抗胆碱能药物设计合成的研究进展

综述了近年来抗胆碱能药物设计合成在阻断基团设计、连接基团设计、阳离子头设计方面的研究进展,     

给、吸电子基团对芳香共轭体系电子结构影响的密度泛函理论研究

采用密度泛函理论,在B3LYP／6—31G^＊方法水平上对8个连接有给、吸电子基团的芳香共轭体系的稳定性、偶极矩、静电荷分布和前线轨道能级进行了研究,并采用TD／DFT方法进一步研究了它们的电子光谱．结果表明a-1,b-1,c-1和d-2分子比它们的同分异构体要稳定;对于苯、呋喃、吡咯与乙烯形成的共轭体系,吸电子基团连接在乙烯一端,给电子基团连接在芳香环上使体系的偶极距增强,而吡啶则相反;前线轨道能级差较小的是吸电子基团连接在芳香环一端的体系,相应的分子最大吸收波长也较大．     

DAR成色剂结构与性能的关系

通过分析DAR成色剂的结构和作用机理,讨论了其结构与照相性能之间的关系.DAR成色剂的结构可表示为:Cp—L—A,其中Cp代表成色剂母体,A代表促进显影的功能基团即增强基团,L代表连接基团同时也有吸附功能即吸附基团.本文指出:当吸附基团和增强基团相同时,母体对照相性能影响不大;当母体及增强基团相同时,吸附基团的吸附性越强,照相性能越好;当母体及吸附基团相同时,增强基团的感染显影作用越强,照相性能越好.     

α-氨基酰胺类化合物的合成新方法

以三氟化硼-乙醚配合物为催化剂,研究了亚胺与氨甲酰基硅烷的反应.考察了亚胺碳原子连接基团(乙基、异丙基、三氟甲基、苯乙烯基、苯基、呋喃基、噻吩基和吡啶基)对反应的影响,合成了几种α-氨基酰胺;当亚胺氮原子连接的烃基和氨甲酰基硅烷中氮原子连接的烃基为手性基团S-1-苯乙基和R-1-苯乙基时,得到了具有高度立体选择性的产物(非对映异构体比率为14:1),是一种不对称合成α-氨基酰胺的新方法.     

功能化单层碳纳米管的自组装

研究了功能化的单层碳纳米管与重氮树脂高分子之间的自组装性能。经过功能化的单层碳纳米管在端头连接有羧基和羧酸根,这些基团可以同重氮树脂重氮基团作用成键,这种键是光敏性的。经紫外光照射后,羧酸根同重氮基之间转变成共价键连接,增加了自组装膜的稳定性。     

三苯基膦氧基团在合成高性能有机电致发光材料中的应用

有机电致发光技术在通讯、信息、显示和照明等领域显现出巨大的商业应用前景, 十几年来一直是光电信息领域的研究热点之一。相对于无机电致发光材料,有机电致发光材料具有许多优点。近年来,三苯基膦氧基团在合成高性能有机电致发光材料方面的研究吸引了大批研究者的关注。由于磷原子自身性质,可以形成5个共价键,所以膦氧基团极易和其他基团连接形成以其为核的衍生物。由于氧原子具有很强的电负性,这就使膦氧结构高度极化并具有强的吸电子性。吸电子的膦氧基团连接苯环形成的三苯基膦氧单元也具有较强的吸电子性,其对所形成的化合物的能级结构也会产生明显影响。本文从材料合成的角度综述了三苯基膦氧基团在合成高性能有机电致发光材料中的应用方面所取得的最新研究进展,重点介绍了三苯基膦氧基团在合成高性能磷光二极管主体材料、电子传输材料和单分子电致发光材料等方面的应用。最后讨论了三苯基膦氧基团在上述领域应用过程中所存在的问题和功能拓展方向,并对下一步需要研究的热点问题作了展望。     

R-基团相似性的比较

介绍了对化学取代基(R-基团)进行相似性比较的工作．每个R-基团主要依赖一些对反应影响较为明显,同时又便于计算的结构描述符来进行描述,例如电负性、氢键受体、氢键给体等参数．由于与反应核心相距过远的环境对反应的影响较小,R-基团相似性比较对象,就由每个R-基团截取从它与母体连接的位点出发向外扩展6层的子结构组成．在确立了对R-基团描述和距离限制的基础上,提出了用一个45维向量表示一个R-基团,并由化学结构的比较,转化为向量比较来实现R-基团相似性比较的方法．采用这一方法,成功地对大量的R-基团进行了相似性的区分,并实现了对未知化合物进行相似性预测的目标．     

化学分子结构式绘制的"超级连接"

常用化学结构绘制软件都提供了大量的基团片段用于快速地绘制较复杂的化学结构。只有通过正确的连接方法,才能得到准确的化学结构式,本文探讨了几种有效的连接方法。     

荧光猝灭研究芳醚树枝形聚合物构象

本工作分别合成了外围修饰一个芘基团和核心修饰一个芘基团两个系列的芳醚树枝形聚合物Py-Gn-OH和Gn-CH₂-Py(n=1~4)。Py-Gn-OH和Gn-CH₂-Py的发光随代数增加而增强,荧光寿命增加。荧光猝灭实验结果表明,树枝形聚合物Py-Gn-OH和Gn-CH₂-Py的双分子猝灭速率常数均随代数增加而减小,表明树枝形聚合物发生了构象折叠,位于核心和外围的芘基团均被树枝形聚合物骨架包裹,随代数增加树枝形聚合物骨架增大,对芘基团包裹作用增强,导致猝灭剂接近芘基团的位阻增大。Gn-CH₂-Py体系的双分子猝灭速率常数均比相应代数Py-Gn-OH体系略小,说明树枝形聚合物骨架对连接在核心的芘基团的包裹程度比对连接在外围的芘基团略强。本工作为新型功能芳醚树枝形聚合物设计和应用提供了参考。     

新型双子表面活性剂的制备及性能研究

制备了一系列羧基支化改性双子表面活性剂,其利用马来酸酐将2个疏水性基团和2个亲水性基团通过弱酯键连接基团连接在一起,以反丁烯二酸为羧化试剂在过氧化自由基的引发下进行羧化接枝反应接入了阴离子亲水基团。用红外光谱和核磁共振表征了合成物的分子结构。测定了合成产物的表面张力、胶团形貌、疏水性能、泡沫性能、润湿性能、乳化性能和分散性能。结果显示所合成的双子表面活性具有优异的表面性能。     

Linkers for oligonucleotide microarray synthesis

A number of linkers for microchip-based (microarray) synthesis of oligonucleotides were synthesized here using photolabile intermediates. The resulting linkers are designed for covalent immobilization on slides containing both hydroxyl and amino groups.The first series of linkers was intended for the synthesis of oligonucleotide arrays for hybridization analysis. These linkers provide a strong covalent bond with the slide surface when amino groups in oligonucleotide heterocyclic bases are deprotected.The second series of linkers allows to cleave the synthesized oligonucleotides from the support on which they were synthesized. Furthermore, the use of such linkers yields oligonucleotides devoid of the phosphate group at their 3′ end.The obtained linkers were successfully tested in the synthesis of oligonucleotides on a microchip for subsequent hybridization analysis and assembly of a DNA fragment.     

有机硅连接体在固相有机合成中的应用

固相合成方法具有传统液相反应无可比拟的优越性,已被越来越多的化学家认可.反应物与高分子支持体的连接则是固相合成中的重要环节,连接体在其中扮演着重要的角色.近20多年来发展起来的有机硅连接体基本满足了理想连接体的要求,具有广阔的应用发展前景.本文从直接法和间接法两方面综述了26年来具有代表性的多种有机硅连接体的设计、制备及其在固相有机合成中的应用.     

Design, synthesis, and validation of rigid linkers for bioactive peptides

Rigid linkers of variable length were synthesized and used to connect two NDP-α-MSH ligands. The linkers were incorporated by solid-phase synthesis. Biological evaluations indicate that there is virtually no effect of these linkers on ligand binding to the human melanocortin 4 receptor.     

Linker molecules in surfactant mixtures

Linker molecules are amphiphiles that segregate near the microemulsion membrane either near the surfactant tail (lipophilic linkers) or the surfactant head group (hydrophilic linkers). The idea of the lipophilic linkers was introduced a decade ago as a way to increase the surfactant–oil interaction and the oil solubilization capacity. Long chain (>9 tail carbons) alcohols were first used as lipophilic linkers. Later it was found that the solubilization enhancement plateaus (saturates) above a certain lipophilic linker concentration. Hydrophilic linkers have been recently introduced as a way to compensate for the saturation effect observed for lipophilic linkers. Hydrophilic linkers are surfactant-like molecules with 6–9 tail carbons that coadsorb with the surfactant at the oil/water interface, thereby increasing the surfactant–water interaction, but have a poor interaction with the oil phase due to their short tail. A special synergism emerges when combining hydrophilic and lipophilic linkers, which further increases the solubilization enhancement over lipophilic linkers alone. We will discuss the profound impact of linker molecules on interfacial properties such as characteristic length, interfacial rigidity and dynamics (coalescence, solubilization and relaxation experiments) of the interface. We also demonstrate how these properties affect the performance of cleaning formulations designed around linker molecules. We describe linker-based formulations for a wide range of oils, including highly hydrophobic oils (e.g. hexadecane) that have proven very hard to clean. We also report on the use of ‘extended’ surfactants as an alternative to self-assembled linker systems.     

活性氧刺激响应纳米载体

纳米载体一般是由天然高分子或人工合成高分子组成的、纳米级范畴的运输系统,具有减少药物毒性、提高药物的靶向性、增加药物有效性等优点。随着生物医学技术的进步,有研究表明,作为氧化代谢产物的活性氧(ROS)在疾病部位常常伴随着过表达的异常现象。基于此,近年来ROS刺激响应纳米载体获得了关注和发展,以不同响应机制的ROS响应基团为基础,发展了一系列的ROS响应纳米载体,实现了疾病部位ROS刺激下的药物特异性可控释放。该文聚焦于近年来常用于纳米载体的ROS响应基团,依据元素划分为两大类:硫族元素类响应基团(硫醚、缩硫酮、硒化物、二硒化物、碲化物)和其他元素类响应基团(芳香硼酸酯、过氧草酸酯、二茂铁);通过不同的设计理念将其引入纳米载体,根据ROS响应纳米载体的不同响应机制(疏水-亲水相变、断裂),探讨了载体各自的ROS响应情况、体外药物释放情况,以及在活体中的应用情况。     

Competitive Excimer Formation and Energy Transfer in Zr‐Based Heterolinker Metal–Organic Frameworks

The spectroscopy and dynamics of a series of Zr‐based MOFs in dichloromethane suspension are reported. These Zr‐NADC MOFs were constructed by using different mixtures of 2,6‐naphthalenedicarboxylate (NDC) and 4‐amino‐2,6‐naphthalenedicarboxylate (NADC) as organic linkers. The fraction of NADC relative to NDC in these heterolinker MOFs ranges from 2 to 35 %. The results indicate two competitive photoprocesses: NDC excimer formation and an energy transfer (ET) from excited NDC linkers to NADC linkers. Increasing the fraction of NADC linkers in the Zr‐NADC nanostructure decreases the mean time constant of NDC excimer formation, while the NADC emission intensity experiences a drop at the highest fraction of this linker in the MOF. The first observation is explained by an increase in the energy‐transfer probability between the two linkers, and the second by emission quenching in the NADC linkers due to ultrafast charge transfer assisted by the amino group. Femtosecond time‐resolved emission studies showed that the ET process (recorded as decaying and rising components) from excited NDC to NADC takes place in 1.2 ps. Direct excitation of the NADC linkers (at 410 nm) shows a decaying, but not rising, component of 250–480 fs, which could reflect the formation of a nonemissive charge‐separation state. The results show that by using MOFs having heterolinkers it is possible to trigger and tune excimer formation and ET processes.     

Phosphate-Based Self-Immolative Linkers for Tuneable Double Cargo Release

Phosphorus-based self-immolative (SI) linkers offer a wide range of applications, such as smart materials and drug-delivery systems. Phosphorus SI linkers are ideal candidates for double-cargo delivery platforms because they have a higher valency than carbon. A series of substituted phosphate linkers was designed for releasing two phenolic cargos through SI followed by chemical hydrolysis. Suitable modifications of the lactate spacer increased the cargo release rate significantly, from 1 day to 2 hours or 5 minutes, as shown for linkers containing p-fluoro phenol. In turn, double cargo linkers bearing p-methyl phenol released their cargo more slowly (4 days, 4 hours, and 15 minutes) than their p-fluoro analogues. The α-hydroxyisobutyrate linker released both cargos in 25 minutes. Our study expands the current portfolio of SI constructs by providing a double cargo delivery option, which is crucial to develop universal SI platforms.     

Phosphate-Based Self-Immolative Linkers for the Delivery of Amine-Containing Drugs

Amine-containing drugs often show poor pharmacological properties, but these disadvantages can be overcome by using a prodrug approach involving self-immolative linkers. Accordingly, we designed l-lactate linkers as ideal candidates for amine delivery. Furthermore, we designed linkers bearing two different cargos (aniline and phenol) for preferential amine cargo release within 15 min. Since the linkers carrying secondary amine cargo showed high stability at physiological pH, we used our strategy to prepare phosphate-based prodrugs of the antibiotic Ciprofloxacin. Therefore, our study will facilitate the rational design of new and more effective drug delivery systems for amine-containing drugs.     

Effect of Linker Length and Flexibility on the <Emphasis Type="Italic">Clostridium thermocellum</Emphasis> Esterase Displayed on <Emphasis Type="Italic">Bacillus subtilis</Emphasis> Spores

In fusion protein design strategies, the flexibility and length of linkers are important parameters affecting the bioactivity of multifunctional proteins. A series of fusion proteins with different linkers were constructed. The effect of temperature, pH, and organic solvents was investigated on the enzymatic activity. Fusion proteins with P1(PTPTPT) and P2((PTPTPT)₂) linkers remained highly active with wide temperature range. At pH 9.6, the relative activity of fusion proteins with (PTPTPT)₂ and S2(EGKSSGSGSESKST) linkers was 70 and 62 % (1.75 and 1.5 times of that of non-linker ones). Fusion proteins with S3((GGGGS)₄) linker retained 55 % activity after 5 h of incubation at 80 °C (1.2-fold of that of non-linker fusion proteins and 1.9-fold of GGGGS-linker fusion proteins). Finally, the relative activity of fusion proteins having different linkers was increased with 20 % dimethyl sulfoxide (DMSO) and methanol; relative activity of fusion proteins with EGKSSGSGSESKST linkers was enhanced 1.5- and 2.2-fold, respectively. These results suggest that longer flexible linker can enhance the activity and stability of displayed esterase than shorter flexible linker. Optimizing peptide linkers with length, flexibility, and amino acid composition could improve the thermostability and activity of the displayed enzyme.     

Solution- and solid-phase syntheses of guanidine-bridged, water-soluble linkers for multivalent ligand design

[reaction: see text] Efficient syntheses of guanidine-bridged poly(ethylene glycol) linkers of various lengths in fully protected form are reported for both solution- and solid-phase protocols. The application of such linkers in the construction of water-soluble and high-affinity multivalent ligands against cholera toxin is demonstrated. Synthetic intermediates for multivalent ligands as large as 20 kDa in molecular weight have been assembled using presynthesized linkers. The final ligands are highly water-soluble, thus enabling proper biophysical characterization.