苯基噻唑衍生物对细胞增殖抑制活性的QSAR模型

基于拓扑化学理论,原子类型电拓扑态指数(E_n)和电性距离矢量(M_k)被用于表征19种苯基噻唑衍生物的化学微环境。采用最佳变量子集回归方法,分别建立上述化合物对HT29(人结肠癌细胞系)、Hela(人宫颈癌细胞系)和Karpas299(人淋巴瘤细胞系)的体外细胞增殖抑制活性(L_i:L_t,L_e,L_a)与E_n和M_k的定量构效关系(QSAR)模型。它们的最佳三元QSAR模型的判定系数(R~2)依次为0. 865、0. 924、0. 937,逐一剔除法交叉验证相关系数(R_(cv)~2)依次为0. 679、0. 898、0. 878。经R_(cv)~2、V_(IF)、F_(IT)、A_(IC)等统计指标检验,该模型具有良好的稳健性及预测能力。结果显示—CH_3、—CH_2—、—NH—、—N=(芳环中)和—OH等分子结构单元直接影响这些化合物的抑制活性。据此提出苯基噻唑衍生物分子与生物受体之间的主要作用是疏水作用、氢键。此与文献[1]的分子对接结果基本一致。     

硫色烯并噻唑胺类衍生物对乙酰胆碱酯酶抑制活性的QSAR模型

基于化学拓扑理论,计算了20种硫色烯并噻唑胺类衍生物分子的电性距离矢量指数(m_t)。经最佳变量子集回归方法建立上述分子对电鳗乙酰胆碱酯酶体外抑制活性(pM)与m_t的最佳三元QSAR模型,其判定系数(R~2)和逐一剔除法交叉验证系数R_(cv)~2依次为0.936和0.850。通过R~2、R_(adj)~2、F、R_(cv)~2、V_(IF)、A_(IC)、F_(IT)等检验,该模型具有令人满意的稳健性和预测能力。依据模型分析硫色烯并噻唑胺类衍生物对电鳗乙酰胆碱酯酶体外抑制的可能机理,其中,氢键起到主要及正向作用,分子疏水性则起次要且为负向作用。     

酪醇酯衍生物抗氧化活性的QSAR研究

抗氧化剂是防止食品氧化、提高食品稳定性的一类食品添加剂。为了研究25种酪醇酯衍生物对Fe~(3+)-TPTZ配合物抗氧化活性Fr的定量构效关系(QSAR),按照分子的拓扑环境编程计算了上述化合物的电性距离矢量(M_d)。通过最佳子集变量回归方法,建立了抗氧化活性的三参数(M_(32)、M_(59)、M_(77))QSAR模型,传统相关系数(R~2)与逐一剔除法交叉验证相关系数(R_(cv)~2)分别为0.939、0.815。经R_(cv)~2、V_(IF)、F_(IT)、A_(IC)、F诊断,显示良好的稳健性和预测能力。根据进入模型的3个变量可知,影响酪醇酯衍生物对Fe~(3+)-TPTZ配合物抗氧化活性的主要结构基团是酚羟基、C-和-NH-等。     

用电性距离矢量研究2,5-二取代-1-杂-3,4-二唑的抑菌活性

基于拓扑理论计算了12种2,5-二取代-1-杂-3,4-二唑的电性距离矢量(Mk)。通过最佳变量子集回归建立了这12种化合物对白色念珠菌、大肠杆菌、金黄色葡萄球菌等抑菌活性(HJ:Hma、Hec和Hsa)的QSAR模型。对于Hma、Hec和Hsa等QSAR模型的相关系数(R2)和逐一剔除法交叉验证系数R2cv依次为0.977和0.957、0.877和0.761、0.897和0.809。通过R2、R2adj、R2cv、AIC、FIT等检验,上述模型具有令人满意的稳健性和预测能力。结果显示氢键、配位键、疏水性和亲水性直接影响这些化合物的生物活性。     

新型苯并噻(噁)唑酮衍生物抑制黄瓜炭疽菌活性的QSAR研究

基于原子类型电性拓扑指数(Es),建立新型苯并噻(噁)唑酮衍生物对黄瓜炭疽菌杀菌活性的定量构效关系模型。通过最佳变量子集回归建立了它们的最佳三元(E_(31)、E_(42)、E_(32))QSAR模型,其判定系数(R~2)为0.863,逐一剔除法交叉验证相关系数(R_(cv)2)为0.677,估计标准误差(R_(MS))为4.198。经R_(cv)2、V_(IF)、F_T、A_C等检验,该模型具有良好的稳健性及预测能力。结果显示,与杀菌活性相关的3个Es描述子对应结构碎片分别为硫醚键(-S-)、共轭硫醚键(a-S-a)和氟键(-F),其中-S-结构碎片与杀菌活性呈负相关关系,而a-S-a、-F则与杀菌活性呈正相关关系。     

基于人工神经网络研究芳胺喹唑啉衍生物的抗胃癌活性

基于分子电性距离矢量(M_t)表征21个芳胺喹唑啉衍生物的分子结构,并与其对人胃癌细胞的抗癌活性(pI)关联。通过最佳变量子集回归方法建立上述化合物抗胃癌活性的三参数(M_(15)、M_(18)、M_(82))定量构效关系模型。其交叉验证系数(R_(cv)~2)、非交叉验证系数(R~2)依次为0.386和0.737。通过R、R_(cv)~2、V_(IF)等检验,模型具有较好的相关性、稳健性和预测能力。结果显示,-CH_2-、-CH、-O-、-S-和-NH-等分子结构单元直接影响这些化合物的抗胃癌活性。将M_(15)、M_(18)、M_(82)作为人工神经网络的输入层结点,采用3∶3∶1的网络结构,利用BP算法获得了令人满意的pI模型,其R~2和标准偏差S_D分别为0.992和0.080,表明pI与三参数呈现优异的非线性关系。     

新型三唑并噻二唑衍生物对PTP1B的抑制活性的比较分子力场分析研究

基于比较分子力场分析(CoMFA)方法建立21种新型三唑并噻二唑衍生物对蛋白酪氨酸磷酸酯酶1B(PTP1B)的抑制活性(pM_P)的三维定量构效关系(3D-QSAR)。训练集中17个化合物用于建立预测模型,测试集5个化合物作为模型验证。已建立的CoMFA模型的交叉验证系数(R_(cv)~2)、非交叉验证系数(R~2)分别为0. 432、0. 975,说明所建模型具有较强的稳定性和良好的预测能力。该模型中立体场、静电场贡献率依次为59. 2%、40. 8%,表明影响抑制活性(pM_P)的主要因素是取代基的空间位阻及疏水性,其次是取代基的氢键及配位作用。基于此研究结果,设计了3个具有较高抑制活性的新化合物,有待医学实验验证。     

基于电性距离矢量研究多氯联苯生物降解速率常数

通过多元线性回归和人工神经网络方法建立66种多氯联苯生物降解速率常数(K1)的定量构效关系(QSAR). 基于电性距离矢量(Mk),建立了lnK1的最佳三参数(M91、M25和M15)线性模型,其传统相关系数(R2)、交叉验证系数(Rcv2)分别为0.833、0.809。经R2、Rcv2、VIF、FIT、AIC检验,所建模型具有较强的稳定性和良好的预测能力. 将M91、M25、M15作为人工神经网络的输入层结点,采用3:10:1的网络结构,利用BP算法获得了一个令人满意的lnK1模型,训练集、验证集、测试集和总体的R2依次为0.991、0.995、0.997和 0.993。与多元线性回归模型相比,非线性lnK1-BP模型具有更好的预测能力。这两种回归方法相辅相成,线性回归方法为神经网络模型提供了具体的物理解释,而神经网络方法为线性模型提供了更准确的预测结果。     

吡啶并嘧啶衍生物抗乳腺癌活性的CoMFA模型

基于比较分子力场分析(CoMFA)方法建立25种吡啶并嘧啶衍生物抗乳腺癌活性(pIC)的三维定量构效关系(3D-QSAR)。训练集中20个化合物用于建立预测模型,测试集6个化合物(含模板分子)作为模型验证。已建立的CoMFA模型的交叉验证系数(R_(cv)~2)、非交叉验证系数(R~2)分别为0.467、0.891,说明所建模型具有较强的稳定性和良好的预测能力。该模型中立体场、静电场对pIC的贡献率依次为40.8%、59.2%。基于此研究结果,设计了4个具有较高抗乳腺癌活性的新化合物,有待医学实验验证。     

酚类化合物对梨形四膜虫毒性的构效关系解析

应用密度泛函理论(DFT)在杂化泛函B3LYP和基组6-311G**水平上对81个标题化合物进行结构优化,计算获得化合物的量化和理化参数,采用最佳变量子集回归构建化合物对梨形四膜虫的毒性与描述符之间的定量结构-活性关系(QSAR)模型。所建最佳四元QSAR模型的复相关系数R~2为0.951,去一法(LOO)交互检验复相关系数R~2_(cv)为0.938,用27个验证集样本进行外部预测,所得外部验证集交互检验系数Q_(ext)~2为0.876,模型具有良好的统计学意义及合理、可信的预报能力,影响毒性的主要因素有正辛醇-水分配系数(log P)、分子最低空轨道能(E_(LUMO))、苯环上所有碳原子电荷之和(Q)和4号位取代基电荷(Q_(R4)),研究结果为理解该类化合物的毒性作用机理和设计合成低毒性的新化合物提供理论参考。     

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.     

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.     

Cu0-catalysed 1,3-dipolar cycloadditions of α-amino acid derived N,N-cyclic azomethine imines to ynones

A series of 20 CuAIAC reactions between eight 4-acylamino substituted pyrazolidine-3-one-1-azomethine imines and four terminal ynones were performed using Cu⁰ as catalyst. The corresponding fluorescent cycloadducts were obtained in very high yields upon simple workup. Thus, Cu-metal turned out to be a better catalyst than Cu^I in terms of yield and ease of isolation. Availability of azomethine imines, mild reaction conditions, and simple workup enable a “click” access to libraries of densely substituted 2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-ones. Reactivity of differently substituted dipoles was evaluated experimentally and by quantum chemical methods (DFT).     

Synthesis and antioxidative/anti-inflammatory activity of novel fullerene–polyamine conjugates

(E)-4-(Fullerenopyrrolidin-1-yl)-3-methylbut-2-enoic acid and its corresponding succinimidyl ester, readily obtained through Prato-type modification of C₆₀, were used for the selective N-acylation of polyamines. The thus obtained conjugates were evaluated for their antioxidative and anti-inflammatory activity and their cytotoxicity was determined. Members of this family of compounds showed interesting anti-lipid peroxidation, anti-lipoxygenase and anti-inflammatory activity and comparable cytocompatibility to spermidine.