紫杉醇构效关系及其类似物的研究开发进展

概括了90年代以来国外关于紫杉醇衍生物的研制进展并简介了其新药开发的情况。     

线粒体通透性转移孔与青蒿素抗疟机制研究

目的:为增进对青蒿素作用机制的了解,探讨参与调节线粒体体积的线粒体通透性转移孔在青蒿素抗疟机制中的作用.方法:分离线粒体,采用分光光度法检测青蒿素能否直接作用于离体线粒体导致线粒体体积变化;利用等效应图分析线粒体通透性转移孔抑制剂是否拮抗青蒿素的抗疟作用.结果:青蒿素可以直接导致离体疟原虫线粒体肿胀,而不会影响鼠肝线粒体体积;两种不同的线粒体通透性转移孔抑制剂均可拮抗青蒿素的抑疟效果.结论:青蒿素可以直接作用于离体疟原虫线粒体导致线粒体肿胀,且青蒿素导致线粒体肿胀的物种选择性与细胞毒性的物种选择性一致.此外,利用抑制剂阻断线粒体通透性转移孔的开放可以拮抗青蒿素的抗疟效果,证明线粒体通透性转移孔在青蒿素抗疟过程中起重要作用.     

一株具有抗疟活性的金鸡纳树内生真菌的研究

为筛选具抗疟疾活性的的内生真菌,采用平板分离法对海南金鸡那树内生真菌进行分离纯化。利用"4日抑制疟疾"测试内生真菌发酵液的抗疟活性,采用TLC、HPLC等分析技术对内生菌发酵液等成分进行分析。从金鸡那树叶片分离到31种内生真菌,通过筛选找到了1株具有抗疟疾活性的产奎宁或奎宁类似物的内生真菌。从金鸡那树叶片中分离得到1株产奎宁的结实串孢霉属内生真菌,为奎宁的资源开发开辟了新途径。     

蜂毒素基因的突变与表达及其构效关系研究

为获得保留有抗菌活性而降低溶血活性作用的蜂毒素,对其分子结构进行了改造.其中一条序列缺失Lys-7,另一条缺失Leu-9.用PCR技术获得两条新的蜂毒素基因,将其克隆到酵母表达载体pPICZα-A,获得重组质粒pPICZα-A-Mel1和pPICZα-A-Mel2.将2个重组质粒分别转化毕赤酵母菌GS115.筛选获得重组酵母菌.对重组酵母菌培养条件进行优化,在YEPD中含甘油2%,pH为7,重组酵母菌培养48h后,0.5%的甲醇诱导72h,表达目的蛋白通过Tricion-SDS-PAGE确定分子质量为5.4kD.杀菌效价分别达0.947、1.085.结果表明两条蜂毒素基因成功的在毕赤酵母中表达,经突变后表达的蜂毒素降低了溶血活性,同时保留了抗菌活性.     

青蒿素类药物的生物学活性应用研究进展

青蒿素是从青蒿中提取出的具有抗疟活性的药物成分,青蒿素内含的过氧桥结构可以生成大量的如蒿甲醚、蒿乙醚、双氢青蒿素、青蒿琥酯等衍生物,目前已证实青蒿素及其衍生物还具有抗寄生虫、抗肿瘤、抗病毒、抗真菌等多重功效。介绍了青蒿素在临床应用的近期情况,并对其在抗肿瘤等其他领域的研究进展进行了简要的综述。这种价廉、低毒的药物在救治身患疟疾的濒危患者的同时,在抗肿瘤治疗等领域中也能发挥重大作用。     

农药醚菊酯类似物构效关系的人工神经网络方法研究

本文以醚菊酯类似物作为研究对象,尝试使用神经网络方法进行构效关系分析,并对该种农药活性进行了预测。在所研究的样本集中,由结构预测活性的成功率可达100％,本文的研究表明：神经网络方法以其极强的非线性能力,可望成为农药构效关系研究的一种有效的工具．     

青蒿素及其衍生物抗肿瘤的研究进展

青蒿素类药物是治疗疟疾的主要药物,其衍生物有青蒿琥酯、蒿甲醚和二氢青蒿素等.近年来研究发现,青蒿素及其衍生物具有明显的抗肿瘤作用.研究表明:青蒿素及其衍生物可以抑制或杀伤肿瘤细胞;抑制肿瘤细胞增殖与诱导肿瘤细胞凋亡;抑制血管生成;选择性杀伤肿瘤细胞;逆转肿瘤细胞的多重耐药;具有放射增敏效应.因青蒿素及其衍生物安全低毒,有望成为新型的广泛、高效、低毒的抗癌药物.     

青蒿素及其衍生物的抗肿瘤研究进展

青蒿素及其半合成衍生物(ARTs)是一类有效的抗疟药物。最近研究显示,ARTs具有抗癌作用,其主要机制是产生活性氧、诱导细胞凋亡、抑制血管生成和阻滞细胞周期等。ARTs能抑制实体肿瘤的生长,表明其可用于抗肿瘤新辅助疗法中。双氢青蒿素和青蒿琥酯在体内实验中对乳腺、肺、胰腺和神经胶质瘤癌细胞有很好的化疗效果,提示其可用于联合抗癌疗法中。现就ARTs的抗癌机制以及其作为抗癌剂的疗效、安全性和剂量范围等方面做一总结。     

蜂毒溶血肽类似物定量构效关系计算分析

采用HyperChem7．0结构分析软件,对蜂毒溶血肽类似物的分予体积等结构参数进行了计算分析．分别利用多元线性回归、BP-神经网络计算法进行统计分析,获得两个相关性好的QsAR（quantitative structure-function relationship）模型．结果显示,蜂毒肽溶血活性与生成热、键合能、表面积、分予体积、极化能、醇水分配系数、水舍能相关．为降低溶血作用,指出在设计蜂毒肽结构时应尽量避免螺旋状结构．少用疏水性氨基酸．     

灵芝多糖的抗癌构效关系及其抗癌作用机制

灵芝多糖是灵芝的主要抗癌活性成分,但灵芝多糖的抗癌构效关系和抗癌机制仍不明了。现有的研究表明,具有抗癌活性的灵芝多糖大多是β-(1→3)-D-葡聚糖。β-葡聚糖中分支度高的有较高的活性,分子量高的也较分子量小的活性大。但新近的一些研究发现,含有其它结构的灵芝多糖和某些小分子量的灵芝多糖也具有免疫调节和抗癌活性。因此,这些灵芝多糖在灵芝抗癌中的作用不可忽视。灵芝多糖的抗癌作用机制目前尚不明了。现已知通过免疫介导作用发挥抗癌作用是灵芝多糖抗癌的主要机制之一。新近的研究发现,膜Ig和TLR-4为灵芝多糖激活机体B细胞的免疫受体,TLR-4也与灵芝多糖激活机体巨噬细胞有关。此外,灵芝多糖抗癌的可能机制还包括活化促分裂原活化蛋白(MAP)激酶,以及抑制肿瘤血管新生等。     

Ab initio prediction of optical rotation: comparison of density functional theory and Hartree-Fock methods for three 2,7,8-trioxabicyclo[3.2.1]octanes

We report ab initio calculations of the frequency-dependent electric dipole-magnetic dipole polarizabilities, beta(nu), at the sodium D line frequency and, thence, of the specific rotations, [alpha](D), of 2,7,8-trioxabicyclo[3.2.1]octane, 1, and its 1-methyl derivative, 2, using the Density Functional Theory (DFT) and Hartree-Fock/Self-Consistent Field (HF/SCF) methodologies. Gauge-invariant (including) atomic orbitals (GIAOs) are used to ensure origin-independent [alpha](D) values. Using large basis sets which include diffuse functions DFT [alpha](D) values are in good agreement with experimental values (175.8 degrees and 139.2 degrees for (1S,5R)-1 and -2, respectively); errors are in the range 25-35 degrees. HF/SCF [alpha](D) values, in contrast, are much less accurate; errors are in the range 75-95 degrees. The use of small basis sets which do not include diffuse functions substantially lowers the accuracy of predicted [alpha](D) values, as does the use of the static limit approximation: beta(nu) approximately beta(o). The use of magnetic-field-independent atomic orbitals, FIAOs, instead of GIAOs, leads to origin-dependent, and therefore nonphysical, [alpha](D) values. We also report DFT calculations of [alpha](D) for the 1-phenyl derivative of 1, 3. DFT calculations find two stable conformations, differing in the orientation of the phenyl group, of very similar energy, and separated by low barriers. Values of [alpha](D) predicted using two different algorithms for averaging over phenyl group orientations are in good agreement with experiment. In principle, the absolute configuration (AC) of a chiral molecule can be assigned by comparison of the optical rotation predicted ab initio to the experimental value. Our results demonstrate the critical importance of the choice of ab initio methodology in obtaining reliable optical rotations and, hence, ACs, and show that, at the present time, DFT constitutes the method of choice.     

Density functional theory calculations of optical rotation: employment of ADZP and its comparison with other basis sets

Density function theory calculations of frequency dependent optical rotations ([alpha]omega) for 30 rigid chiral molecules are reported. Calculations have been carried out at the sodium D line frequency, using the augmented double zeta valence quality plus polarization functions (ADZP) basis set and the BP86 nonhybrid and B3LYP hybrid functionals. Gauge-invariant atomic orbitals were used to guarantee origin-independent values of [alpha]D. Comparison between corresponding results obtained with nonhybrid and hybrid functionals as well as with theoretical optical rotations reported in the literature is done. Excited electronic states of three molecules are also discussed in light of circular dichroism spectra and B3LYP and BP86 calculated excitation energies and rotatory strengths. One verifies that the B3LYP/ADZP results are in better agreement with experiment.     

Density functional theory for the selective adsorption of small molecules on a surface modified with polymer brushes

A density functional method based on weighted density approximation is extended to study the selective adsorption of small molecules on a surface modified with end-grafted square-well chains. The excess part of the Helmholtz free energy functional is divided into two components: the hard sphere repulsion and the square-well attraction. The equation of state for hard sphere chain fluids developed by Liu et al. is used to calculate the repulsive part of the excess Helmholtz free energy functional, and the equation of state for square-well chain fluid with variable range developed by Li et al. is employed to calculate the attractive part. With this theoretical model, we examine the physical properties of the grafted polymer and the selective adsorption of small molecules on the modified surface.     

Density functional theory studies of oxygen and carbonate binding to a dicopper patellamide complex

In this work we present results of density functional theory (DFT) calculations on dicopper patellamides and their affinity for molecular oxygen and carbonate. Patellamides are cyclic octapeptides that are produced by a cyanobacterium, and may show promise as therapeutics. Thus, carbonate binding to a dicopper patellamide center gives a stable cyclic octapeptide with a twist of almost 90°. The system exists in close-lying open-shell singlet and triplet spin states with two unpaired electrons in orthogonal σ^∗ orbitals on each metal center. Subsequently, we replaced carbonate with dioxygen and found a stable Cu₂(μ-O)₂ diamond shaped patellamide core. In this structure the original dioxygen bond is significantly weakened to essentially a single bond, which should enable the system to transfer these oxygen atoms to substrates. We predicted the IR and Raman spectra of the Cu₂(μ-O)₂ diamond shaped patellamide structure using density functional theory and found a considerable isotope effect on the O-O stretch vibration for ¹⁶O₂ versus ¹⁸O₂ bound structures. Our studies reveal that carbonate forms an extremely stable complex with dicopper patellamide, but that additional molecular oxygen to this system does not give a potential oxidant. Therefore, it is more likely that carbonate prepares the system for dioxygen binding by folding it into the correct configuration followed in the proposed catalytic cycle by a protonation event preceding dioxygen binding to enable the system to reorganize to form a stable Cu₂(μ-O)₂-patellamide cluster. Alternatively, carbonate may act as an inhibitor that blocks the catalytic activity of the system. It is anticipated that the Cu₂(μ-O)₂-patellamide structure is a potential active oxidant of the dicopper patellamide complex.     

Effects of aligned α‐helix peptide dipoles on experimental electrostatic potentials

Aligned protein α‐helix dipoles have been implicated in protein function and structure. The recent breakthroughs in high‐resolution electron microscopy (EM) of macromolecules makes it possible to explore fundamental aspects of structural biology at the detailed molecular level. The electrostatic potential (ESP) generated by aligned protein α‐helix dipole should be observable in high‐resolution EM maps despite the fact that the effect may be partially screened by induced electric fields. Here, we show that aligned backbone dipoles in protein α‐helices account for long‐range features in the protein ESP functions. Our results are consistent with experimental EM maps and density functional theory calculations, including direct Fourier summation for proper calculation of the ESP due to the nonlocal nature of the ESP function from aligned dipoles and other partial atomic charges.     

Density functional studies on copper-catalysed asymmetric aziridination of diazoacetate with imines

Density functional theory has been used to study copper(I)-catalysed aziridination of diazoacetate with imines. All the intermediates and the transition states were optimised completely at B3LYP/6-31G(d) level. Calculation results confirm that copper(I)-catalysed aziridination of diazoacetate with imines is exothermic, and the total released Gibbs free energy is about ? 170 kJ/mol. Copper(I)-catalysed aziridination has two reaction modes: I and II, and thus the reaction mode I is dominant. The formation of the copper(I)–carbene–imine complex M3 (i.e. the attack of imines on copper–carbon(carbene) of copper–carbene intermediate M2) is the rate-determining step and the chirality-limiting step for copper-catalysed asymmetric aziridination. The reaction channel CA2 → M1a → TS1a → M2 → TS2a2 → M3a2 → TS3a2 → M4a2 → P1 is the most favourable one. The dominant products predicted theoretically are of (R)-chirality.     

Density functional theory studies of model complexes for molybdenum-dependent nitrate reductase active sites

Molybdenum and tungsten complexes as models for the active sites of assimilatory or dissimilatory nitrate reductases (NR) were computed at the CPCM-B98/SDDp//B3LYP/Lanl2DZp* plus zero point energy level of density functional theory. The ligands were chosen on the basis of available experimental protein or small chemical model structures. A water molecule is found to bind to assimilatory NR models [(Me₂C₂S₂)MO(YMe)]⁻ (−11.5 kcal mol⁻¹ for M is Mo, Y is S) and may be replaced by nitrate (−4.5 kcal mol⁻¹) (but a hydroxy group may not). Nature’s choice of M is Mo and Y is S for NR has the largest activation energy for protein-free models (13.3 kcal mol⁻¹) and the least exothermic reaction energy for the nitrate reduction (−14.9 kcal mol⁻¹) compared with M is W and Y is O or Se alternatives. Water binding to dissimilatory NR model complexes [(Me₂C₂S₂)₂M(YR)]⁻ is considerably endothermic (10.3 kcal mol⁻¹); nitrate binding is only slightly so (1.5 kcal mol⁻¹ for RY⁻ is MeS⁻). The exchange of an oxo ligand (assimilatory NR) for a dithiolato ligand (dissimilatory NR model) reduces the exothermicity (−8.6 kcal mol⁻¹ relative to the fivefold-coordinate reduced complex) and raises the barrier for oxygen atom transfer (OAT) in the nitrate complex (19.2 kcal mol⁻¹). Not for the mono but only for the bisdithiolato complexes hydrogen bonding involving the coordinated substrate may significantly lower the OAT barrier as shown by explicitly adding water molecules. Substitution of tungsten for molybdenum generally lowers OAT activation energies and makes nitrate reduction reaction energies more negative. Bidentate carboxylato binding identified in Escherichia coli NarGHI is the preferred binding mode also for an acetato model. However, one dithiolato ligand folds when the Mo^VI center is bare of a good π-donor ligand, e.g., an oxo group. Computations on [(mnt)₂Mo^IV(YR)(PPh₃)]⁻ [mnt is (CN)₂C₂S₂ ²⁻] gave a smaller nitrate reduction activation energy for RY⁻ is Cl⁻, compared with RY⁻ is PhS⁻, although experimentally only the phenyl thiolato complex and not the chloro complex was found to be a functional NR model. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Design and Construction of Aroyl‐Hydrazone Derivatives: Synthesis,Crystal Structure,Molecular Docking and Their Biological Activities

Here, we report the synthesis and characterization of four new aroyl‐hydrazone derivatives L₁ – L₄ , and their structural as well as biological activities have been explored. In addition to docking with bovine serum albumin (BSA) and duplex DNA, the experimental results demonstrate the effective binding of L₁ – L₄ with BSA protein and calf thymus DNA (ct‐DNA) which is in agreement with the docking results. Further biological activities of L₁ – L₄ have been examined through molecular docking with different proteins which are involved in the propagation of viral or cancer diseases. L₁ shows best binding affinity with influenza A virus polymerase PB2 subunit (2VY7) with binding energy ?11.42 kcal/mol and inhibition constant 4.23 nm , whereas L₂ strongly bind with the hepatitis C virus NS5B polymerase (2WCX) with binding energy ?10.47 kcal/mol and inhibition constant 21.06 nm . Ligand L₃ binds strongly with TGF‐beta receptor 1 (3FAA) and L₄ with cancer‐related EphA2 protein kinases (1MQB) with binding energy ?10.61 kcal/mol, ?10.02 kcal/mol and inhibition constant 16.67 nm and 45.41 nm , respectively. The binding energies of L₁ – L₄ are comparable with binding energies of their proven inhibitors. L₁ , L₃ and L₄ can be considered as both 3FAA and 1MQB dual targeting anticancer agents, while L₁ and L₃ are both 2VY7 and 2WCX dual targeting antiviral agents. On the other side, L₂ and L₄ target only one virus related target (2WCX). Furthermore, the geometry optimizations of L₁ – L₄ were performed via density functional theory (DFT). Moreover, all four ligands ( L₁ – L₄ ) were characterized by NMR, FT‐IR, ESI‐MS, elemental analysis and their molecular structures were validated by single crystal X‐ray diffraction studies.     

Predicting CO2 adsorption and reactivity on transition metal surfaces using popular density functional theory methods

ABSTRACT

In this work, with Ni (110) as a model catalyst surface and CO₂ as an adsorbate, a performance study of Density Functional Theory methods (functionals) is performed. CO being a possible intermediate in CO₂ conversion reactions, binding energies of both, CO₂ and CO, are calculated on the Ni surface and are compared with experimental data. OptPBE-vdW functional correctly predicts CO₂ binding energy on Ni (?62?kJ/mol), whereas CO binding energy is correctly predicted by the rPBE-vdW functional (?138?kJ/mol). The difference in computed adsorption energies by different functionals is attributed to the calculation of gas phase CO₂. Three alternate reaction systems based on a different number of C=O double bonds present in the gas phase molecule are considered to replace CO₂. The error in computed adsorption energy is directly proportional to the number of C=O double bonds present in the gas phase molecule. Additionally, both functionals predict similar carbon–oxygen activation barrier (40?kJ/mol) and equivalent C1s shifts for probe species (?2.6?eV for CCH₃ and +1.5?eV CO₃^?), with respect to adsorbed CO₂. Thus, by including a correction factor of 28?kJ/mol for the computed CO₂ gas phase energy, we suggest using rPBE-vdW functional to investigate CO₂ conversion reactions on different metals.     

Density functional theory based probe of the affinity interaction of saccharide ligands with extra-cellular sialic acid residues

Changes in glycosylation pattern leads to malignant transformations among the cells. In combination with upregulated actions of sialyltransferases, it ultimately leads to differential expression of sialic acid (SA) at cell surface. Given its negative charge and localization to extracellular domain, SA has been exploited for the development of targeted theranostics using approaches, such as, cationization and appending recognition saccharides on carrier surface. In this study, we have performed quantum mechanical calculations based on density functional theory (DFT) to study the interaction of saccharides with extracellular SA. Gradient-corrected DFT with the three parameter function (B3) was utilized for the calculation of Lee–Yang–Parr (LYP) correlation function. Atomic charge, vibrational frequencies and energy of the optimized structures were calculated through B3LYP. Our calculations demonstrate a stronger galactose–sialic acid interaction at tumour-relevant low pH and hyperthermic condition. These results support the application of pH responsive delivery vehicles and targeted hyperthermic chemotherapy for eradicating solid tumour deposits. These studies, conducted a priori, can guide the formulation scientists over appropriate choice of ligands and their applications in the design of ‘smart’ theranostic tools.