姜黄素衍生物与类似物的构效关系研究进展

根据目前对姜黄素衍生物与类似物的结构与药理作用的关系的研究现状,论述了姜黄素衍生物与类似物的结构与其抗氧化、抗炎和抗肿瘤的药理作用的关系,包括对姜黄素及其衍生物与类似物的结构修饰与其活性之间的关系的论述。大量的实验结果显示姜黄素衍生物与类似物的药理作用与其结构中所具有的官能团有着密切的关系,这为新药开发提供了一个很好的方向。     

姜黄素及其类似物诱导人早幼粒白血病(HL-60)细胞调亡

姜黄素(Curcumin,Cur)是烹饪调味品姜黄中的一种黄色色素,具有抗癌、抗炎、抗氧化等多种药理作用[1～3].为了研究它的抗肿瘤构效关系,我们合成了一系列姜黄素类似物(结构见Scheme 1),研究了它们诱导HL-60细胞凋亡的活性及构效关系.采用MTT法测定细胞存活率,通过细胞形态学、DNA电泳梯形条带、流式细胞仪来观察及检测细胞的凋亡.结果发现姜黄素及其类似物作用48 h后能抑制HL-60细胞增值,诱导HL-60细胞凋亡.其中Cur,DMCur,MCur,DiMCur和DiACCur的作用较强.     

螺杂环单羰基姜黄素类似物的合成、晶体结构与抗肿瘤活性研究

为了发现新型姜黄素类抗肿瘤先导化合物,通过1,3-偶极环加成反应合成了14个螺杂环单羰基姜黄素类似物.该反应利用无需加催化剂的"一锅煮"方法合成,具有环境友好的优点.所有化合物结构经ESI-MS、ESI-HRMS和1H NMR确认,通过X衍射确证B6的晶体结构为单斜晶系,该类化合物的合成具有良好的区域选择性和立体选择性.通过噻唑兰(MTT)法测定所有化合物对人胃癌细胞SGC-7901、神经胶质瘤细胞U251、人大细胞肺癌细胞株NCI-H460的增殖抑制活性,部分化合物表现出了较好的活性.其中B1、B6、B7和B11对三种肿瘤细胞均表现出较好的抗肿瘤活性,而对正常人肝细胞HL-7702显示了相对较低的细胞毒性.化合物B1和B7均能明显诱导凋亡相关蛋白含半胱氨酸的天冬氨酸蛋白水解酶3(caspase3)和多聚ADP-核糖聚合酶(PARP)的活化,诱导肿瘤细胞发生凋亡.所合成的螺杂环单羰基姜黄素类似物为新型的抗肿瘤化合物,该类化合物可能在靶向抗肿瘤药物研发方面具有较好的研究前景.     

放线菌素D新类似物的设计、合成与体外抗肿瘤活性

为了提高临床抗肿瘤药物放线菌素D(AMD)的抗肿瘤效果和治疗指数,在AMD构效关系研究基础上,设计全合成了包括9个新类似物在内的两类共13个AMD类似物.保持环肽2位D-Val不变,环肽5位分别用Sar,D-Me-Leu和Me-Ile等氨基酸替换以改变侧链基团长度,合成了类似物8b～8e;以环肽2位D-Phe替换的低毒性类似物[D-Phe2]2AMD为基础,在环肽5位进行氨基酸替换,改变侧链基团长度和空间指向,并引入芳香族氨基酸等,合成了类似物8f～8m.优化了类似物的合成中的反应条件,提高了五肽环化产率,避免了消旋产物的生成.所有类似物经[α]D,1HNMR和高分辨质谱表征后,采用MTT法进行了体外抗肿瘤活性筛选,结果表明,保留环肽2位D-Val及延长5位氨基酸侧链基团能显著提高类似物的抗肿瘤活性,而2位D-Phe替换后类似物的抗肿瘤活性普遍下降.     

罂粟花粉十七肽类似物和片段的合成及其抗肿瘤活性研究

以从罂粟花粉中分离得到的具有促免疫和抗肿瘤活性的十七肽为先导化合物,设计了4个类似物和3个片段,并用固相法合成,通过CD谱测定了它们在溶液中的初级二级结构,同时测定了它们对人胃癌和人膀胱癌肿瘤细胞的抑制活性,初步讨论了构效关系.     

单羰基姜黄素衍生物的合成、晶体结构、体外抗菌及抗肿瘤活性研究

以姜黄素为先导化合物合成了两个对称的单羰基姜黄素类似物和五个查尔酮类单羰基姜黄素类似物,结构经IR,1HNMR及ESI-MS确认,用11种临床常用耐药株对其进行了体外抗菌活性筛选,同时采用MTT法测定了它们对3种人体肿瘤细胞株的细胞毒活性.其中化合物A5的体外抗肿瘤活性与姜黄素相当,并且A5对部分临床耐药菌也有一定的抑菌活性.通过单晶培养得到了A5的晶体结构,经测定表明其结构属于正交晶系,空间群Fdd2.晶胞参数a=26.085(3),b=28.248(3),c=7.9615(9),α=90.00°,β=90.00°,γ=90.00°,V=5866.4(12)3,Z=16,DX=1.288Mg/m3,μ=0.09mm-1,F(000)=324,最终偏离因子R=0.047,wR=0.112.     

不对称姜黄素类似物的合成及其清除自由基的研究

姜黄素类化合物中,非对称结构的单去甲氧基姜黄素具有一些特殊的生物活性.通过碱法合成2-单取代苯亚甲基环戊酮中间体,再用酸催化合成了10不对称的单羰基姜黄素类似物,多酚羟基的类似物可以不通过羟基保护直接合成,其中,除A1外其它9个为新化合物,并测试了所合成类似物对DPPH自由基的清除能力.结果表明类似物的酚羟基对自由基清...     

山竹醇新类似物的合成及其抗肿瘤活性研究

山竹醇具有广泛的生物学活性,例如抗炎、抗肿瘤、抗氧化、诱导细胞凋亡等.通过对山竹醇进行结构修饰,研究其侧链基团对山竹醇活性的影响,以期提高其抗肿瘤活性.以乙酰丙酮为原料,经过Michael加成、Knoevenagel缩合等多步反应,合成了三个未见文献报道的山竹醇类似物,并用噻唑蓝(MTT)法对其进行生物活性研究,分析其构效关系.结果表明,合成的三种新类似物对口腔鳞癌细胞的抑制活性均低于山竹醇,由此可知,C4位置的异戊烯基和C8位置的烯丙基对山竹醇的生物活性起关键作用.     

姜黄素及其类似物对自由基诱导的线粒体过氧化的保护作用

姜黄素(curcumin,1)是烹饪调味品姜黄中的一种黄色色素,具有抗炎、抗氧化、免疫调节、抗癌、抗高血脂等多种药理作用[1-3].为了研究它的抗氧化活性构效关系,我们合成了一系列姜黄素类似物,研究了它们对自由基诱导的大鼠肝脏线粒体过氧化的保护作用.分别采用水溶性的偶氮引发剂2,2'-偶氮二(2-脒基丙烷)二盐酸盐(AAPH)热分解产生过氧自由基(ROO·)及Fenton反应产生羟自由基(HO·)引发大鼠线粒体的过氧化,通过检测硫代巴比妥酸反应物质(TBARS)的含量测量过氧化的程度,结果发现姜黄素及其类似物均能够不同程度地抑制线粒体的过氧化.其中Curcumin,DMC和MC的抗氧化作用较强(Figure 1).     

姜黄素对酵母细胞影响的荧光分析

以最简单的真核生物——酿酒酵母为材料,利用姜黄素的荧光性质,借助荧光光谱法和荧光显微镜研究了姜黄素在酵母细胞中的定位及其对酵母生长的影响.结果表明,姜黄素可以进入酵母细胞中并抑制酵母生长,初步得到了姜黄素对酵母作用的量效关系和时间效应结果,证明了姜黄素可以与酵母细胞线粒体结合.本文结果为以酵母为模型研究姜黄素通过线粒体影响细胞代谢及其与细胞凋亡的关系奠定了基础.     

α-Amino acid derived enaminones and their application in the synthesis of N-protected methyl 5-substituted-4-hydroxypyrrole-3-carboxylates and other heterocycles

A new and simple synthesis of novel N-protected methyl 5-substituted-4-hydroxypyrrole-3-carboxylates, which exist in equilibrium with their 4-oxo tautomers, has been developed in two steps starting from N-protected α-amino acids. The key intermediates are enaminones, which can also be isolated, characterized, and used for the construction of other functionalized heterocycles, before they spontaneously decompose to pyrrole products. 4-Hydroxypyrroles are prone to partial aerial oxidation but can be efficiently alkylated or reduced to stable polysubstituted pyrrolidine derivatives.     

Specific intramolecular aromatic CH insertion of diazosulfonamides

The chemoselectivity in the intramolecular CH insertion of various diazosulfonamides has been experimentally studied. The results reveal that the aliphatic 1,4-, 1,5-, or 1,6-C(sp³)?H insertions of diazosulfonamides are not accessible, while the aromatic 1,5-C(sp²)?H insertion can be realized specifically by adjusting the diazo-adjacent group. In addition, the general chemoselectivities in the intramolecular CH insertions of diazosulfonyl compounds are summarized. Generally, diazosulfones undergo both aromatic 1,5-C(sp²)?H and aliphatic 1,5- and 1,6-C(sp³)?H insertions, while diazosulfonates undergo aliphatic 1,5- and 1,6-C(sp³)?H insertions. However, diazosulfonamides only undergo aromatic 1,5-C(sp²)?H insertion.     

N-Heterocyclic carbene-palladacyclic complexes: synthesis,characterization and their applications in the C-N coupling and α-arylation of ketones using aryl chlorides

N-Heterocyclic carbene-palladacyclic complexes 3 were successfully achieved in a one-pot procedure under mild conditions. The structure of 3a was unambiguously confirmed by X-ray single crystal diffraction and it was an active catalyst in the Buchwald-Hartwig amination and α-arylation of ketones even at very low catalyst loadings (0.01?mol%).     

Iodine-mediated oxidative Pictet-Spengler reaction using terminal alkyne as the 2-oxoaldehyde surrogate for the synthesis of 1-aroyl-β-carbolines and fused-nitrogen heterocycles

An efficient iodine-mediated oxidative Pictet-Spengler reaction in dimethyl sulphoxide (DMSO) using terminal alkynes as the 2-oxoaldehyde surrogate for the synthesis of aryl (9H-pyrido[3,4-b]indol-1-yl)methanones is described. The scope of the protocol includes the total synthesis of Fascaplysin, Eudistomins Y₁ and Y₂. The methodology is extended for preparing pyrrolo[1,2-a]-quinoxaline and indolo[1,5-a]quinoxaline derivatives. The utility of 1-aroyl-β-carbolines was demonstrated by performing palladium-catalyzed β-carboline directed ortho-C(sp2)-H functionalization of the phenyl ring with thiomethyl (SMe) group using DMSO as source and for accessing 4-aryl-canthin-6-ones.     

Facile synthesis of bicyclic 1-arylpyrazol-5-ones

In this Letter, we described a facile method for constructing fused bicyclic 1-arylpyrazol-5-one ring system. We employed various methylene-containing carboxylic acids as the substrates and proved that the pyrazolone ring closure requires activated methylene group in intermediate II. Accordingly, a series of structurally diversified, fused bicyclic 1-arylpyrazol-5-ones was prepared in moderate to high yields using the requisite substrates.     

A carbanion induced synthesis of highly congested pyrazole and imidazole containing heterocycles

An efficient approach to the synthesis of highly congested di, penta and hexacyclic pyrazoles as well as imidazole fragment containing novel heterocyclic molecule has been developed through a carbanion induced transformation of suitably functionalized 2H-pyran-2-ones, benzo[h]chromene and thiochromeno[4,3-b]pyrans. Due to the presence of fluorescence, we report their prime application metal sensor as off/on switching in ferric ions.     

Synthesis of pyrrolo[1,2-a]pyrazines and pyrazino[1,2-a]indoles by Curtius reaction in Morita-Baylis-Hillman derivatives

Synthesis of substituted pyrrolo[1,2-a]pyrazines and pyrazino[1,2-a]indoles from the Morita-Baylis-Hillman derivatives of acrylates via saponification followed by Curtius reaction is described.     

正丁胺对激光染料荧光谱影响的研究

用正丁胺作为碳源,采用射频辉光放电制备碳膜,选用激光染料R6G和聚乙二醇混合液作为蒸气源,采用单源热蒸发,在蒸发室与染料同时沉积得到混合膜,用拉曼光谱和红外光谱分析了碳膜的结构和键合方式,分析表明:碳膜中存在胺基团和氢原子.混合膜的荧光谱测量结果表明,认为正丁胺对染料荧光谱的影响是因为胺基和氢原子的存在.     

Selective synthesis of 4,5-dihydroimidazo- and imidazo[1,5-a]quinoxalines via modified Pictet–Spengler reaction

An efficient tandem approach for the selective synthesis of 4,5-dihydroimidazo[1,5-a]quinoxalines 6a–g and imidazo[1,5-a]quinoxalines 7a–h by the reaction of 2-imidazolyl anilines 4a–c with aryl aldehydes 5a–k under mild reaction conditions is described. Introduction of electron releasing alkyl groups in substrates 4a–b was found to be instrumental for the success of the reaction.     

Understanding the Diels-Alder reactivity of 1,2-azaborine analogues

The Diels-Alder reactivity of 1,2-heteroborines (H₄C₄B(H)X, X?=?NH, PH, AsH; O, S, Se) has been computationally explored by means of Density Functional Theory (DFT) calculations. The influence of the HB?=?X fragment on the reactivity of the system has been quantitatively analyzed in detail by means of the so-called Activation Strain Model (ASM) of reactivity. It is found that the interaction between these species and the dienophile is significantly stronger than that computed for their all-carbon isoelectronic counterpart, benzene. In addition, the strain energy plays a key role in the observed reactivity trends. The role of the aromaticity strength of these heteroarenes on the reactivity is also assessed.