对于乙酰胆碱酯酶的抑制作用,结果显示:硫黄菊素的B环3',4'位酚羟基醚化,且A环C-6位醚化这一化合物表现出很强的抑制乙酰胆碱酯酶的作用,这个作用相当于抗AD药物加兰他敏(galanthamine)的6倍。这一结果表明,具有酚羟基的橙酮类化合物的A环,B环醚化有利于其抗AD作用。

7 新型黄酮类

新型黄酮泛指自然界中存在的结构新颖的类黄酮化合物,其基本结构与黄酮类化合物既有一些共同点,也有些许区别,然而这些区别也造成这些新型黄酮类在活性上与传统黄酮类有很大差异。

7.1 呫吨酮类(xanthones)

心血管疾病是一系列涉及循环系统的疾病。最近的研究显示,氨基取代呫吨酮类化合物能有效缓解心血管疾病。由于呫吨酮类化合物与典型的β-受体阻断药(如普萘洛尔)结构存在极大差异,因此研究治疗心血管疾病的呫吨酮类药物具有十分重要的意义[32]

SZKARADEK等[33]合成6个A环C-4位氨基取代呫吨酮类化合物,并分别评价其对心血管的调节作用,结果显示:①在整个观察期间,所有化合物都能明显降低处于麻醉状态下大鼠血压的收缩压和舒张压;②其中两个化合物显示对肾上腺素受体有亲和力,同时在心律失常大鼠模型中,两者表现出相似的活性,半数有效量(ED50)分别为0.53和0.81 mg·kg-1,这一数据明显高于抗心律失常药物盐酸乌拉地尔(ED50=1.26 mg·kg-1);③在抗心律失常方面,R型呫吨酮类化合物更有优势。由于呫吨酮类化合物的A环和B环处于对称结构,因此对于B环取代呫吨酮类抗心律失常药物可能会成为未来研究的热点。

7.2 紫檀素类

黄檀属植物属于豆科植物,广泛分布于美国中部和南部、非洲、马达加斯加和南亚,大约有275个品种,该属植物具有多样的生物活性,包括抗菌、抗炎、镇痛、解热、抗胃溃疡和抗疟原虫等[34]。近期研究表明,该类植物主要含有紫檀素类化合物(Pterocarpans) [35]

KAENNAKAM等[36]从黄檀属velutina中提取6种全新的紫檀素类化合物,并采用噻唑蓝(MTT)法研究这些化合物对人口腔表皮样癌细胞与HeLa细胞系的细胞毒性,结果表明:所有的化合物都具有一定的细胞毒性,结构不同,活性差异较大。其中B环C-8,9位醚化的化合物其活性明显高于未醚化化合物。

7.3 高异黄酮类

眼科疾病的特点是眼部血管过度的生成从而导致失明。据相关文献报道,Cremastranone是一种能够抑制血管增生的天然高异黄酮类化合物 (Homoisoflavones) [37]。BASAVARAJAPPA等[38]发现带有苯丙氨酰基的化合物能明显抑制视网膜微血管内皮细胞增生,并以Cremastranone为基本骨架合成了一系列苯丙氨酰基高异黄酮类化合物,结果显示:当Cremastranone B环3'位使用叔丁氧甲酰胺基取代的衍生物,无论是体外人视网膜内皮细胞增生的抑制作用,还是体内视网膜病变模型的抑制作用,都最为显著。

7.4 鱼藤酮类

鱼藤酮类(rotenoids)是一类特殊的异黄酮类化合物,在C环上多一个碳原子,与B环形成含氧杂环。这个环系统是由2’-甲氧基异黄酮经氧化、环合形成。(l)-鱼藤素(deguelin)是存在于植物鱼藤酮中一种自然产物。最新研究表明,这种化合物体内外均能显著抑制肿瘤细胞,因此这一化合物也成了国内外抗肿瘤药物研究的热点[39]

FARMER等[40]通过化学方法合成类似的鱼藤酮类化合物,其构型为d-,并且通过对比研究发现:非天然的(d)-鱼藤素能显著的抑制MCF-7乳腺癌和肝癌HepG2细胞的增殖,同时这一作用明显强于天然的(l)-鱼藤素。这一发现对鱼藤酮类化合物在抗肿瘤方面的认识将更进一步深入。

7.5 原芹菜素

原芹菜素(protoapigenone)是一类比较罕见的类黄酮化合物,拥有特殊的p-喹啉基团。在自然界中通常存在于某些蕨类植物中。近期研究发现,原芹菜素类化合物显示出优良的生物活性,因此已经成为生物医学研究的焦点。

尿酸水平升高会导致各种病理状态,包括痛风和肾结石的形成。黄嘌呤氧化酶(xanthine oxidase from buttermilk, XO)是一种嘌呤代谢的关键酶,在体内能使次黄嘌呤和黄嘌呤转化为尿酸,从而使体内尿酸水平升高。研究表明,类黄酮XO抑制药需具有平面结构[41]。HUNYADI等[42]首次合成一系列非平面的原芹菜素衍生物,发现这些衍生物能有效抑制XO的活性,其中当1'位羟基形成炔丙基醚时,其IC50为3.61 μmol·L-1,这一结果明显低于抗痛风药物别嘌呤醇(其IC50为8.72 μmol·L-1)。因此,“平面结构”不是类黄酮XO抑制剂的必须条件,为进一步开发黄酮类抗痛风药物提供参考。

8 结束语

国内外研究发现,天然黄酮类化合物的母核、取代基、取代位置分布对其药理活性都可能会产生不同影响,其生理活性与化学结构关系密切:①天然黄酮类化合物通过酯化、醚化、酰基化等衍生化反应可以改变理化性质,扩大应用范围,增强生理活性,目前黄酮类化合物的结构修饰主要集中在A环5, 7位,B环2',3', 4'位,C环2, 3位,其中B环取代基的变化对生理活性影响最大。②对于新型黄酮化合物来说,化合物的空间构型对其生理活性的影响至关重要,由于其与传统结构具有一定差异,通过构效关系的研究,化学合成及结构修饰设计新型具有类黄酮骨架结构的化合物,得到活性更好、作用机制独特的类黄酮化合物,具有极为重要的现实意义。

植物药以天然低毒的特点倍受青睐,而黄酮类化合物更是以其广谱的药理作用引人瞩目,且广泛分布于自然界。随着自然界新的结构不断被发现,研制潜在的黄酮类药物极可能成为未来国内外药物学家的一个热点。但是黄酮类化合物的缺点也十分明显:结构过于复杂,并且作用位点较多,对一些病症缺乏针对性和选择性。虽然目前对黄酮类药物化学结构和生物活性的关系进行较多的研究,但深度不够,在弄清构效关系的基础上缺乏针对性和选择性。

因此,将来黄酮类化合物结构修饰前景广阔,除加强修饰衍生物的生物活性和专一性外,作用靶点与结构特异性的结合是将来研究的方向,随着现代分子生物学和分子筛选技术的发展,在不久的将来会有安全性更好和活性更强的新颖黄酮类化合物用于临床。

The authors have declared that no competing interests exist.

参考文献

[1] NAM T G, LEE S M, PARK J H, et al.Flavonoid analysis of buckwheat sprouts[J]. Food Chem, 2015, 170: 97-101.
It is known that common buckwheat sprouts contain several flavonoids, including orientin, isoorientin, vitexin, isovitexin, rutin, and quercetrin, whereas tartary buckwheat sprouts contain only rutin. In this study, we evaluated flavonoids present in buckwheat sprouts and identified a previously unreported flavonoid. Simultaneous detection by HPLC was used to separate rutin and a compound that was not separated in previous studies. We used a novel HPLC elution gradient method to successfully separate rutin and the previously unidentified compound, for which we performed structural analysis. The identification of six flavonoids by HPLC was confirmed using HPLC–ESI–MS/MS analysis. The newly identified compound, [M+H] + =611.17, was identified by NMR as the rutin epimer quercetin-3- O -robinobioside. Unlike common buckwheat sprout, tartary buckwheat sprout contained rutin as a main flavonoid, whereas other flavonoids appeared only in trace amounts or were not detected. Quercetin-3- O -robinobioside was not detected in tartary buckwheat sprout.
DOI:10.1016/j.foodchem.2014.08.067      PMID:25306322      URL    
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[2] FERREIRA R D Q, GRECO S J, DELARMELINA M, et al. Electrochemical quantification of the structure/antioxidant activity relationship of flavonoids[J]. Electrochim Acta, 2015, 163: 161-166.
Ceric Reducing/Antioxidant Capacity (CRAC) is an electrochemical test that has recently emerged as an alternative to the spectrophotometric tests employed in the determination of antioxidant capacity. CRAC simply and rapidly quantifies the reducing capacity of antioxidant compounds based on the consumption of a standard oxidizer (Ce 4+ ). In this study, eight samples of flavonoids from three distinct groups were evaluated and showed the following antioxidant hierarchy: morin>kaempferol63quercetin>fisetin>apigenin>luteolin>catechin>chrysin. This hierarchy is correlated with the behavior expected according to the structure/antioxidant activity relationship (SAR) of these polyphenolic compounds. Additionally, other correlations were established using SAR to explain the antioxidant behavior of the compounds with unrelated groups: OH(C2′C4′)>OH(C4′)63OH(C3′C4′)>C2=C3+4-oxo>OH(C3,C5)+4-oxo>OH(C3)+4-oxo>OH(C5)+4-oxo>OH(C3,C5). Therefore, the use of these two tools together is very important for the study of the antioxidant behavior of flavonoids, contributing uniquely to the understanding of electronic transfer mechanisms involved in the antioxidant processes.
DOI:10.1016/j.electacta.2015.02.164      URL    
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[3] QIAN J Z,WANG B C, FAN Y, et al.QSAR study of flavonoid-metal complexes and their anticancer activities[J]. J Struct Chem, 2015, 56(2):338-365.
ABSTRACT Flavonoid-metal complexes have anticancer activities. However, the quantitative structure-activity relationship (QSAR) of flavonoid-metal complexes and their anticancer activities has not been known so far. Based on the 14 structures of flavonoid-metal complexes and their anticancer activities for HepG2 from the references, we optimised their structures using the density functional theory (DFT) method, and subsequently calculated 19 quantum chemical descriptors, such as dipole, charge, and energy. Then, we chose several quantum chemical descriptors that are very important for IC50 which represents the anticancer activities of flavornoid-metal complexes for HepG2 through the stepwise linear regression method. Meanwhile, we obtained six new variables through the principal component analysis. Finally, we built QSAR models based on those important quantum chemical descriptors, six new variables as independent variables, and IC50 as a dependent variable using an artificial neural network (ANN). At last, we validated the models using the experimental data from the references. The results show that models presented in this paper are accurate and predictive.
DOI:10.1134/S0022476615020195      URL    
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[4] ABDALLAH H M,ALMOWALLAD F M, ESMAT A, et al.Anti-inflammatory activity of flavonoids from Chrozophora tinctoria[J]. Phytochem Lett, 2015, 13:74-80.
Chemical investigation of Chrozophora tinctoria (L.) A. Juss. growing in Saudi Arabia revealed the isolation of two new acylated flavonoids identified as acacetin-7- O -β- d -[α- l -rhamnosyl(102→026)]3″- E - p -coumaroyl glucopyranoside ( 4 ) and apigenin-7- O -(6″- Z - p -coumaroyl)-β- d -glucopyranoside ( 5 ), in addition to amentoflavone ( 1 ), apigenin-7- O -β- d -glucopyranoside ( 2 ), apigenin-7- O -6″- E - p -coumaroyl-β- d -glucopyranoside ( 3 ) and rutin ( 6 ). The structures of isolated compounds were established by 1D, 2D NMR and HRESIMS spectral data, in addition to comparison with literature data. The anti-inflammatory activities of isolated compounds were assessed by measuring the levels of IL-1β, IL-6, TNF-α and PGE 2 in the supernatant media of human peripheral blood mononuclear cells (PBMCs) stimulated by phytohaemagglutinin (PHA). At a concentration of 10002μM, compounds 1 , 2 , 4 and 6 significantly decreased Il-1β, Il-6 and PGE 2 to nearly normal values. All tested compounds caused a dose-dependent decrease in TNF-α level but failed to reach that of the control values.
DOI:10.1016/j.phytol.2015.05.008      URL    
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[5] DONGAMANTI A,AAMATE V K, DEVULAPALLY M G, et al.Synthesis, antimicrobia activity and molecular docking of novel tetracyclic scaffolds incorporating a flavonoid framework with medium sized oxygen heterocycles[J]. Bioorg Med Chem Lett, 2015, 25(4):898-903.
DOI:10.14233/ajchem.2015.18417      URL    
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[6] POLLICINO T, MUSOLINO C, BITTO A, et al.OC-29 antiviral activity of flavonoid-derived compounds against hepatitis B virus[J]. J Hepatol, 2013, 45(Suppl 1): 10.
DOI:10.1016/S1590-8658(13)60030-4      URL    
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[7] ONISHI S, NISHI K, YASUNAGA S, et al.Nobiletin, a polymethoxy flavonoid, exerts anti-allergic effect by suppressing activation of phosphoinositide 3-kinase[J]. J Funct Foods, 2014, 6(1): 606-614.
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[8] AL-NUMAIR K S, CHANDRAMOHAN G, VEERAMANI C, et al. Ameliorative effect of kaempferol, a flavonoid, on oxidative stress in streptozotocin-induced diabetic rats[J]. Redox Rep, 2015, 20(5): 198-209.
ABSTRACT Objective The aim of the present study was to evaluate the protective effect of kaempferol against oxidative stress in streptozotocin (STZ)-induced diabetic rats. Methods Diabetes was induced in male, adult albino rats of the Wistar strain, by intraperitoneal administration of STZ (40 mg/kg body weight (BW)). Kaempferol (100 mg/kg BW) or glibenclamide (600 碌g/kg BW) was administered orally once daily for 45 days to normal and STZ-induced diabetic rats. Results The STZ-induced diabetic rats showed significantly increased levels of plasma glucose, thiobarbituric acid reactive substances, lipid hydroperoxides, and conjugated dienes in plasma, liver, kidney, and heart whereas they showed significantly decreased level of plasma insulin. The levels of non-enzymic antioxidants (vitamin C, vitamin E, reduced glutathione) in plasma, liver, kidney, and heart and the activities of enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase) in liver, kidney, and heart were significantly decreased in diabetic rats. Administration of kaempferol to diabetic rats was showed brought back in plasma glucose, insulin, lipid peroxidation products, enzymatic, and non-enzymatic antioxidants to near normal. Conclusion The present study indicates that kaempferol has a good antioxidant property, as evidenced by its increase of antioxidant status and decrease of lipid peroxidation markers, thus providing protection from the risks of diabetic complications.
DOI:10.1179/1351000214Y.0000000117      PMID:25494817      URL    
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[9] BRAUNBERGER C, ZEHL M, CONRAD J, et al.Flavonoids as chemotaxonomic markers in the genus Drosera[J]. Phytochemistry, 2015, 118: 74-82.
The botanical classification of the huge genus Drosera remains controversial since long. In the present study, the pattern of major phenolic compounds in ten Drosera species belonging to seven different subgenera and/or sections of the genus was investigated for chemotaxonomic allocation. The composition of flavonoids and ellagic acid derivatives in Drosera adelae, Drosera burmannii, Drosera dielsiana, Drosera hilaris, Drosera montana, Drosera petiolaris, and Drosera pygmaea was elucidated for the first time. The scarce data on these compounds in Drosera binata, Drosera aliciae, and Drosera spatulata were complemented significantly. Detailed LC-DAD-MS, LC-NMR, and offline 1D and 2D NMR analyses resulted in the unambiguous identification of around 40 different substances, three of them (8-hydroxy-luteolin-8-O-arabinopyranoside, tricetin-7-O-xylopyranoside and 8-hydroxytricetin-8-O-arabinopyranoside) being natural products described for the first time. The distribution of the compounds characterized underlines their potential to serve as chemotaxonomic markers in this genus.
DOI:10.1016/j.phytochem.2015.08.017      PMID:26342620      URL    
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[10] CROZIER A, DEL RIO D,CLIFFORD M N.Bioavailability of dietary flavonoids and phenolic compounds[J]. Mol Aspects Med, 2010, 31(2): 446-467.
Abstract This paper reviews recent human studies on the bioavailability of dietary flavonoids and related compounds, including chlorogenic acids and ellagitannins, in which the identification of metabolites, catabolites and parent compounds in plasma, urine and ileal fluid was based on mass spectrometric methodology. Compounds absorbed in the small intestine appear in the circulatory system predominantly as glucuronide, sulfate and methylated metabolites which seemingly are treated by the body as xenobiotics as they are rapidly removed from the bloodstream. As a consequence, while analysis of plasma provides valuable information on the identity and pharmacokinetic profiles of circulating metabolites after acute supplementation, it does not provide accurate quantitative assessments of uptake from the gastrointestinal tract. Urinary excretion, of which there are great variations with different classes of flavonoids, provides a more realistic figure but, as this does not include the possibility of metabolites being sequestered in body tissues, this too is an under estimate of absorption, but to what degree remains to be determined. Even when absorption occurs in the small intestine, feeding studies with ileostomists reveal that substantial amounts of the parent compounds and some of their metabolites appear in ileal fluid indicating that in volunteers with a functioning colon these compounds will pass to the large intestine where they are subjected to the action of the colonic microflora. A diversity of colonic-derived catabolites is absorbed into the bloodstream and passes through the body prior to excretion in urine. There is growing evidence that these compounds, which were little investigated until recently, are produced in quantity in the colon and form a key part of the bioavailability equation of dietary flavonoids and related phenolic compounds. Copyright 漏 2010 Elsevier Ltd. All rights reserved.
DOI:10.1016/j.mam.2010.09.007      PMID:20854839      URL    
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[11] WIN T, HTWE T T, SHWE H H, et al.Lavandulyl flavanones from the stems of Hypericum calycinum L[J].Chem Biodivers, 2012, 9(6): 1198-1204.
One novel lavandulyl flavanone (=2,3-dihydro-2-phenyl-4H-1-benzopyran-4-one) with an unusual 5,2',4',6'-tetrahydroxy substitution, calycinigin A (1), was isolated from the stems of Hypericum calycinum L. (Hypericaceae). The structure was elucidated on the basis of 1D- and 2D-NMR analysis, as well as mass spectrometry (LR-EI- and HR-EI-MS) and circular dichroism. Three known lavandulyl flavanones with 5,7,2',4',6'-pentahydroxy substitution, i.e., 24, were also isolated. Chemosystematically, this is the first report on the occurrence of prenylated flavanones in the family Hypericaceae. Reduction of cell viability by all compounds was evaluated in a MTT (=3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assay using HeLa cells. Compound 1 showed moderate activity with an IC50 value of 9.7 +/- 1.8 mu M, whereas compounds 24 were less active exhibiting IC50 values of 11.6 +/- 0.9, 19.3 +/- 1.5, and 40.7 +/- 2.4 mu M, respectively. The antioxidant activity was evaluated by an ORAC (Oxygen Radical Absorbance Capacity) assay, and calycinigin A (1) was again the most active compound with a Trolox equivalent of 2.3 +/- 0.2. None of the compounds was able to reduce the TNF-a induced ICAM-1 expression in vitro using human microvascular endothelial cells (HMEC-1).
DOI:10.1002/cbdv.201100310      Magsci    
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[12] 石磊,班树荣,冯秀娥,. 二氢黄酮类衍生物的合成及抗肿瘤活性研究[J]. 中国药物化学杂志, 2010, 20(3):176-179.
目的设计合成一系列全新二氢黄酮类化合物,并评价其抗肿瘤活性。方法以间二甲苯为原料,经硝化、还原、水解、缩合等反应制得目标化合物。采用SRB法、MTT法,以顺铂为阳性对照药,以人肿瘤细胞Bel-7402、HL-60、BGC-823和KB为测试细胞株对目标化合物进行体外抗肿瘤活性评价。结果与结论合成了11个二氢黄酮类化合物,目标化合物的结构经质谱、核磁共振氢谱确证。化合物5b、5 c、5d、5 f、5h对人肿瘤细胞KB具有很好的抑制活性,化合物5 f、5h同时也对人肿瘤细胞Bel-7402、BGC-823具有一定的抑制作用。
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[13] SINHA S, LOPES D H, DU Z, et al.Lysine-specific molecular tweezers are broad-spectrum inhibitors of assembly and toxicity of amyloid proteins[J]. J Am Chem Soc, 2011, 133(42): 16958-16969.
Amyloidoses are diseases characterized by abnormal protein folding and self-assembly, for which no cure is available. Inhibition or modulation of abnormal protein self-assembly, therefore, is an attractive strategy for prevention and treatment of amyloidoses. We examined Lys-specific molecular tweezers and discovered a lead compound termed CLR01, which is capable of inhibiting the aggregation and toxicity of multiple amyloidogenic proteins by binding to Lys residues and disrupting hydrophobic and electrostatic interactions important for nucleation, oligomerization, and fibril elongation. Importantly, CLR01 shows no toxicity at concentrations substantially higher than those needed for inhibition. We used amyloid beta-protein (A beta) to further explore the binding site(s) of CLAW and the impact of its binding on the assembly process. Mass spectrometry and solution-state NMR demonstrated binding of CLR01 to the Lys residues in A beta at the earliest stages of assembly. The resulting complexes were indistinguishable in size and morphology from A beta oligomers but were nontoxic and were not recognized by the oligomer-specific antibody A11. Thus, CLR01 binds already at the monomer stage and modulates the assembly reaction into formation of nontoxic structures. The data suggest that molecular tweezers are unique, process-specific inhibitors of aberrant protein aggregation and toxicity, which hold promise for developing disease-modifying therapy for amyloidoses.
DOI:10.1021/ja206279b      Magsci    
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[14] MECOCCI P, POLIDORI M C.Antioxidant clinical trials in mild cognitiveim pairment and Alzheimer’s disease[J]. Biochim Biophys Acta, 2012, 18(2): 631-638.
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[15] SATO M, MURAKAMI K, UNO M, et al.Site-specific inhibitory mechanism for amyloid β42 aggregation by catechol-type flavonoids targeting the Lys residues[J].J Bio Chem, 2013, 288(32): 23213-23224.
The aggregation of the 42-residue amyloid β-protein (Aβ42) is involved in the pathogenesis of Alzheimer disease (AD). Numerous flavonoids exhibit inhibitory activity against Aβ42 aggregation, but their mechanism remains unclear in the molecular level. Here we propose the site-specific inhibitory mechanism of (+)-taxifolin, a catechol-type flavonoid, whose 3',4'-dihydroxyl groups of the B-ring plays a critical role. Addition of sodium periodate, an oxidant, strengthened suppression of Aβ42 aggregation by (+)-taxifolin, whereas no inhibition was observed under anaerobic conditions, suggesting the inhibition to be associated with the oxidation to form o-quinone. Because formation of the Aβ42-taxifolin adduct was suggested by mass spectrometry, Aβ42 mutants substituted at Arg(5), Lys(16), and/or Lys(28) with norleucine (Nle) were prepared to identify the residues involved in the conjugate formation. (+)-Taxifolin did not suppress the aggregation of Aβ42 mutants at Lys(16) and/or Lys(28) except for the mutant at Arg(5). In addition, the aggregation of Aβ42 was inhibited by other catechol-type flavonoids, whereas that of K16Nle-Aβ42 was not. In contrast, some non-catechol-type flavonoids suppressed the aggregation of K16Nle-Aβ42 as well as Aβ42. Furthermore, interaction of (+)-taxifolin with the β-sheet region in Aβ42 was not observed using solid-state NMR unlike curcumin of the non-catechol-type. These results demonstrate that catechol-type flavonoids could specifically suppress Aβ42 aggregation by targeting Lys residues. Although the anti-AD activity of flavonoids has been ascribed to their antioxidative activity, the mechanism that the o-quinone reacts with Lys residues of Aβ42 might be more intrinsic. The Lys residues could be targets for Alzheimer disease therapy.
DOI:10.1074/jbc.M113.464222      PMID:23792961      URL    
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[16] PANDURANGAN N, BOSE C, BANERJI A.Synthesis and antioxygenic activities of seabuckthorn flavone-3-ols and analogs[J]. Bioorg Med Chem Lett, 2011, 21(35): 5328-5330.
A practical of polyhydroxy- and regiospecifically methylated -3-ols which are components of commercial '' has been achieved by modified Algar-Flynn-Oyamada method. of extracts, isolated products and a number of -3-ols have been determined. Structure-activity relationships have been discussed. Amongst the compounds tested, , which is also present in , was found to be the most effective antioxidant and radioprotectant.
DOI:10.1016/j.bmcl.2011.07.008      PMID:21821414      URL    
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[17] 刘瑞. 三种天然黄酮结构修饰及其生物活性研究[D]. 杨凌: 西北农林科技大学, 2013:89-143.
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[18] 刘菊娜,班树荣,赵承孝,. 脱氧安息香与二氢异黄酮类化合物的合成及其对血管内皮细胞(VEC)损伤保护作用的初步活性研究[J].中国药物化学杂志, 2012, 22(4): 268-281.
目的设计合成系列新型脱氧安息香类和二氢异黄酮类化合物并初步测定其保护血管内皮细胞(VEC)活性。方法以间二甲苯为原料,经硝化、还原、水解、Hoeush-Houben缩合反应得到中间体脱氧安息香类化合物,该中间体经甲基保护,与多聚甲醛反应得到甲基保护的二氢异黄酮类化合物,再脱去甲基得到羟基二氢异黄酮类化合物。采用MTT法对目标化合物进行过氧化氢损伤VEC保护活性测定。结果与结论合成了12个新脱氧安息香类和12个新二氢异黄酮类化合物,目标化合物的结构经质谱、核磁共振氢谱确认。化合物3f、4c、4f、5c、5e对VEC有较好的保护作用。
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[19] SWEIS R F, HUNT J A, SINCLAIR P J, et al.2-(4-Carbonylphenyl)benzoxazole inhibitors of CETP: attenuation of hERG binding and improved HDLc-raising efficacy[J]. Bioorg Med Chem Lett, 2011, 21(9): 2597-2600.
The development of 2-phenylbenzoxazoles as inhibitors of cholesteryl ester transfer protein (CETP) is described. Efforts focused on finding suitable replacements for the central piperidine with the aim of reducing hERG binding: a main liability of our benchmark benzoxazole (1a). Replacement of the piperidine with a cyclohexyl group successfully attenuated hERG binding, but was accompanied by reduced in vivo efficacy. The approach of substituting a piperidine moiety with an oxazolidinone also attenuated hERG binding. Further refinement of this latter scaffold via SAR at the pyridine terminus and methyl branching on the oxazolidinone led to compounds 7e and 7f, which raised HDLc by 33 and 27 mg/dl, respectively, in our transgenic mouse PD model and without the hERG liability of previous series. (C) 2011 Elsevier Ltd. All rights reserved.
DOI:10.1016/j.bmcl.2011.02.049      Magsci    
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[20] WANG W, HE Y, XU P, et al.Synthesis and biological evaluation of isoflavone amide derivatives with antihyperlipidemic and preadipocyte antiproliferative activities[J]. Bioorg Med Chem, 2015, 23(15): 4428-4433.
A series of isoflavone amides were designed with isoflavone in place of the scaffold of 2-arylbenzoxazole as cholesterol ester transfer protein (CETP) inhibitors. Twelve new compounds were synthesized, and their inhibitory activities of CETP and preadipocyte proliferation were assayed. The hypolipidemic potency of the most effective compound HY-2c was further tested in vivo by hamster. The results indicate that HY-2c exhibited favorable antihyperlipidemic and preadipocyte antiproliferative activities.
DOI:10.1016/j.bmc.2015.06.032      PMID:26145818      URL    
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[21] HANEISHI A, TAKAGI K, ASANO K, et al.Genistein stimulates the insulin-dependent signaling pathway[J]. Front Biosci(Elite Ed), 2011, 3: 1534-1540.
ABSTRACT Small compounds that activate the insulin-dependent signaling pathway have potential therapeutic applications in controlling insulin-independent diabetes mellitus. In this study, we investigated whether soybean isoflavones could induce the expression of SHARP-2, a downstream component of insulin-dependent signaling pathway, associated with the regulation of blood glucose. One such compound called genistein, rapidly and temporarily induced SHARP-2 mRNA levels in a dose-dependent manner in rat H4IIE hepatoma cells. This induction process was rapidly stimulated by a protein kinase C (PKC) activator and blocked by a PKC inhibitor, suggesting that SHARP-2 may be induced via PKC activation. Upon Western blot analysis, genistein showed a stimulation of PKC phosphorylation. Therefore, we concluded that genistein might transcriptionally induce SHARP-2 through the activation of PKC in H4IIE cells. Our results suggest that genistein might be a useful dietary supplement to control insulin-independent diabetes mellitus by inducing the SHARP-2 expression via a bypass of the insulin-dependent signaling pathway.
PMID:21622157      URL    
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[22] LI P S, SHI X J, WEI Y, et al.Synthesis and biological activity of isoflavone derivatives from chickpea as potent anti-diabetic agents[J]. Molecules, 2015, 20(9): 17016-17040.
ABSTRACT A set of novel isoflavone derivatives from chickpea were synthesized. The structures of derivatives were identified by proton nuclear magnetic resonance (鹿H-NMR), carbon-13 ((13)C)-NMR and mass spectrometry (MS) spectral analyses. Their anti-diabetic activities were evaluated using an insulin-resistant (IR) HepG2 cell model. Additionally, the structure-activity relationships of these derivatives were briefly discussed. Compounds 1c, 2h, 3b, and 5 and genistein exhibited significant glucose consumption-enhancing effects in IR-HepG2 cells. In addition, the combinations of genistein, 2h, and 3b (combination 6) and of 3b, genistein, and 1c (combination 10) exhibited better anti-diabetic activity than the individual compounds. At the same dosage, there was no difference in effect between the combination 10 and the positive control (p > 0.05). Aditionally, we found the differences between the combination 10 and combination 6 for the protective effect of HUVEC (human umbilical vein endothelial cells) under high glucose concentration. The protective effects of combination 10 was stronger than combination 6, which suggested that combination 10 may have a better hypoglycemic activity in future studies. This study provides useful clues for the further design and discovery of anti-diabetic agents.
DOI:10.3390/molecules200917016      PMID:26393547      URL    
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[23] WILHELM A, KENDREKAR P, NORELJALEEL A E, et al.Syntheses and in vitro antiplasmodial activity of aminoalkylated chalcones and analogues[J]. J Nat Prod, 2015, 78(8): 1848-1850.
ABSTRACT A series of readily synthesized and inexpensive aminoalkylated chalcones and diarylpropane analogues (1鈭55) were synthesized and tested against chloroquinone-sensitive (D10 and NF54) and-resistant (Dd2 and K1) strains of Plasmodium falciparum. Hydrogenation of the enone to a diarylpropane moiety increased antiplasmodial bioactivity significantly. The influence of the structure of the amine moiety, A-ring substituents, propyl vs ethyl linker, and chloride salt formation on further enhancing antiplasmodial activity was investigated. Several compounds have IC 50 values similar to or better than chloroquine (CQ). The most active compound (26) had an IC 50 value of 0.01 渭M. No signs of resistance were detected, as can be expected from compounds with structures unrelated to CQ and other currently used antimalarial drugs. Toxicity tests (in vitro CHO cell assay) gave high SI indices.
DOI:10.1021/acs.jnatprod.5b00114      PMID:26235033      URL    
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[24] KARTHIKEYAN C, MOORTHY N S, RAMASSMY S, et al.Advances in chalcones with anticancer activities[J]. Recent Pat Anticancer Drug Discov, 2015, 10(1): 97-115.
Abstract Chalcones are naturally occurring compounds exhibiting broad spectrum biological activities including anticancer activity through multiple mechanisms. Literature on anticancer chalcones highlights the employment of three pronged strategies, namely; structural manipulation of both aryl rings, replacement of aryl rings with heteroaryl scaffolds, molecular hybridization through conjugation with other pharmacologically interesting scaffolds for enhancement of anticancer properties. Methoxy substitutions on both the aryl rings (A and B) of the chalcones, depending upon their positions in the aryl rings appear to influence anticancer and other activities. Similarly, heterocyclic rings either as ring A or B in chalcones, also influence the anticancer activity shown by this class of compounds. Hybrid chalcones formulated by chemically linking chalcones to other prominent anticancer scaffolds such as pyrrol[2,1-c][1,4]benzodiazepines, benzothiazoles, imidazolones have demonstrated synergistic or additive pharmacological activities. The successful application of these three pronged strategies for discovering novel anticancer agents based on chalcone scaffold has resulted in many novel and chemically diverse chalcones with potential therapeutic application for many types of cancer. This review summarizes the concerted efforts expended on the design and development of anticancer chalcones recorded in recent literature and also provides an overview of the patents published in this area between 2007 and 2014 (WO2013022951, WO201201745 & US2012029489).
DOI:10.2174/1574892809666140819153902      PMID:25138130      URL    
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[25] WINTER E, LOCATELLI C, DIPIETRO A D, et al.Recent trends of chalcones potentialities as antiproliferative and antiresistance agents[J]. Anticancer Agent Med Chem, 2015, 15(1): 592-604.
ABSTRACT Chalcones are natural compounds found in plants, fruits and vegetables.This class of compounds has shown many biological activities including antioxidant, antimicrobial, anti-inflammatory, antifungal and antihypertensive,among others. In cancer, it has been reported that chalcones interfere in several points of the signal transduction pathways related to cellular proliferation, angiogenesis, metastasis, apoptosis and the reversal of multidrug resistance. The largenumber of research articles and patents related to chalcones is already an indication of their importance as a lead class of compounds. This articlegathers recent efforts to elucidate the molecular mechanisms of action of chalcones,associatedwith their anticancer and antiresistance potential.
PMID:25553434      URL    
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[26] BUARQUE C D, SALUSTIANO E J, FRAGA K C,et al.11a-N-Tosyl-5-deoxi-pterocarpan (LQB-223), a promising prototype for targeting MDR leukemia cell lines[J]. Eur J Med Chem, 2014, 78: 190-197.
Aza-deoxi-pterocarpans (1) were synthesized through palladium-catalyzed aza-arylation of dihydronaphtalen, and showed antineoplastic effect on MDR leukemic cell lines (K562, Lucena-1 and FEPS). Compounds 1c-d were prepared to identify the pharmacophoric group responsible for the activity as well as compounds 2a-c were prepared to evaluate the structural requirements in the D-ring. LQB-223 (1b) is the most promising antileukemic agent since it was the most active on MDR cells without detectable toxicity to normal immune system cells. (C) 2014 Elsevier Masson SAS. All rights reserved.
DOI:10.1016/j.ejmech.2014.03.039      PMID:24681983      Magsci     URL    
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[27] DYRAGERA C, WICKSTROM M, FRIDENSAXIN M, et al.Ihibitors and promoters of tubulin polymerization: synthesis and biological evaluation of chalcones and related dienones as potential anticancer agents[J]. Bioorg Med Chem, 2011, 19(8) : 2659-2665.
Abstract A series of dihalogenated chalcones and structurally related dienones were synthesized and evaluated for their antiproliferative activity in 10 different cancer cell lines and for their effect on microtubule assembly. All compounds showed cytotoxic activity, with IC(50) values in the 5-280 渭M range depending on the chalcone structure and the cell line. Five of the compounds were found to be tubulin polymerization inhibitors. In contrast, one of the compounds was found to stabilize tubulin to the same extent as the anticancer drug docetaxel. Molecular modeling suggested that the tubulin inhibitors bind to the colchicine binding site of 尾-tubulin while the novel tubulin stabilization agent seems to interact with the paclitaxel binding site.
DOI:10.1016/j.bmc.2011.03.005      PMID:21459004      URL    
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[28] JHIN C, HWANG K T.Prediction of radical scavenging activities of anthocyanins applying adaptive neuro-fuzzy inference system (ANFIS) with quantum chemical descriptors[J]. Int J Mol Sci, 2014, 15(8):14715-14727.
Radical scavenging activity of anthocyanins is well known, but only a few studies have been conducted by quantum chemical approach. The adaptive neuro-fuzzy inference system (ANFIS) is an effective technique for solving problems with uncertainty. The purpose of this study was to construct and evaluate quantitative structure-activity relationship (QSAR) models for predicting radical scavenging activities of anthocyanins with good prediction efficiency. ANFIS-applied QSAR models were developed by using quantum chemical descriptors of anthocyanins calculated by semi-empirical PM6 and PM7 methods. Electron affinity (A) and electronegativity (蠂) of flavylium cation, and ionization potential (I) of quinoidal base were significantly correlated with radical scavenging activities of anthocyanins. These descriptors were used as independent variables for QSAR models. ANFIS models with two triangular-shaped input fuzzy functions for each independent variable were constructed and optimized by 100 learning epochs. The constructed models using descriptors calculated by both PM6 and PM7 had good prediction efficiency with Q-square of 0.82 and 0.86, respectively.
DOI:10.3390/ijms150814715      PMID:4159877      URL    
[本文引用:1]
[29] ALI H M, ALMAGRIBI W, AL-RASHIDI M N. Antiradical and reductant activities of anthocyanidins and anthocyanins, structure-activity relationship and synthesis[J]. Food Chem, 2015, 194:1275-1282.
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[30] ZHENG X, WANG H, LIU Y M, et al.Synthesis, characterization, and anticancer effect of trifluoromethylated aurone derivatives[J]. J Heterocyclic Chem, 2015, 52(1): 296-301.
A series of trifluoromethylated aurone derivatives were synthesized, and the structure of 6‐hydroxy‐4‐trifluoromethylated aurone was determined by single crystal X‐ray analysis. Their anticancer activities against leucocythemia (HL‐60) and colorectal adenocarcinoma (HT‐29) were evaluated by the standard MTT method with 5‐fluorouracil as a positive contrast drug. The results showed that all the ()‐trifluoromethylated aurone derivatives had potential anticancer activities.
DOI:10.1002/jhet.1969      URL    
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[31] LEE Y H, SHIN M C, YUN Y D, et al.Synthesis of aminoalkyl-substituted aurone derivatives as acetylcholinesterase inhibitors[J]. Bioorg Med Chem, 2015, 23(1): 231-240.
Abstract A novel series of 7-aminoalkyl-substituted flavonoid derivatives 5a-5r were designed, synthesized and evaluated as potential cholinesterase inhibitors. The results showed that most of the synthesized compounds exhibited potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities at the micromolar range. Compound 2-(naphthalen-1-yl)-7-(8-(pyrrolidin-1-yl)octyloxy)-4H-chromen-4-one (5q) showed the best inhibitory activity (IC50, 0.64渭M for AChE and 0.42渭M for BChE) which were better than our previously reported compounds and the commercially available cholinergic agent Rivastigmine. The results from a Lineweaver-Burk plot indicated a mixed-type inhibition for compound 5q with AChE and BChE. Furthermore, molecular modeling study showed that 5q targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds (5a-5r) did not affect PC12 and HepG2 cell viability at the concentration of 10渭M. Consequently, these flavonoid derivatives should be further investigated as multipotent agents for the treatment of Alzheimer's disease.
DOI:10.1016/j.bmc.2015.12.031      PMID:26752094      URL    
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[32] KHAN M F, NEGI N, SHARMA R, et al.Bioactive flavanoids from Glycosmis arborea[J]. Org Med Chem Lett, 2013, 3(1): 4-8.
ABSTRACT Glycosmis is a genus of evergreen glabrous shrub and distributed all over India. It possesses various medicinal properties and is used in indigenous medicine for cough, rheumatism, anemia, and jaundice. Glycosmis arborea is a rich source of alkaloids, terpenoids, coumarins, as well as flavonoids. The chemical investigation of methanol fraction of the leaves of G. arborea led to the isolation of one new flavone C-glycoside along with three known flavanoids, named as 5,7-dihydroxy-2-[4-hydroxy-3-(methoxy methyl) phenyl]-6-C-β-d-glucopyranosyl flavone (4), 5,7,4'-trihydroxy-3'-methoxy flavone (1), 5,4'-dihydroxy-3'-methoxy-7-O-β-d-glucupyranosyl flavanone (2), and 5,4'-dihydroxy-3'-methoxy-7-O-(α-l-rhamnosyl-(164→664)-β-d-glucopyranosyl) flavanone (3), respectively. The structures of all compounds were elucidated with the help of nuclear magnetic resonance spectrometry. Pure compounds and fractions were evaluated for pest antifeedant and antimicrobial activity. Four compounds were isolated from the leaves of G. arborea. Among them, compound 4 showed significant antimicrobial activity.
DOI:10.1186/2191-2858-3-4      PMID:3599570      URL    
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[33] SZKARADEK N, RAPACZ A, PYTKA K, et al.Cardiovascular activity of the chiral xanthone derivatives[J]. Bioorg Med Chem, 2015, 23(20): 6714-6724.
ABSTRACT A series of 6 derivatives of xanthone were synthesized and evaluated for cardiovascular activity. The following pharmacological experiments were conducted: the binding affinity for adrenoceptors, the influence on the normal electrocardiogram, the effect on the arterial blood pressure, the effect on blood pressor response and prophylactic antiarrhythmic activity in adrenaline induced model of arrhythmia (rats, iv). Two compounds revealed nanomolar affinity for 伪1-adrenoceptor which was correlated with the strongest cardiovascular (antiarrhythmic and hypotensive) activity in animals' models. They were enantiomers of previously described (R,S)-4-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-9H-xanthen-9-one hydrochloride and revealed similar antiarrhythmic potential in adrenaline induced model of arrhythmia in rats after intravenous injection (ED50=0.53mg/kg and 0.81mg/kg, respectively). These values were lower than values obtained for reference drug urapidil. These compounds were more active in this experiment than urapidil (ED50=1.26mg/kg). The compound 5 administered iv at doses of 0.62-2.5mg/kg at the peak of arrhythmia prevented and/or reduced the number of premature ventricular beats in a statistically significant manner. The ED50 value was 1.20mg/kg. The S-enantiomer (6) given at the same doses did not show therapeutic antiarrhythmic activity in this model. These compounds significantly decreased the systolic and diastolic blood pressure throughout the whole observation period in anesthetized, normotensive rats. The studied enantiomers showed higher toxicity than urapidil, but imperceptibly higher that another cardiovascular drugs, that is, carvedilol or propranolol. They were also evaluated for mutagenic potential in the Ames (Salmonella) test. It was found that at the concentrations tested the compounds were non mutagenic when compared to solvent control. Results were quite promising and suggested that in the group of xanthone derivatives new potential antiarrhythmics and hypotensives might be found.
DOI:10.1016/j.bmc.2015.09.005      PMID:26386822      URL    
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[34] ZHENG L H, HUANG X, WANG L, et al.Physicochemical properties, chemical compositionand antioxidant activity of Dalbergia odorifera T. Chen seed oil[J]. J Am Oil Chem Soc, 2012, 89(5):883-890.
The heartwood or root of Dalbergia odorifera T. Chen is an important traditional medicine in Asia. The aim of the present study was to evaluate the physicochemical properties, chemical composition and antioxidant activity of Dalbergia odorifera T. Chen seed oil. Oil, protein, carbohydrate, moisture, ash and total phenolic contents were found to be 12.96, 26.86, 42.58, 13.70, 3.90 and 5.55%, respectively. Free fatty acids, iodine number, peroxide value, saponification number and unsaponifiable matter were 1.66%, 106.53 g/100 g, 5.07 meq O-2/Kg, 196.78 mg KOH/g and 1.70%, respectively. The oil showed high absorbance in the UV-B and UV-C ranges with potential for use as a broad spectrum UV protectant. The major fatty acids were linoleic acid (60.03%), oleic acid (17.48%) and palmitic acid (16.72%). The total tocopherol, total phenolics and beta-carotene were 511.9, 351.1 and 62.2 mg/kg oil, respectively. In addition, the methanol extract of seed oil showed significant in vitro antioxidant activity in four assays including DPPH radical scavenging activity, reducing power, linoleic acid peroxidation inhibition and chelating activity. This study suggests that Dalbergia odorifera T. Chen seed oil has the potential to be used in new products in the functional food, cosmetic or pharmaceutical industries.
DOI:10.1007/s11746-011-1967-9      Magsci    
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[35] MUTAI P, HEYDENREICH M, THOITHI G, et al.3-Hydroxyisoflavanones from the stem bark of Dalbergia melanoxylon: isolation,antimycobacterial evaluation and molecular docking studies[J]. Phytochem Lett, 2013, 6(4): 671-675.
Two new 3-hydroxyisoflavanones, ( S )-3,4′,5-trihydroxy-2′,7-dimethoxy-3′-prenylisoflavanone (trivial name kenusanone F 7-methyl ether) and ( S )-3,5-dihydroxy-2′,7-dimethoxy-2″,2″-dimethylpyrano[5″,6″:3′,4′]isoflavanone (trivial name sophoronol-7-methyl ether) along with two known compounds (dalbergin and formononetin) were isolated from the stem bark of Dalbergia melanoxylon . The structures were elucidated using spectroscopic techniques. Kenusanone F 7-methyl ether showed activity against Mycobacterium tuberculosis , whereas both of the new compounds were inactive against the malaria parasite Plasmodium falciparum at 1002μg/ml. Docking studies showed that the new compounds kenusanone F 7-methyl ether and sophoronol-7-methyl ether have high affinity for the M. tuberculosis drug target INHA.
DOI:10.1016/j.phytol.2013.08.018      URL    
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[36] KAENNAKAM S, SIRIPONG P,TIP-PYANG S.Velucarpins A-C, three new pterocarpans and their cytotoxicity from the roots of Dalbergia velutina[J]. Fitoterapia, 2015, 105: 165-168.
Three new pterocarpans, named velucarpins A–C ( 1 – 3 ), along with three known pterocarpans ( 4 – 6 ) were isolated from the roots of Dalbergia velutina . Their structures were determined by spectroscopic analysis. All isolated compounds were evaluated for their cytotoxicity against KB and HeLa cell lines. Compounds 3 and 5 showed good cytotoxicity against KB and HeLa cells with IC 50 values of 8.22, 8.0902μM and 5.99, 8.6902μM, respectively.
DOI:10.1016/j.fitote.2015.07.004      PMID:26164635      URL    
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[37] LEE B, BASAVARAJAPPA H D, SULAIMAN R S, et al.The first synthesis of the antiangiogenic homoisoflavanone,cremastranone[J]. Org Biomol Chem, 2014, 12(39): 7673-7677.
An antiangiogenic homoisoflavanone, cremastranone, was synthesized for the first time. This scalable synthesis, which includes selective demethylation, could be used to develop lead molecules to treat angiogenesis-induced eye diseases. Synthetic cremastranone inhibited the proliferation, migration and tube formation ability of human retinal microvascular endothelial cells, important steps in pathological angiogenesis.
DOI:10.1039/c4ob01604a      Magsci    
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[38] BASAVARAJAPPA H D, LEE B, LEE H, et al.Synthesis and biological evaluation of novel homoisoflavonoids for retinal neovascularization[J]. J Med Chem, 2015, 58(12):5015-5027.
ABSTRACT Eye diseases characterized by excessive angiogenesis such as wet age-related macular degeneration, proliferative diabetic retinopathy, and retinopathy of prematurity are major causes of blindness. Cremastranone is an anti-angiogenic, naturally occurring homoisoflavanone with efficacy in retinal and choroidal neovascularization models and antiproliferative selectivity for endothelial cells over other cell types. We undertook a cell-based structure-activity relationship study to develop more potent cremastranone analogs, with improved antiproliferative selectivity for retinal endothelial cells. Phenylalanyl-incorporated homoisoflavonoids showed improved activity and remarkable selectivity for retinal microvascular endothelial cells. A lead compound inhibited angiogenesis in vitro without inducing apoptosis, and had efficacy in the oxygen-induced retinopathy model in vivo.
DOI:10.1021/acs.jmedchem.5b00449      PMID:26035340      URL    
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[39] GARCIA J, BARLUENGA S, GORSKA K, et al.Synthesis of deguelin-biotin conjugates and investigation into deguelin's interactions[J]. Bioorg Med Chem, 2012, 20(2):672-680.
Deguelin, a rotenoid, has emerged as an attractive pharmacophore for chemoprevention showing in vivo activity in several xenografts. Recently, several lines of evidence have suggested its mode of action may involve inhibition of HSP90, however binding in a different mode than known pharmacophores. To further probe the target of deguelin and related rotenoids, several biotin conjugates were prepared. None of the conjugates showed significant affinity for HSP90, however two conjugates showed a strong cellular co-localization with mitochondria, consistent with binding to mitochondrial complex 1. Contrarily to rotenone, deguelin and tephrosin were not found to inhibit tubulin polymerization demonstrating a dramatic pharmacological difference between these closely related rotenoids.
DOI:10.1016/j.bmc.2011.09.064      PMID:22037048      URL    
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[40] FARMER R L, SCHEIDT K A.A concise enantioselective synthesis and cytotoxic evaluation of the anticancer rotenoid deguelin enabled by a tandem Knoevenagel/conjugate addition/decarboxylation sequence[J]. Chem Sci, 2013, 4(8):3304-3309.
(-)-Deguelin is a rotenoid natural product that possesses significant potential as a chemopreventive and chemotherapeutic agent. While several racemic syntheses of deguelin have been reported, a formal evaluation of the anticancer activity of both the natural and unnatural enantiomers remains lacking. We describe herein the successful application of a flexible and selective thiourea-catalyzed cyclization strategy toward the enantioselective total synthesis of deguelin, which allows access to either stereoisomer for biological studies. The synthesis was completed in six steps (longest linear) with no protecting groups. The evaluation of both enantiomers of the natural product demonstrated potent inhibition of several cancer cell lines by these compounds, but interestingly showed that the unnatural (+)-deguelin preferentially inhibited the growth of MCF-7 breast cancer and HepG2 liver carcinoma cells when compared to the natural product.
DOI:10.1039/c3sc50424g      Magsci    
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[41] YUAN Q, LIU Z, XIONG C, et al.A novel, broad-spectrum antitumor compound containing the 1-hydroxycyclohexa-2,5-dien-4-one group: the disclosure of a new antitumor pharmacophore in protoapigenone 1[J]. Bioorg Med Chem Lett, 2011, 21(11):3427-3430.
The synthesis of a new compound 9 containing the 4-hydroxy-2,5-cyclohexadien-1-one system, a key elements toward elucidation of the protoapigenone 1 antitumor pharmacophore, was described. The compound showed potent in vitro antitumor potency with low micromolar IC(50)'s against breast, ovarian, prostate, liver, pancreas, and blood cancer cell lines tested and could inhibit tumor growth in vivo but no significant impairment of hematopoiesis or immune function was observed. The minimum structural pharmacophore of 1 has now been refined. (C) 2011 Elsevier Ltd. All rights reserved.
DOI:10.1016/j.bmcl.2011.03.108      Magsci    
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[42] HUNYADI A, MARTINS A, DANKO B, et al.Discovery of the first non-planar flavonoid that can strongly inhibit xanthine oxidase: protoapigenone 1'-O-propargyl ether[J].Tetrahedron Lett, 2013,54(48):6529-6532.
Xanthine oxidase (XO) is a key enzyme in purine metabolism with an important role in various pathologies. Several flavonoids have been reported for their capacity to inhibit this enzyme, and, for these compounds, the ability to adopt a planar 3D structure has been accepted as fundamental prerequisite for such activity. Here we report the in vitro investigation of a series of non-planar protoflavone derivatives as XO inhibitors, among which protoapigenone 1′- O -propargyl ether was found to be an efficient competitive inhibitor of the enzyme with an IC 50 value of 3.6102μM, significantly ( p <0.001) stronger than the anti-gout drug allopurinol (IC 50 02=028.7202μM). Methoxy substitution at C-7, however, resulted in complete loss of activity. In silico docking supported the observed structure–activity relationships, based on which a ‘planar structure’ itself can no longer be considered as a criterion for flavonoid-type inhibitors of XO.
DOI:10.1016/j.tetlet.2013.09.087      URL    
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作者
周宗宝
王红
叶晓川
胡春玲