乙酰胆碱酯酶抑制剂Corydaline的分子对接与开环衍生物的虚拟筛选

用分子对接软件GOLD, 研究了延胡索类生物碱corydaline与乙酰胆碱酯酶的结合模型, 并虚拟筛选了一系列具有不同碳链长度和取代基的开环衍生物以指导潜在高活性化合物的合成. 分子对接结果表明, corydaline与开口构象的酶结合可能性最大. 结合模型显示, corydaline的A环与外周阴离子位点Tyr334产生π-π堆积; 质子化氮原子与疏水位点Phe330产生阳离子-π作用; 而D环上的甲氧基则深入到活性口袋底部占据催化位点. 开环衍生物虚拟筛选发现, 大部分化合物的得分均高于母体, 得分排名前15位的化合物主要为被苄氧基等大基团取代且连接碳链长为2-7的衍生物. 基于预测结果, 合成了化合物7, 其抑制活性为现有药物加兰他敏的3倍.     

蛋白质分子的HNP格点模型

从 6 0种球形蛋白质的结构出发 ,采用Miyazawa Jernigan相互作用矩阵 ,计算了蛋白质分子中氨基酸之间的相互作用能 .发现构成蛋白质分子的 2 0种氨基酸可分成疏水 (Hydrophobic ,H)、中性 (Neutral,N)、亲水(Hydrophilic ,P)基团 .在计算它们之间相互作用能的基础上 ,建立了蛋白质分子的HNP格点模型 .用这个模型计算了二维蛋白质分子在自然态 (Nativestate)时的构象性质 .同时研究了氨基酸序列为HHNHNPNHPP HPNPPHPHPPHHPHNH的折叠过程 ,得到其基态能量为 - 6 4 89RT .这能为研究球形蛋白质的构象性质及折叠过程提供一种更合理的格点模型     

新型手性基团修饰的金属卟啉的合成及性质研究

合成了一种手性基团修饰的金属卟啉化合物[5-对(L-亮氨酰氧乙氧基)苯基-10, 15, 20-三苯基卟啉锌]. 通过元素分析、紫外可见光谱、红外光谱、圆二色光谱及核磁共振波谱对该化合物进行了较详细的表征. 同时, 采用分子力学方法搜索了主体的最低能量构象, 从理论上进一步解释实验结果. 利用Z扫描技术测定了该化合物的三阶非线性光学性质.     

新型手性锌卟啉对氨基酸酯的分子识别

合成并表征了一种新型用Boc保护的L-酪氨酸修饰的手性锌卟啉Zn（L-BocTyr）TAPP（主体）. 运用紫外可见光谱滴定法, 研究了主体化合物与四对氨基酸酯对映体的识别反应. 主体与各客体缔合常数均为K_D>K_L, 且按K(PheOMe)>K(LeuOMe)>K(ValOMe)>K(AlaOMe)的顺序依次减少. 主体化合物对氨基酸酯的识别作用是由主-客体之间手性匹配产生的. 识别体系的焓熵补偿关系揭示出该识别体系是焓驱动的过程，在识别过程中客体氨基酸酯分子构象自由度损失较大.通过圆二色光谱的研究，确定在进行识别反应时，D型氨基酸酯比L型氨基酸酯更易与主体反应，形成的化合物更趋于稳定. 我们认为圆二色产生的机理是由主体侧链中羰基的电子过渡态与卟啉平面的电子过渡态之间相互偶合所致.通过量子化学计算, 进一步揭示识别反应的本质特征. 在理论计算中，首先运用模拟退火的方法搜索了主体、主－客体体系的最低能量构象, 并在此最低能量构象的基础上进行Gaussian 98的理论计算. 通过所得理论计算结果证实, D型氨基酸酯与主体所形成的配合物更稳定. 理论计算较好地解释了实验事实.     

新型氮杂大环化合物的合成及其超分子识别性能

含氮杂芳环结构单元(如吡啶、吡唑或咪唑环等)的大环化合物,因其与金属离子形成具有特殊化学性能的配合物而被广泛研究并用于生物化学、药物化学、材料化学等领域.生命体系中的受体通常含有不同类型的配位部位,因而具有对不同底物的识别作用.设计合成含有不同配位原子和特定结构的大环化合物,对于模拟某些生命现象具有重要的研究意义.近年来开展的酶模型研究中,能对氨基酸进行有效手性识别和液膜传输的主体分子多为氮杂大环化合物.为此,本文合成了两种带有侧链功能基团和手性基团的氮杂大环化合物.     

丙二酸亚异丙酯衍生物的构象分析与分子集团结构适应理论

本文根据5-取代丙二酸亚异丙酯的核磁共振谱,利用“分子集团结构适应理论”观点,阐述了5-取代丙二酸亚异丙酯的构象,表明此化合物一般具有椅式构象;当取代基中含有芳基及羰基时,显示了这些基团对2-位甲基的远程屏蔽及远程去屏蔽效应,从而认为此时以船式构象存在。     

锥形构象含氟杯芳烃衍生物对铜离子的高选择性识别（英文）

合成了具有锥形构象的含氟功能基团的杯芳烃衍生物1～3,并用单晶X射线衍射和核磁共振证实了其锥形构象。在混合溶剂中,研究了杯芳烃衍生物1～3对多种金属离子的识别行为。测试了化合物1～3的紫外-可见吸收光谱和荧光发射光谱,结果显示铜离子对化合物1～3具有明显的荧光猝灭特性,而其它金属离子(如Na~+,K~+,Cs~+,Mg~(2+),Ca~(2+),Ba~(2+),Fe~(3+),Cd~(2+),Mn~(2+),Co~(2+),Ni~(2+),Zn~(2+))对化合物1～3的紫外-可见吸收光谱和荧光发射强度无显著的影响,表明化合物1～3对铜离子的识别具有高选择性。     

基于分子动力学模拟的TRPM8通道门控特性分析

TRPM8通道的温度感知等生理功能依赖于正常的门控, 但现有晶体结构中S6跨膜螺旋C末端形成的门控结构存在氨基酸缺失, 所以其门控特性未能揭晓. 本文基于已有的晶体结构和AlphaFold算法构建了 11个完整不同构象的TRPM8通道, 发现其S6跨膜螺旋C末端构成的门控存在回环和螺旋2种构象. 在回环构象中, 多个氨基酸参与形成阻碍离子通透的孔道区; 而在螺旋构象中, 仅有关键氨基酸V956发挥门控作用. 由于回环构象的柔性大于螺旋构象, 导致回环构象参与阻碍离子通透的关键氨基酸构象和数量变化多样. 二级结构预测与模建结果表明, S6跨膜螺旋C末端存在回环构象向螺旋构象的转变, 此过程中柔性的回环构象结构域向胞外侧上移, 关键氨基酸向孔道衬外扭转, 增强了与相邻跨膜螺旋S5的相互作用以及S5与TRP螺旋之间的相互作用, 进而形成刚性、 稳定且有序的螺旋构象. 这增加了TRPM8通道各结构域间的协同性, 使能量信息更高效地传递到门控结构域, 为TRPM8通道开启蓄势.     

稀土离子（Ⅲ）与牛血清白蛋白作用的紫外光谱

用紫外光谱研究了稀土离子（Ⅲ）与牛血清白蛋白（BSA）的作用．14种稀土离子均使BSA～280um特征吸收峰强增加，诱导BSA构象发生改变．紫外差谱结果表明，只有氧原子参加与稀土配位．BSA与稀土配位基团为亲水外壳的氨基酸波基和肽键上的C＝O基团．     

手性氨基酸卟啉化合物的CD光谱及紫外-可见光谱研究

在合成的手性氨基酸卟啉化合物ThrTPPZn和SerTPPZn(Thr:苏氨酸,Ser:丝氨酸)中,氨基酸残基与卟啉单元相互作用使氨基酸残基的构象相对固定,卟啉化合物在Soret区产生分裂的CD光谱.而在LeuTPPZn中氨基酸残基与卟啉单元的相互作用很弱,卟啉化合物的CD光谱很弱.在室温下,手性氨基酸卟啉化合物对映体的紫外-可见吸收光谱相同,当温度降低时,ThrTPP,SerTPP及其锌配合物在240 nm处的吸收光谱随着温度的降低吸收值减小,在278 K时,L-SerTPP,L-ThrTPP,D-ThrTPPZn 和D-SerTPPZn在275 nm处有强、宽的吸收峰,这是由于在低温下分子的内能减小,氨基酸残基的旋转受到限制,分子内的相互作用增大,羰基与卟啉环之间的共轭增大所致.     

Preparation of Unconventional Dendrimers that Contain Rigid NH?Triazine Linkages and Peripheral tert‐Butyl Moieties for CO2‐Selective Adsorption

Three unconventional dendrimers that contained rigid NH? triazine linkages and peripheral tert‐butyl moieties were prepared by using a convergent approach and characterized by ¹H and ¹³C NMR spectroscopy, mass spectrometry, and elemental analysis. Based on a thermogravimetric analysis study, these dendrimers were observed to display thermal stability at about 300 °C. The NH? triazine moiety, which possessed protonated and proton‐free nitrogen sites (like the imidazole unit), displayed the capture of polarizable CO₂ molecules through hydrogen‐bond and/or dipole–quadrupole interactions. In addition, the adsorption of various amounts of CO₂ and N₂ at different pressures suggests that the dendritic pores, which arise from the stacking of the middle co‐planar and rim protuberant dendrimers, G _n ‐N～N‐G _n (n=1–3), either swell or shrink at high pressure, thus indicating that these dendrimers may have a breathing ability.     

Photoresponsive nanocarriers based on PAMAM dendrimers with a o‐nitrobenzyl shell

Gn (n = 3, 4, and 5) poly(amidoamine) (PAMAM) dendrimers were synthesized and peripherally modified with photocleavable o‐nitrobenzyl (NB) groups by reacting o‐nitrobenzaldehyde with the terminal amine groups of PAMAM dendrimers, followed by reducing the imine to amine groups with NaBH₄. The NB‐modified dendrimers, Gn‐NB (n = 3, 4, and 5), were characterized by nuclear magnetic resonance and fourier transform infrared spectroscopy. The results showed that the NB groups were successfully attached on the periphery of the dendrimers with near 100% grafting efficiency. Such a photosensitive NB shell could be cut off on irradiation with 365 nm ultraviolet (UV) light. The encapsulation and release of guest molecules, that is, salicylic acid (SA) and adriamycin (ADR), by Gn‐NB were explored. The encapsulation capability of these dendrimers was found to increase as the guest molecular size was decreased and have dependence on the generation of dendrimers as well. For both of SA and ADR, the average encapsulation numbers per dendrimer decreased in the order of G4‐NB > G5‐NB > G3‐NB, indicating that the fourth generation dendrimer was a better container for the guest molecules. The rate of SA release was found to be greater with UV irradiation than that without, suggesting that the NB‐shelled PAMMAM dendrimers could function as a molecular container/box with photoresponsive characteristics. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 551–557, 2010     

Synthesis of Chiral Starburst Dendrimers from PHB-Derived Triols as Central Cores

Chiral triols 1 – 3 (‘tris(hydroxymethyl)methane’ derivatives), prepared from (R)-3-hydroxybutanoic acid and aldehydes, are used as center pieces of dendrimers. The triols may be employed as such or after attachment of spacers containing alkyl or aryl moieties (see 5 and 7 ). The branches combined with the original or elongated triols are those first reported by Fréchet ( 9 – 12 , benzyl ethers of 3,5-dihydroxybenzyl alcohol and bromide). In this way, 1st-, 2nd-, and 3rd-generation chiral dendrimers without ( 13 – 15 ), or with aliphatic ( 16 – 18 ) or aromatic ( 19 – 21 ) spacers are prepared. The molecular weights range from 447 to 2716 Dalton. Two of the chiral triols, i.e., 2 and 3 , are used as center pieces for chiral dendrimers containing 6 NH₂, or 6 and 12 NO₂ groups on the periphery ( 22 – 27 ), with 3,5-dinitrobenzoyl chloride as the branching unit. All compounds thus synthesized are of course monodisperse and are fully characterized. In some cases, the optical activity of the dendrimers indicates that conformationally chiral substructures might be present. The NH₂- and NO₂-substituted compounds avidly clathrate smaller molecules; they are sorbents exchanging host molecules through the gas phase.     

Quaternary ammonium ion dendrimers from methylation of poly(propylene imine)s

The poly(propylene imine) dendrimers DAB‐dendr‐(NH₂)₈, DAB‐dendr‐(NH₂)₃₂, and DAB‐dendr‐(NH₂)₆₄ were fully converted with iodomethane to quaternary ammonium ions at both chain ends and branch points and, with less iodomethane, were partially converted to quaternary ammonium ions mainly at end groups. Amidation of the primary amine ends followed by treatment with iodomethane gave the first dendrimers with quaternary ammonium ions only at branch points. After an exchange of iodide counterions for chloride, all of the quaternary ammonium ion dendrimers slightly increased the rate of decarboxylation of 6‐nitrobenzisoxazole‐3‐carboxylate ion in an aqueous solution. Similar quaternary ammonium ion dendrimers with more hydrophobic interiors or more hydrophobic chains on the ends were much more active catalysts for the decarboxylation. © 2001 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 821–832, 2001     

Formation of Columnar Liquid Crystals on the Basis of Unconventional Triazine‐Based Dendrimers by the C3‐Symmetric Approach

Two series of unconventional triazine‐based dendrimers with C₂ symmetry and C₃ symmetry were prepared. The newly prepared C₃‐symmetrical dendrimers were characterized by ¹H and ¹³C NMR spectroscopy, mass spectrometry, and elemental analysis. Differential scanning calorimetry, polarizing microscopy, and powder XRD showed that the C₃‐symmetrical dendrimers display columnar liquid‐crystalline phases during thermal treatment, but the C₂‐symmetrical dendrimers were not observed to behave correspondingly. The molecular conformations of C₃‐ and C₂‐symmetrical dendrimers were obtained by computer simulation with the MM2 model of the CaChe program in the gas phase. The simulation results reasonably explain the different mesogenicities of C₃‐ and C₂‐symmetric dendrimers. This new strategy should be applicable to other types of unconventional dendrimers with rigid frameworks for displaying columnar liquid‐crystalline behavior.     

Induction of the Columnar Phase of Unconventional Dendrimers by Breaking the C2 Symmetry of Molecules

Two triazine‐based unconventional dendrimers were prepared and characterized by ¹H and ¹³C NMR spectroscopy, mass spectrometry, and elemental analysis. Differential scanning calorimetry, polarizing microscopy, and powder XRD studies showed that these dendrimers display columnar liquid‐crystalline phases during thermal treatment. This is ascribable to breaking of their C₂ symmetry. The molecular conformations of prepared dendrimers were obtained by computer simulation with the MM3 model of the CaChe program in the gas phase. The simulation showed that the conformations of the prepared dendrimers are rather flat and disfavor formation of the LC phase. However, due to C₂‐symmetry breaking, the prepared dendrimers have structural isomers in the solid state and thus show the desired columnar phases. This new strategy should be applicable to other types of unconventional dendrimers with rigid frameworks.     

Molecular characteristics of poly(propylene imine) dendrimers as studied with translational diffusion and viscometry

 The generation of dendrimers based on poly(propylene imine) with CN end groups [DAB–dend–(CN) _x ] and with palmitoyl end groups [DAB–dend–(C15) _x ] was studied by methods of translational diffusion and viscometry. The volumes of the DAB–dend–(CN) _x and DAB–dend–(C15) _x dendrimers and the previously studied DAB–dend–(lacto) _x dendrimer were compared to evaluate the volumes of the end groups in hybrid dendrimers. The volume of the hybrid dendrimers compared to that of the initial dendrimers increases proportionally to the number of end groups: this means that the end groups are predominantly located on the periphery of each molecule, thus ensuring this volume will increase. It is shown that the volume of the end groups for DAB–dend–(C15) _x is 3.5 times greater, and for DAB–dend–(lacto) _x it is 5.0 times greater than that occupied by free mole- cules corresponding to the end groups. The values of the intrinsic viscosity were compared with the values of the diffusion coefficient and the chemical formula molecular weight. Received: 7 August 2001 Accepted: 2 November 2001     

Interactions and Encapsulation of Vitamins C,B3, and B6 with Dendrimers in Water

Titrations of commercial diaminobutane (DAB) and polyamidoamine (PAMAM) dendrimers by vitamins C (ascorbic acid, AA), B₃ (nicotinic acid), and B₆ (pyridoxine) were monitored by ¹H NMR spectroscopy using the chemical shifts of both dendrimer and vitamin protons and analyzed by comparison with the titration of propylamine. Quaternarizations of the terminal primary amino groups and intradendritic tertiary amino groups, which are nearly quantitative with vitamin C, were characterized by more or less sharp variations (Δδ) of the ¹H chemical shift (δ) at the equivalence points. The peripheral primary amino groups of the DAB dendrimers were quaternarized first, but not selectively, whereas a sharp chemical‐shift variation was recorded for the inner methylene protons near the tertiary amines, thereby indicating encapsulation, when all the dendritic amines were quaternarized. With DAB‐G5‐64‐NH₂, some excess acid is required to protonate the inner amino groups, presumably because of basicity decrease due to excess charge repulsion. On the other hand, this selectivity was not observed with PAMAM dendrimers. The special case of the titration of the dendrimers by vitamin B₆ indicates only dominant supramolecular hydrogen‐bonding interactions and no quaternarization, with core amino groups being privileged, which indicates the strong tendency to encapsulate vitamins. With vitamin B₃, a carboxylic acid, titration of DAB‐G3‐16‐NH₂ shows that only six peripheral amino groups are protonated on average, even with excess vitamin B₃, because protonation is all the more difficult due to increased charge repulsion, as positive charges accumulate around the dendrimer. Inner amino groups interact with this vitamin, however, thus indicating encapsulation presumably with supramolecular hydrogen bonding without much charge transfer.     

Design and synthesis of novel amphiphilic Janus dendrimers for bone-targeted drug delivery

In this paper, we synthesized a range of amphiphilic Janus dendrimers, which consisted of acidic amino acid and naproxen molecules as the peripheral groups, as novel potential bone-targeting dendritic drug delivery. These dendrimers take advantage of a dendritic display to carry multiple drug molecules and targeting moieties simultaneously. All of the dendrimers exhibited more than 80% binding rates to hydroxyapatite (HAP), especially the [G₂]-dendrimers (2a and 2b) showed dramatic binding rates (>95%). Moreover, the solubility of naproxen was remarkably enhanced by the dendritic drug delivery system, especially the naproxen concentration of 2b achieved 5.37 mg/ml, which is more than 28-fold over that of native drug. Furthermore, cell viability studies showed that all the dendrimers exhibited no significant cytotoxicity against HEK293 cells. These results provided an effective entry to the development of new bone-targeting drugs.     

Ester‐ and amide‐terminated dendrimers with alternating amide and ether generations

Ester‐terminated polyamide dendrimers up to the third generation and amide‐terminated polyamide dendrimers of the first generation were synthesized by convergent growth. The Williamson ether synthesis and diphenylphosphoryl azide (DPPA) coupling of amines to carboxylic acids were used for the construction of the dendrimers, having alternate ether and amide generations. The methyl ester‐ and N,N‐diethylamide‐terminated dendrimers were readily soluble in common organic solvents while the N‐methylamide‐ and N‐benzylamide‐terminated dendrimers were soluble only in DMF and DMSO. Both the end and internal amide groups of the N,N‐diethylamide‐terminated dendrimer were reduced by LiAlH₄ to form a polyamine dendrimer. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 1533–1543, 2000