A 3D‐QSAR Study of Celebrex‐Based Pdk1 Inhibitors Using Comfa Method

A 3D‐QSAR study of celebrex‐based compounds of PDK1 inhibitors using comparative molecular field analysis (CoMFA) was carried out. The structures of the compounds were obtained using quantum chemistry calculation. CoMFA calculations for a number of grouped subsets of compounds gave q² values of correlation in the range from 0 to 0.8. The low q² values should be mainly due to the narrow span of biological activity. Calculations for several subsets of 11–13 compounds gave high q² values, with 0.5–0.8. Factors affecting the results of the calculations are discussed. Calculated results with high q² values suggest that further chemical modifications of the compounds could lead to enhanced activity and could be an aid in the design of celebrex‐based cancer drugs.     

Docking Study and Three‐Dimensional Quantitative Structure‐Activity Relationship (3D‐QSAR) Analyses and Novel Molecular Design of a Series of 4‐Aminoquinazolines as Inhibitors of Aurora B Kinase

The Aurora proteins are critical regulators of major mitotic events and attractive targets for anticancer therapy. 3D‐QSAR studies based on molecular docking were performed on a dataset of 40 4‐aminoquinazolines compounds. The CoMSIA model produced significantly better results than CoMFA model, with q²=0.652 and r²=0.991. The contours analysis provides useful information about the structural requirements for 4‐aminoquinazolines for inhibiting Aurora B. Scaffold hopping method was used to generate new structures based on the maximum common substructure of the training and test set compounds. The ADMET property, binding affinity and inhibitory activity of the new designed compounds were predicted, respectively. Finally 16 compounds were identified as the novel inhibitors for Aurora B kinase.     

Norbornane Mimics of Distorted β‐D‐Glucopyranosides – Inhibitors of β‐D‐Glucopyranosidases?

The racemic gluco‐configured norbornanes 4 and 16 were prepared and tested as inhibitors of β‐glucosidases. The known alcohol 5 was deprotected to provide the triol 6 . Silylation (→ 7 ), monobenzoylation (→ 8 / 9 ), and oxidation provided the regioisomeric ketones 10 and 11 . Reduction of 10 gave the desired endo‐alcohol 13 , albeit in low yield, while reduction of the isomeric ketone 11 provided mostly the altro‐configured endo‐alcohol 12 . The alcohol 13 was desilylated to 14 . Debenzoylation to 15 followed by hydrogenolytic deprotection gave the amino triol 4 that was reductively aminated to the benzylamine 16 . The amino triols 4 and 16 proved weak inhibitors of the β‐glucosidase from Caldocellum saccharolyticum ( 4 : IC₅₀ = 5.6 mm; 16 : IC₅₀ = 3.3 mm) and from sweet almonds ( 16 : IC₅₀ = 5.5 mm) . A comparison of 4 with the manno‐configured norbornane 3 shows that 3 is a better inhibitor of snail β‐mannosidase than 4 is of β‐glucosidases, in keeping with earlier results suggesting that these β‐glycosidases enforce a different conformational itinerary.     

马来酰胺类糖原合成酶激酶-3β抑制剂的分子对接和三维定量构效关系

通过分子对接和三维定量构效关系(3D-QSAR)两种方法来确定两类马来酰胺类的糖原合成酶激酶-3β(GSK-3β)抑制剂的结合方式. 首先, 用分子对接确定抑制剂与GSK-3β结合模式及其相互作用; 然后用比较分子力场分析法(CoMFA)与比较分子相似性指数分析法(CoMSIA)对48个化合物做三维定量构效关系的分析. 两种方法得出的交互验证回归系数分别为0.669(CoMFA)和0.683(CoMSIA), 证明该模型具有很好的统计相关性, 同时也说明该模型具有较高的预测能力.根据该模型提供的信息, 设计出9个预测活性较好的分子.     

A New Route to N‐Aryl 2‐Alkenamides,N‐Allyl N‐Aryl 2‐Alkenamides,and N‐Aryl α,β‐Unsaturated γ‐Lactams from N‐Aryl 3‐(Phenylsulfonyl)propanamides

A series of N‐aryl 2‐alkenamides were produced efficiently by treating N‐aryl 3‐(phenylsulfonyl)‐propanamides with potassium tert‐butoxide in THF at 0°C. With out isolation, it was further treated with an additional equivalent of potassium tert‐butoxide and allyl bromide to give N‐allyl N‐aryl 2‐alkenamides in one pot in good yields. Followed by a ring‐closing metathesis reaction, these N‐allyl N‐aryl 2‐alkenamides were respectively converted into corresponding N‐aryl α,β‐unsaturated γ‐lactams in moderate yields.     

3D－QSAR Study on Diindolylmethane and Its Analogues with Comparative Molecular Field Analysis(CoMFA)

Comparative molecular field analysis (CoMFA),a three dimensional quantitative structure-activity relationship (3D-QSAR) method was applied to a series of diindolylmethane(DIM) analogs to study the relationship between their structure and their induction of CYP 1A1-associated ethoxyresorufin-O-deethylase(EROD) activity.A DISCO model of pharmacophore was derved to guide the superposition of the compounds.The coefficient of cross-validation (q^2) and non cross-validation(r^2) for the model established by the study are 0.827 and 0.988 respectively,the value of variance ratio (F) is 103.53 and standard error estimate (SEE)is 0.044.These values indicate that the CoMFA model derived is significant and might have a good prediction for the catalytic activity of DIM compounds.As a consequence,the predicted activity values of new designed compounds were all higher than that of the reported value.     

Molecular Docking and 3D-QSAR Research of Biphenyl Carboxylic Acid MMP-3 Inhibitors

The molecular docking by LigandFit docking of Discovery Studios 2.5 was employed to the three-dimensional quantitative structure-activity relationship(3D-QSAR) studies of biphenyl carboxylic acid MMP3 inhibitors.A significant correlation coefficient was obtained between dock scores and biological activities.Based on the optimal docking conformations,3D-HoVAIF was employed to the QSAR studies of 51 biphenyl carboxylic acid MMP-3 inhibitors.R2 and Q_CV2(leave-one-out,LOO) of the optimal 3D-HoVAIF-PLS model were 0.873 and 0.841 respectively.The conclusions obtained from the PLS analysis were in agreement with the docking results.     

Studies on the Mass Spectra of N‐Aryl α,β‐Unsaturated γ‐Lactams

The mass spectra of a series of N‐aryl α,β‐unsaturated γ‐lactams were studied. Besides the molecular ion, the three characteristic fragments such as [M⁺‐29], [M⁺‐55], and [M⁺‐82] were commonly found in a series of N‐Aryl α,β‐unsaturated γ‐lactams in EI/MS. Further more the mechanism for the interpretation of these fragments is also de scribed.     

Molecular Modeling Studies of Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors Combining Molecular Docking and 3D-QSAR Methods

The vascular endothelial growth factor (VEGF) and its receptor tyrosine kinases VEGFR-2 or kinase insertdomain receptor (KDR) have emerged as attractive targets for the design of novel anticancer agents. In the present work, molecular docking method combined with three dimensional quantitative structure-activity relationships (comparative molecular field analysis (CoMFA) and comparative molecular similarity indice analysis (CoMSIA)) to analyze the possible interactions between KDR and those derivatives which acted as selective inhibitors. The CoMFA and CoMSIA models gave a cross-validated coefficient Q2 of 0.713 and 0.549, non-cross-validated R2 values of 0.974 and 0.878, and predicted R2 values of 0.966 and 0.823, respectively. The 3D contour maps generated by the CoMFA and CoMSIA models were used to identify the key structural requirements responsible for the biological activity. The information obtained from 3D-QSAR and docking studies were very helpful to design novel selective inhibitors of KDR with desired activity and good chemical property.     

Ligand and structure‐based models for the prediction of ligand‐receptor affinities and virtual screenings: Development and application to the β2‐adrenergic receptor

In this study, we evaluated the applicability of ligand‐based and structure‐based models to quantitative affinity predictions and virtual screenings for ligands of the β₂‐adrenergic receptor, a G protein‐coupled receptor (GPCR). We also devised and evaluated a number of consensus models obtained through partial least square regressions, to combine the strengths of the individual components. In all cases, the bioactive conformation of each ligand was derived from molecular docking at the crystal structure of the receptor. We identified the most effective models applicable to the different scenarios, in the presence or in the absence of a training set. For ranking the affinity of closely related analogs when a training set is available, a ligand‐based consensus model (LI‐CM) seems to be the best choice, while the structure‐based MM‐GBSA score seems the best alternative in the absence of a training set. For virtual screening purposes, the structure‐based MM‐GBSA score was found to be the method of choice. Consensus models consistently had performances superior or close to those of the best individual components, and were endowed with a significantly increased robustness. Given multiple models with no a priori knowledge of their predictive capabilities, constructing a consensus model ensures results very close to those that the best model alone would have yielded. © 2009 Wiley Periodicals, Inc. J Comput Chem 2010     

Chemoselective Synthesis of β‐Amino Ester or β‐Lactam via Sonochemical Reformatsky Reaction

A series of β‐amino esters were synthesized by the reaction of N‐tosyl aldimine or N‐hydroxy aldimine with bromoacetate by sonochemical Reformatsky reaction. The β‐N‐hydroxyamino ester was obtained and the formed sensitive hydroxylamino functionality was resistant under the reaction condition. The β‐lactam also was synthesized by the reaction of N‐p‐methoxy aldimine as reacting substrate under this sonochemical Reformatsky reaction condition.     

Palladium‐catalyzed carbonylative cyclization of β‐bromo‐α,β‐unsaturated carboxylic acids with primary amines leading to N‐alkylmaleimides

Cyclic β‐bromo‐α,β‐unsaturated carboxylic acids are carbonylatively cyclized with primary amines under carbon monoxide pressure in MeCN in the presence of a catalytic amount of PdCl₂(PPh₃)₂ to give N‐alkylmaleimides. Copyright © 2012 John Wiley & Sons, Ltd.     

Expression,Purification and Characterization of a Bifunctional α‐L‐Arabinofuranosidase/β‐D‐Xylosidase from Trichoderma Koningii G‐39

A gene of α‐L ‐arabinofuranosidase (Abf) from Trichoderma koningii G‐39 was successfully expressed in Pichia pastoris. The recombinant enzyme was purified to > 90% homogeneity by a cation‐exchanged chromatography. The purified enzyme exhibits both α‐L ‐arabinofuranosidase and β‐D ‐xylosidase (Xyl) activities with p‐nitrophenyl‐α‐L ‐arabionfuranoside (pNPAF) and 2,4‐dinitrophenyl‐β‐D ‐xylopyanoside (2,4‐DNPX) as substrate, respectively. The stability and the catalytic feature of the bifunctional enzyme were characterized. The enzyme was stable for at least 2 h at pH values between 2 and 8.3 at room temperature when assayed for Abf and Xyl activities. Enzyme activity decreased dramatically when the pH exceeded 9.5 or dropped below 1.5. The enzyme lost 35% of Abf activity after incubation at 55 °C for 2 h, but retained 95% of Xyl activity, with 2,4‐DNXP as substrate, under the same conditions. Further investigation of the active site topology of both enzymatic functions was performed with the inhibition study of enzyme activities. The results revealed that methyl‐α‐L ‐arabinofuranoside inhibition is noncompetitive towards 2,4‐DNPX as substrate but competitive towards pNPAF. Based on the thermal stability and the inhibition studies, we suggest that the enzymatic reactions of Abf and Xyl are performed at distinct catalytic sites. The recombinant enzyme possesses both the retaining transarabinofuranosyl and transxylopyranosyl activities, indicating both enzymatic reactions proceed through a two‐step, double displacement mechanism.     

Palladium‐catalyzed cyclization of β‐bromo‐α,β‐unsaturated ketones with arylhydrazines leading to 3‐substituted 1‐aryl‐1 H‐pyrazoles

β‐Bromo‐α,β‐unsaturated ketones are condensed with arylhydrazines to form hydrazones, which are in situ intramolecularly cyclized into 3‐substituted 1‐aryl‐1 H‐pyrazoles under a catalytic system of Pd(OAc)₂/1,3‐bis(diphenylhosphino)propane (dppp)/NaO^tBu. Copyright © 2012 John Wiley & Sons, Ltd.     

Synthesis and Biological Evaluation of Andrographolide C‐Glycoside Derivatives as α‐Glycosidase Inhibitors

A series of new andrographolide C‐glycoside derivatives were synthesized by a facile route. The new compounds showed higher potency than the parent andrographolide evaluated as α‐glycosidase inhibitors in the preliminary study.     

β‐cyclodextrin‐capped palladium nanoparticle‐catalyzed ligand‐free Suzuki and Heck couplings in low‐melting β‐cyclodextrin/NMU mixtures

Low‐melting β‐cyclodextrin/N‐methylurea (NMU) mixture, an efficient catalytic system for ligand‐free Suzuki and Heck couplings in the presence of fresh native β‐CD‐capped Pd⁰ nanoparticles, has been successfully reported. This natural and convenient system can be performed in air and could afford the corresponding cross‐coupled products in good to excellent isolated yields after a simple workup under every low Pd loading (0.05 mol%). Remarkably, the catalytic system can be recycled and reused without loss of catalytic activity. Copyright © 2014 John Wiley & Sons, Ltd.     

Synthesis of β‐Haloketones by β‐Addition Reactions of α,β‐Unsaturated Ketones with BX3 (X = Br,Cl) as Halide Source

A series of β‐bromoketones and β‐chloroketones were synthesized by the addition reactions of α,β‐unsaturated ketones under BX₃ (X = Br, Cl) and ethylene glycol reaction system. The α,β‐unsaturated ester also was successfully converted to its corresponding β‐bromoester under the reaction condition.