唇形科香茶菜属二萜类化合物分布规律

香茶菜属（Isodon）由于富含二萜类化合物（Diterpenoids）而具有较高的药用价值,本研究根据其所含二萜的骨架和氧化状态,对该类化合物在香茶菜属植物中的分布规律进行研究。UPGMA聚类分析结果显示：含二环和三环二萜为主的植物种类聚在一支上,含四环二萜为主的植物种类聚在另一支上。进一步将二萜分为二环、三环、四环三大类绘制到分子系统树上结果显示：三环二萜主要分布在较原始的类群中,如：线纹香茶菜（I.lophanthoides）和小花线纹香茶菜（I.lophanthoides var. micranthus）;而四环二萜主要分布在较进化的类群中,如：旱生香茶菜（I.xerophilus）和腺花香茶菜（I.adenanthus）。本研究通过对二萜类化合物与香茶菜属系统发育之间存在的联系进行探讨,有助于对香茶菜属植物中的二萜类化合物活性成分进行筛选与研发。     

旱生香茶菜中三个新的对映-贝壳杉烷型二萜

从旱生香茶菜（ｌｓｏｄｏｎ ｘｅｒｏｐｈｉｌｕｓ）叶中分离得到３个新的对映－贝壳杉烷型二萜,旱生香茶菜素Ｇ,Ｈ和Ｌ０通过波谱方法鉴定它们的结构。     

牛尾草中一新的对映-贝壳杉烷型二萜

从牛尾草[Isodon ternifolius(D.Don)Kudo]的地上部分分离得到一个新的对映－贝壳杉烷型二萜,命名为牛尾草素H（1）,通过波谱方法鉴定了它的结构。此外,还分离得到5个已知的对映－贝壳杉烷型二萜化合物：香茶菜醛（2）,长管香茶菜素A,E和G（3－5）,开展香茶菜素E（6）,以及木樨草素（7）,芹菜素（8）,α－香树脂醇（9）,乌索酸（10）和2α－羟基乌索酸（11）。     

大萼香茶菜辛素的化学结构

大萼香茶菜（Ｒａｂｄｏｓｉａｍａｃｒｏｃａｌｙｘ（Ｄｕｎｎ）Ｈａｒａ）系唇形科（Ｌａｂｉａｔａｅ）香茶菜属植物,民间用于治疗肿瘤等疾病。我们曾报道了它的具有抗菌和细胞毒活性的７个新二萜成分：大萼香茶菜甲素、乙素、丙素、丁素、戊素、己素和庚素［１—５］。进一步研究又分得３个结晶单体。其中,结晶Ⅰ鉴定为新化合物,命名为大萼香茶菜辛素;结晶Ⅱ和Ⅲ鉴定为已知化合物ｏｒｉｄｏｎｉｎ和ｅｎｍｅｎｏｌ。大萼香茶菜辛素（Ⅰ）　Ｃ２２Ｈ３４Ｏ８,ｍｐ２３０℃,［α］２２Ｄ－４１．８（ｃ０．２２,ＭｅＯＨ）。ＩＲ不…     

疏花毛萼香茶菜中一新的对映-贝壳杉烷型二萜

从疏花毛萼香茶菜（Ｉｓｏｄｏｎ ｅｒｉｏｃａｌｙｘ ｖａｒ．ｌａｘｉｆｌｏｒａ）叶中分离得到一新的对映－贝壳杉烷型二萜,命名为疏花丁素（１）,通过波谱方法鉴定了它的结构。此外,还分离得到６个已知对映－贝壳杉烷型二萜化合物：疏花甲素（２）,毛萼晶Ａ－Ｃ（３－５）和Ｑ（６）,毛萼乙素（７）,以及ｃｉｒｓｉｍａｒｉｔｉｎ（８）和２α－羟基乌索酸（９）。     

大萼香茶菜庚素的化学结构

从大萼香茶菜（Ｒａｂｄｏｓｉａ ｍ ａｃｒｏｃａｌｙｘ （Ｄｕｎｎ） Ｈａｒａ）叶的乙醇提取物中又分离到３ 个二萜成分（结晶Ⅰ、Ⅱ、Ⅲ）,通过ＩＲ、ＭＳ、１Ｈ－１Ｈ ＣＯＳＹ、１３Ｃ－１Ｈ ＣＯＳＹ和ＮＯＥ等光谱分析及衍生物的制备,确定结晶Ⅰ的结构为ｅｎｔ－７β－２０－ｅｐｏｘｙ－６α, ７α,１４α,１５α,１６α－ｐｅｎｔａｈｙｄｒｏｋａｕｒａｎｅ－１７－ａｃ－ｅｔａｔｅ,为新的二萜化合物,命名为大萼香茶菜庚素;结晶Ⅱ和Ⅲ为已知化合物ｒａｂｄｏｐｈｙｌｌｉｎ Ｈ和ｐｏｎｉｃｉｄｉｎ。     

Xerophinoid C, 旱生香茶菜中一个新的二萜糖苷化合物

从旱生香茶菜(Isodon xeropene)枝叶的乙酸乙酯部位分离到一个新的松香烷型二萜苷类化合物。通过现代波谱技术,确定其结构为16,18-二羟基-7,15(17)-二烯-对映-松香烷-3α-O-β-D-吡喃葡萄糖苷。     

香茶菜属二萜化合物的高效液相色谱分析

本文报道了香茶菜属四种类型八个二萜化合物的HPLC定性分析,测定了它们的保留时间tR,容量因子K′,分离系数α,分离度Rs。实验结果表明,此法对香茶菜属植物的有效成份分析及其二萜化合物系统研究提供了前导性筛选手段。方法简便、微量、快速。     

细锥香茶菜化学成分的研究

从细锥香茶菜（Ｒａｂｄｏｓｉａｃｏｅｔｓａ（Ｂｕｃｈ．Ｈａｍ．ｅｘＤ．Ｄｏｎ）Ｈａｒａ）的叶中分离到９个化合物,通过波谱分析阐明其结构,其中１个为新的二萜酸———７α,１２α,１４β三羟基１５酮对映贝壳杉１８羧酸,命名为细锥香茶菜酸（ｃｏｅｔｓａｎｏｉｃａｃｉｄ）。另外８个化合物分别为二氢昆明香茶菜丙素、昆明香茶菜丙素、白柔毛香茶菜甲素、大萼香茶菜丙素、４羟基Δ８,９（Ｚ）鞘氨醇２′羟基正二十（二十一二十六）碳酸酰胺、乌苏酸、２α,３β二羟基乌苏酸和胡萝卜甙。神经酰胺类化合物系首次从该属植物中分离得到。     

7—乙酰基—鲁山冬凌草甲素,紫萼香菜菜甲素及其有关二萜化合物…

从无毛狭叶香茶菜（Ｉｓｏｄｏｎａｎｇｕｓｔｉｆｏｌｉｕｓｖａｒ．ｇｌａｂｒｅｓｃｅｎｓＨ．Ｗ．Ｌｉ）中分离得到４个已知二萜化合物;７－乙酰基－鲁山冬凌草甲素,鲁山冬凌草甲素,乙素和紫萼香茶菜甲素,经二维核磁共振波谱（２Ｄ－ＮＭＲ）解析表明,它们的结构分别由先前报道的５、６、７和８应修订为结构１,２,３和４。     

3D QSAR Studies on Cytotoxin Actives of Ent- kauranoids from Isodon xerophilus ( Labiatae) by CoMFA

It is our aim to establish the CoMFA models of the en-t kauranoids from Isodon x erophilus and guide the design for new ant-i cancer drugs. The advanced 3D-QSAR ( quantitative structure- activity relationship) method CoMFA ( comparative molecular field analysis) was used to study the QSAR relationship of en-t kauranoids with cytotoxicity activity in vitro and led to four CoMFA models. The results of CoMFA models reveal the 3D- relationship between bioactivities and structures of these en-t kauranoids, and will be helpful to further design and find new drugs for higher ant-i cancer activities.     

A comparative molecular field and comparative molecular similarity indices analyses (CoMFA and CoMSIA) of N-phenyl-N'-(2-chloroethyl)ureas targeting the colchicine-binding site as anticancer agents

To decipher the mechanism underlying the covalent binding of N-phenyl-N'-(2-chloroethyl)ureas (CEU) to the colchicine-binding site on beta(II)-tubulin and to design new and selective antimitotic drugs, we developed 3D quantitative structure-activity relationships (3D-QSAR) models using CoMFA and CoMSIA analyses. The present study correlates the cell growth inhibition activities of 56 structurally related CEU derivatives to several physicochemical parameters representing steric, electrostatic, and hydrophobic fields. Both CoMFA and CoMSIA models using two different optimum numbers of components (ONC) 10 and 4, respectively, gave good internal predictions and their cross-validated r2 values were between 0.639 and 0.743. These comprehensive CoMFA and CoMSIA models are useful in understanding the structure-activity relationships of CEU. The two models were compared to the X-ray crystal structure of the complex of tubulin-colchicine and analyzed for similarities between the two modes of analysis. These models will inspire the design of new CEU derivatives with enhanced inhibition of tumor cell growth and targeting specificity of beta(II)-tubulin and the cytoskeleton.     

3D-QSAR design of novel antiepileptic sulfamides

A three-dimensional quantitative structure-activity relationship method, the comparative molecular field analysis (CoMFA), was applied to design new anticonvulsant symmetric sulfamides. The training set (27 structures) was comprised by traditional and new-generation anticonvulsant (AC) ligands that exhibit a potent activity in MES test. Physicochemical determinants of binding, such as steric and electrostatic properties, were mapped onto the molecular structures of the set, in order to interpret graphically the CoMFA results in terms of field contribution maps. The 3D-QSAR models demonstrate a good ability to predict the activity of the designed compounds (r(2)=0.967, q(2)=0.756).     

CoMFA and CoMSIA 3D QSAR analysis on N1-arylsulfonylindole compounds as 5-HT6 antagonists

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series of N(1)-arylsulfonylindole compounds as 5-HT(6) antagonists. Evaluation of 20 compounds served to establish the models. The lowest energy conformer of compound 1 obtained from random search was used as template for alignment. The best predictions were obtained with CoMFA standard model (q2 = 0.643, r2 = 0.939 ) and with CoMSIA combined steric, electrostatic, hydrophobic, and hydrogen bond acceptor fields (q2 = 0.584, r2 = 0.902 ). Both the models were validated by an external test set of eight compounds giving satisfactory predictive r2 values of 0.604 and 0.654, respectively. The information obtained from CoMFA and CoMSIA 3D contour maps can be used for further design of specific 5-HT(6) antagonists.     

Molecular docking and 3-D-QSAR studies on the possible antimalarial mechanism of artemisinin analogues

Artemisinin (Qinghaosu) is a natural constituent found in Artemisia annua L, which is an effective drug against chloroquine-resistant Plasmodium falciparum strains and cerebral malaria. The antimalarial activities of artemisinin and its analogues appear to be mediated by the interactions of the drugs with hemin. In order to understand the antimalarial mechanism and the relationship between the physicochemical properties and the antimalarial activities of artemisinin analogues, we performed molecular docking simulations to probe the interactions of these analogues with hemin, and then performed three-dimensional quantitative structure-activity relationship (3-D-QSAR) studies on the basis of the docking models employing comparative molecular force fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Molecular docking simulations generated probable 'bioactive' conformations of artemisinin analogues and provided a new insight into the antimalarial mechanism. The subsequent partial least squares (PLS) analysis indicates that the calculate binding energies correlate well with the experimental activity values. The CoMFA and CoMSIA models based on the bioactive conformations proved to have good predictive ability and in turn match well with the docking result, which further testified the reliability of the docking model. Combining these results, that is molecular docking and 3-D-QSAR, together, the binding model and activity of new synthesized artemisinin derivatives were well explained.     

Molecular modeling of some 1H-benzimidazole derivatives with biological activity against Entamoeba histolytica: a comparative molecular field analysis study

Comparative molecular field analysis (CoMFA) was performed on a set of 1H-benzimidazole derivatives. Molecular modeling and 3D-QSAR were employed to determine the tautomeric form that would probably fit a target receptor in Entamoeba histolytica. CoMFA results suggest that the antiamoebic activity is favored with steric bulk at position 5 of the benzimidazole ring and low electron density on the group at position 2. To the best of our knowledge this is the first 3D-QSAR study performed for benzimidazoles as antiamoebic agents. The CoMFA models derived will be very valuable to design new and more potent compounds against E. histolytica.     

Molecular docking and 3D-QSAR study on 4-(1H-indazol-4-yl) phenylamino and aminopyrazolopyridine urea derivatives as kinase insert domain receptor (KDR) inhibitors

Vascular endothselial growth factor (VEGF) and its receptor tyrosine kinase VEGFR-2 or kinase insert domain receptor (KDR) have been identified as new promising targets for the design of novel anticancer agents. It is reported that 4-(1H-indazol-4-yl)phenylamino and aminopyrazolopyridine urea derivatives exhibit potent inhibitory activities toward KDR. To investigate how their chemical structures relate to the inhibitory activities and to identify the key structural elements that are required in the rational design of potential drug candidates of this class, molecular docking simulations and three-dimensional quantitative structure-activity relationship (3D-QSAR) methods were performed on 78 4-(1H-indazol-4-yl)phenylamino and aminopyrazolopyridine urea derivatives as KDR inhibitors. Surflex-dock was used to determine the probable binding conformations of all the compounds at the active site of KDR. As a result, multiple hydrophobic and hydrogen-bonding interactions were found to be two predominant factors that may be used to modulate the inhibitory activities. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) 3D-QSAR models were developed based on the docking conformations. The CoMFA model produced statistically significant results with the cross-validated correlation coefficient q² of 0.504 and the non-cross-validated correlation coefficient r² of 0.913. The best CoMSIA model was obtained from the combination of steric, electrostatic and hydrophobic fields. Its q² and r² being 0.595 and 0.947, respectively, indicated that it had higher predictive ability than the CoMFA model. The predictive abilities of the two models were further validated by 14 test compounds, giving the predicted correction coefficients r_pred² of 0.727 for CoMFA and 0.624 for CoMSIA, respectively. In addition, the CoMFA and CoMSIA models were used to guide the design of a series of new inhibitors of this class with predicted excellent activities. Thus, these models may be used as an efficient tool to predict the inhibitory activities and to guide the future rational design of 4-(1H-indazol-4-yl)phenylamino and aminopyrazolopyridine urea derivatives-based novel KDR inhibitors with potent activities.     

Comparative quantitative structure-activity study of radical scavengers

Classic and three-dimensional (3-D) QSAR analyses of 13 radical scavengers (1-13) were performed to derive two classic, two Apex-3-D and one comparative field analysis (CoMFA) models. Two classical models with predictive cross-validated r2 (Q2) over 0.96 indicated that the activity was attributed to the electronic COH and ELUMO, steric molar refractivity (MR) and lipophilic log P. Three-dimensional quantitative structure-activity relationship (3-D-QSAR) studies were performed by 3-D pharmacophore generation (Apex-3-D) and CoMFA techniques. For Apex-3-D studies, two best models with high Q2 (0.94 and 0.97) were yielded. Structural properties contributing to the activity were not only lipophilic but also the optimum steric property and geometry of side-chain composition. For CoMFA studies, the sp3 C(+1) probe provided the best Q2 of 0.79 with steric and electrostatic contributions of 42.3 and 57.7%, respectively. The activity of four new compounds (14-17) not included in the derivation were predicted with these models. Although the derived models were from limited data, the statistic relation was predictive. The linear correlations between the experimental IC50 values and the predicted values from classical and Apex-3-D models were found to be high and significant. The predicted activity of 17 from CoMFA was much lower than the experimental value; this deviation occurred according to the missing of hydrophobic field in standard CoMFA study. In vitro and ex vivo antilipid peroxidation in mouse brain and ESR studies of 14-17 were investigated for the radical-scavenging ability. The difference between the in vitro results, antilipid peroxidation and electron spin resonance (ESR) and ex vivo results in coumarin series was found. Thus, other properties for good bioavailability besides log P should also be taken into consideration.     

Molecular docking and 3D-QSAR studies of Yersinia protein tyrosine phosphatase YopH inhibitors

Three-dimensional quantitative structure-activity relationship (QSAR) studies were conducted on two classes of recently explored compounds with known YopH inhibitory activities. Docking studies were employed to position the inhibitors into the YopH active site to determine the probable binding conformation. Good correlations between the predicated binding free energies and the inhibitory activities were found for two subsets of phosphate mimetics: alpha-ketocarboxylic acid and squaric acid (R2=0.70 and 0.68, respectively). The docking results also provided a reliable conformational alignment scheme for 3D-QSAR modeling. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed based on the docking conformations, giving q2 of 0.734 and 0.754 for CoMFA and CoMSIA models, respectively. The 3D-QSAR models were significantly improved after removal of an outlier (q2=0.829 for CoMFA and q2=0.837 for CoMSIA). The predictive ability of the models was validated using a set of compounds that were not included in the training set. Mapping the 3D-QSAR models to the active site of YopH provides new insight into the protein-inhibitor interactions for this enzyme. These results should be applicable to the prediction of the activities of new YopH inhibitors, as well as providing structural implications for designing potent and selective YopH inhibitors as antiplague agents.