富勒烯结构B_(80)分子静电势的理论研究

在混合密度泛函B3LYP理论下,用6-31G*基函数对富勒烯结构B80分子的3个异构体(1个具有Ih对称性,2个具有Th对称性)构型进行优化和分子静电势计算.结果表明:3个异构体球内全部为正电势,球外五元环中心所对应的区域都为负电势,B80Ih,Th(A)和Th(B)球外静电势的最大负值分别对应于20个六元环中心的B原子,五元环中心和12个六元环中心的B原子周围,它们组成了化学反应中最可能的活性点.     

应用分子图形学、分子力学、量子化学及静电势研究农药分子结构与性能的关系（Ⅴ）──磺酰脲类分子中的化学键及电子结构

用半经验分子轨道方法ＭＮＤＯ及ＣＮＤＯ／２对农药分子结构进行计算，确认磺酰脲超高效除草剂分子中存在３个原子平面，分别形成离域π键，硫原子的空ｄ轨道参与了共轭体系的形成，静电势计算结果表明在分子两侧存在着２个明显的负电势区域，该结构与分子活性密切相关。     

应用分子图形学,分子力学,量子化学及静电势研究农药分…

用半经验分子轨道方法ＭＮＤＯ及ＣＮＤＯ／２对农药分子结构进行计算，确认磺酰脲类超高效除草剂分子中存在３个原子平面，分别形成离域π键，硫原子的空ｄ轨道参与了共轭体系的形成，静电势计算结果表明在分子两侧存在着２个明显的负电势区域，该结构与分子活性密切相关。     

4-取代Fentanyl类化合物电子结构及构效关系研究

本文对十一个4-取代Fentanyl类化合物进行了量子化学(INDO)计算, 研究了它们的电子结构及构效关系. 结果表明, 这些化合物同其他Fentanyl类化合物在主要活性部位和电子结构趋势上基本相同. 酰胺氧原子是最重要的负电中心, 哌啶氮原子在季铵化后发挥正电中心作用. 4-取代基的极性基团可能以电荷转移作用或氢键接受体形式与受体极性部位结合, 并能影响其他活性部位电子密度. 另外, 4-取代基的立体因素与疏水因素同生物活性相关.     

含哌啶结构杂环醇的立体化学研究

用分子力学和量子化学计算方法(AM1)研究了含哌啶结构杂环醇(1_4)及其羧酸酯类化合物的立体化学问题.结果表明,在哌啶醇(1)及醇(3)分子中,4位羟基处于哌啶环的a键位时,环上的氮原子和羟基氧原子之间可能形成非经典的轨道超共轭作用,使其构型构象得到稳定.     

紫杉醇类似物C13侧链手性构型与活性关系的从头算研究

应用从头算RHF/STO-3G方法优化了四个紫杉醚异构体,在RHF/6-31G*水平进行单点计算,并计算了四个分子的静电势。分子立体构型表明:C13侧链上2 R构型的2-OH和3 S构型的3-NH均处于分子外侧,有利于与受体极性基团结合;2 S构型的2-OH和3 R构型的3-NH在分子的内侧,不利于与受体极性基团结合。静电势的结果表明,R构型的2-OH和S构型的3-NH可以产生相应的负电势区域。当C13侧链为天然构型(2 R,3 S)时,分子可能以双基结合的方式通过负静电势区域与受体作用,活性较高。     

从头计算法研究沙蚕毒和杀虫环分子的几何构型与电子结构

用Hartree-Fock/6-31G^*从头算确定了沙蚕毒和杀虫环分子的几何构型,在全局优化中发现杀虫环分子的椅式和船式两种稳定构象,在二级Moller-plesset微扰理论MP2/6-31^*水平下,椅式较船式稳定27.06kJ/mol.用MP2/6-31G^*波函数计算电子相关校正的分子静电势,以此为基础讨论生物活性与静电势的关系。发现对此二分子,Mulliken布居分析获得的原子净电荷存在问题,本文用Breneman提出的从静电势导出原子净电荷的CHELPG方法计算了原子净电荷。     

4, 6-二芳基-2-氨基嘧啶类衍生物的合成与生物活性

合成并表征了5种4,6-二芳基-2-氨基嘧啶类化合物。 测试了它们对大肠肝菌甲硫酰胺肽酶(EcMetAP)的抑制作用及对CXCR4受体的拮抗作用。 发现5种化合物均对EcMetAP酶活有抑制作用,除化合物2外均对CXCR4受体有拮抗作用。 利用FieldTemplater和FieldAlign软件对化合物1～5的上述活性构效关系进行了分析,初步认为化合物的嘧啶环3位N原子及4位取代苯环上若引入给电子基团,可增强这类化合物的EcMetAP酶抑制活性;在嘧啶环2位引入负电性较强的基团取代,改造2个苯环和嘧啶环的4、5、6位Ｃ原子的结构可增强其CXCR4受体拮抗活性。     

N-(芳亚甲基)芳胺Schiff碱汞化反应区域选择性研究

本文用量子化学的MNDO方法对N-(苯亚甲基)苯胺、N-(苯亚甲基)-2-甲苯胺与N-(4-硝基苯亚甲基)-2-甲氧基苯胺Schiff碱汞化反应区域选择性进行了研究,结果表明,在其稳定构象下,芳胺环上的电荷密度大于苯基亚甲基环, 故汞化反应发生在芳胺环上；分子中亚胺氮原子的电荷密度最大, 在汞化反应过程中, 亚胺氮原子首先与醋酸汞配位,然后再进行邻位亲电进攻,生成邻位汞化产物；而在N-(苯亚甲基)-2-甲苯胺分子中, 邻位甲基阻碍了亚胺氮原子与汞原子的配位作用,故无邻位汞化产物生成。计算结果与实验结果一致, 并进一步支持了已经提出的反应机理。     

分子亲脂-亲水性的量子化学描述(Ⅰ)——分子的亲脂和亲水表面

给出基于分子结构的“启发式”亲脂-亲水势HMLP(Heuristic molecular lipophilicity-hydrophilicity potential)的理论分析和有说服力的算例.用量子化学计算其分子表面的静电势V(r)的分布,通过与周围原子表面静电势的比较,构造表达分子静电势的极性和大小的函数L(r).亲脂势L(r)保留了静电势V(r)描述分子静电作用的能力,并把应用范围扩展到疏水性的描述.HMLP不使用原子的经验参数,但在L(r)的构造中使用了经验的函数形式.经参数化和指标化后,HMLP有望用于蛋白质结构与功能的研究和药物分子配体与生物大分子受体结合自由能的估算.     

A 3D QSAR pharmacophore model and quantum chemical structure--activity analysis of chloroquine(CQ)-resistance reversal

Using CATALYST, a three-dimensional QSAR pharmacophore model for chloroquine(CQ)-resistance reversal was developed from a training set of 17 compounds. These included imipramine (1), desipramine (2), and 15 of their analogues (3-17), some of which fully reversed CQ-resistance, while others were without effect. The generated pharmacophore model indicates that two aromatic hydrophobic interaction sites on the tricyclic ring and a hydrogen bond acceptor (lipid) site at the side chain, preferably on a nitrogen atom, are necessary for potent activity. Stereoelectronic properties calculated by using AM1 semiempirical calculations were consistent with the model, particularly the electrostatic potential profiles characterized by a localized negative potential region by the side chain nitrogen atom and a large region covering the aromatic ring. The calculated data further revealed that aminoalkyl substitution at the N5-position of the heterocycle and a secondary or tertiary aliphatic aminoalkyl nitrogen atom with a two or three carbon bridge to the heteroaromatic nitrogen (N5) are required for potent "resistance reversal activity". Lowest energy conformers for 1-17 were determined and optimized to afford stereoelectronic properties such as molecular orbital energies, electrostatic potentials, atomic charges, proton affinities, octanol-water partition coefficients (log P), and structural parameters. For 1-17, fairly good correlation exists between resistance reversal activity and intrinsic basicity of the nitrogen atom at the tricyclic ring system, frontier orbital energies, and lipophilicity. Significantly, nine out of 11 of a group of structurally diverse CQ-resistance reversal agents mapped very well on the 3D QSAR pharmacophore model.     

Transformations of dibenzo(γ-oxopiperidino)aza-14-crowns-4 upon acylation. Molecular structure of dibenzo-16-crown-3

The result of acylation of dibenzoaza-14-crowns-4 containing a 4-oxopiperidine fragment with acetic anhydride depends on the substituent on the nitrogen atom. The NH-substrates initially undergo acylation at the piperidine nitrogen atom, followed by enolization and O-acylation. The acylation of N-methyl derivatives is accompanied by cleavage of the piperidine ring at the C-N bond with formation of acetylamino-substituted dibenzo-16-crowns-3. The structure of the latter was determined by X-ray analysis.     

Ortho-substituent effect promoted rapid cleavage of amide C–N bond under mild conditions

This article reports the ortho-substituent effect on the cleavage of the amide C–N bond. In the structure of N ^α -Phth-N-pyridinyl-amide, when the hydrogen atom in the 3-position of pyridine ring was replaced by alkoxy group, the amide C–N cleavage can take place in the 2-position of the pyridine ring. This transformation can proceed rapidly in methylamine ethanol solution under mild conditions to afford 2-amino-3-alkoxy pyridines.     

3-氰基吡啶与Grignard试剂的反应研究

3-取代酰基吡啶可由3-氰基吡啶与相应的卤代烷基镁加成,然后酸化水解来制备.我们曾用该法顺利地制备了一系列的3-取代酰基吡啶,另外还得到少量的4-烷基-3-取代酰基吡啶.但当用氯化苄基镁时,只得到少量的3-取代酰基吡啶,而主要产物却是4-苄基-3-氰基吡啶.为了探讨这两种反应中各组分的相对含量,用高压液相色谱分别对3-氰基吡啶与溴化丁基镁、氯化苄基镁的反应产物进行了分析.为了解释反应产物的异常现象,对反应物进行了量子化学计算,用前线轨道理论对以上反应进行了讨论.     

Molecular modeling of sigma receptor ligands: A model of binding based on conformational and electrostatic considerations

We have performed molecular modeling studies on four representative sigma receptor specific ligands, (+)haloperidol, (+)3-PPP, (+)pentazocine and progesterone, to develop a model for sigma receptor-ligand binding. The modeling studies have investigated the conformational and electrostatic properties of the ligands. Based on the complementarity of the conformational and electrostatic properties of the ligands, a model of binding has been proposed which shows that the four ligands can fit a common receptor sit. Unlike the binding model for haloperidol that was previously proposed by Manallack and Andrews, our model binds haloperidol in the gauche conformation. The first site binds the fluorophenyl group and the second site the lone pair of the piperidine nitrogen. This pharmacophore can be presented by (+)3-PPP and (+)pentazocine, but for progesterone the binding model requires the ring junction of the cyclohexenyl ring A and ring B to fit the fluorophenyl region, while the lone pair of the acetylcarbonyl oxygen at ring D emulates the nitrogen lone pair of the piperidine ring. Calculations were performed using RCG5 for generating conformations, molecular mechanics for calculating steric energies, quantum mechanical methods for generating charges, and ARCHEM for calculating electrostatic potentials on the Van der Waals surface.     

取代基对螺噁嗪类化合物光致变色性能影响的探究

本文合成了4种螺噁嗪类化合物,并通过FTIR、1H NMR、ESI-MS对其结构进行了表征。研究了吲哚环上氮原子和噁嗪环9′位不同的取代基及溶剂化效应对其光致变色性能的影响。结果表明,吲哚环的氮原子引入体积较大的基团对螺噁嗪最大吸收波长无明显影响,然而有利于开环体的稳定性,且溴原子的引入会影响螺噁嗪的光响应性;噁嗪环9′位上的供电子基团会降低螺噁嗪的开环体稳定性;螺噁嗪开环体的褪色过程符合一级动力学方程;在非质子溶剂中,螺噁嗪开环体的最大吸收波长呈现正向溶剂化效应;有机酸的加入,可以增加开环体的热稳定性。     

Redox regulation of protein tyrosine phosphatase 1B (PTP1B): a biomimetic study on the unexpected formation of a sulfenyl amide intermediate

The effect of steric and electronic environments around the sulfur and nitrogen atoms and the role of nonbonded S...O/N interactions on the cyclization reactions of amide substituted benzene sulfenic acids are described. The reaction profiles and the role of different substituents on the cyclization are investigated in detail by theoretical calculations. It is shown that the synthetic thiols having ortho-amide substituents may serve as good models for the enforced proximity of the amide and cysteine thiol groups at the active site of protein tyrosine phosphatase 1B (PTP1B). However, some of the sulfenic acids derived from such models do not effectively mimic the cyclization of protein sulfenic acids. This is mainly due to the requirement of very high energy for breaking the S-O bond to form a planar five-membered ring of isothiazolidinone. It is shown that the sulfenic acid having two substituents-an amide moiety and a heterocyclic group-in the ortho-positions undergoes a rapid cyclization reaction to produce the corresponding sulfenyl amide species. These studies reveal that the introduction of a substituent at the 6-position of the benzene ring enhances the cyclization process not only by facilitating a closer approach of the -OH group and the backbone -NH moiety but also by increasing the electrophilicity of the sulfur atom in the sulfenic acid.     

Mass spectra of substituted 4-aminopiperidines with a shielded nitrogen atom

The principal fragmentation pathway of 4-aminopiperidines under the influence of electron impact are determined by charge localization on the nitrogen atom of the piperidine ring or on the nitrogen atom of the substituent in the 4 position. In the case of electron-donor substituents in the 4 position and in the absence of a substituent attached to the nitrogen atom of the polysubstituted piperidine ring the charge is primarily localized on the nitrogen atom of the substituent; this is expressed in the specific fragmentation pathways. The principles found in this research make it possible to establish the structures of nitrogen-containing compounds that are similar to the investigated compounds.Communication 10 in the series Application of mass spectrometry in structural and stereochemical studies. See [1] for Communication 9.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 72–77, January, 1981.     

Design and synthesis of trans-3-aminopyran-2-carboxylic acid (APyC) and α/β-peptides with 9/11-helix

A new β-amino acid, trans-3-aminopyran-2-carboxylic acid (APyC), was designed and synthesized from (R)-glyceraldehyde derivative and used in the synthesis of α/β-peptides in a 1 : 1 alternating pattern with d-Ala. The presence of oxygen atom at the Cβ(2)-position in APyC was envisaged to provide opportunity for additional interaction. These hybrid peptides have shown the presence of 9/11-helix through extensive NMR and MD studies. The amide protons of d-Ala, in addition to participating in 9-mr H-bonding with CO of succeeding β-residue, were also involved in additional electrostatic interaction with pyran ring oxygen of preceding β-residue, which facilitated further stabilization to the 9/11-mixed helix. The study thus results in a new 'motif' for a 9/11-helix, and the first example from a cyclic β-amino acid.