β-模拟肽的构象限制在药物设计中的应用

传统肽类药物在体内环境下易水解,具有不稳定性,以β-氨基酸为基本单位的β-肽相比传统的α-肽,药代动力学参数更加良好,因此蕴藏更大的药物开发价值。β-氨基酸构象限制后,可发展为β-模拟肽。构象限制的目的是使β-模拟肽链趋向于形成固定的二级结构,按特定方式折叠,最终具备理想的三维空间结构,嵌合于特定的酶和受体,从而提高目标肽的生物活性和代谢稳定性。本文主要综述β-模拟肽局部修饰和肽链整体环化的构象限制方法以及限制后生物活性或物理化学参数的变化,以此为β-肽类药物的设计原则和方法提供指导,减少设计盲目性。     

4—（N—烷基）胺甲基苯丙氨酸的合成

在生物活性肽研究中,通过在肽主链中引入特定结构的氨基酸,得到其活性类似物,可以使人们进一步认识肽结构与生物活性之间的关系,发展高活性、低副作用的肽类药物。蛋白氨基酸的结构都是一定的,不能满足研究工作的需要,所以需要设计合成特定结构的非蛋     

类肽与金属蛋白酶抑制剂类抗肿瘤药物研究进展

类肽作为天然活性肽的结构或功能模拟物,具有3个优点：一是能够保留天然肽的底物功能,二是可改善其代谢性质,三是可提高其作用的靶向专一性等特点．高活性的类肽分子设计可通过构象限定、结构改造和非肽模拟物设计的构思等多种手段实现．目前肿瘤化疗药物开发的研究热点已由细胞毒药物转向靶向治疗药物,在肿瘤发生发展过程中起关键作用的许多蛋白酶和肽酶陆续被发现,因此类肽作为潜在的肿瘤化疗药物已倍受关注,而如何设计具有抗肿瘤活性的小分子类肽酶抑制剂则已成为研究的热点．本课题组多年来一直致力于研究开发APN、MMPs及HDACs的小分子类肽抑制剂作为靶向抗肿瘤药物先导物．这三种锌离子依赖性金属蛋白酶在肿瘤的生长侵袭转移、血管生成和基质降解等发展进程中起着关键作用,靶向于该类生物靶点的小分子类肽抑制剂具有开发成为高选择性抗肿瘤药物的巨大潜力．     

3，5-二氟-4-碘-苯甲醚的合成

生物活性含氟化合物作为活性强、选择性高的药物[1]及农药[2]已广泛应用;生物活性含氟化合物可以作为标记化合物模拟体内代谢过程[3],在酪氨酸分子的一定位置上氟代后,用电子能量损耗光谱可以对酪氨酸及其代谢产物进行分子水平的跟踪,而且酪氨酸分子中某些特定位置上的氢原子被     

磺酰基在药物分子设计中的应用

含磺酰基药物在临床治疗药物中占有相当比重,将磺酰基引入到小分子中是药物分子结构改造的重要策略之一,综述了磺酰基在药物分子设计中的应用.就结构而言,磺酰基和羰基、羧基、四氮唑、磷酸基具有相似的大小和电荷分布,可以作为它们的生物电子等排体而引入到小分子中,从而保持或增强小分子的生物活性;磺酰基具有独特的物理化学性质,磺酰基的引入可以调节小分子的溶解性和酸碱性;磺酰基能提供两个氢键受体,合理的引入磺酰基可以通过增加小分子和作用靶标的氢键相互作用而提高化合物的生物活性;磺酰基结构较稳定,引入磺酰基可以通过阻断易代谢位点而提高药物代谢稳定性,延长其作用时间,提高其生物利用度,从而改善小分子的药代动力学性质;磺酰基属于极性基团,磺酰基的引入还可以增加小分子的极性从而降低h ERG毒性.     

碱性离子液体催化合成取代萘并吡喃衍生物

离子液体具有强极性、不挥发、化学稳定性好等特点,其极性和亲水/亲脂性可通过改变烷基碳链的长短和阴、阳离子的种类来进行调节,对其结构进行化学修饰,可以得到具有特定功能的离子液体[1-3],因此被誉为绿色溶剂和可设计的溶剂[2]。许多萘并吡喃衍生物都具有重要的生物活性和药     

多肽定量构效关系与分子设计

综述了多肽定量构效关系和计算机辅助多肽分子设计方法的最新进展,重点介绍了多肽定量构效关系研究中的化学结构定量描述符和建立数学模型的统计方法,并对模拟肽学和虚拟组合多肽库在多肽分子设计中的应用进行了简要的论述.     

催化水解反应的肽基模拟酶的活性来源、催化机理及应用

肽基材料由于其与蛋白质高度相似和结构可控等优势,是构建人工模拟酶的一种理想材料;此外,小肽中氨基酸排列的多样性、序列的自组装特性、纳米结构稳定性、结构简单易于设计、良好生物相容性等优势,使得构建具有高效催化活性的肽基模拟酶具有非常好的应用前景。利用肽基材料通过理性设计活性位点来构建模拟酶具有多方面优势:(1) 氨基酸序列可以直接从天然酶中的活性位点获得,保留酶的功能,但降低了酶固有的复杂性;(2) 肽序列中可以嵌入各种具有特定结构及功能的活性位点,便于对模拟酶进行人工理性设计;(3) 肽具有良好的生物相容性,可以在温和条件下催化反应进行。根据催化降解化学键的不同,可将肽基水解模拟酶分为以下几种:催化酯键降解的肽基模拟酶、催化肽键降解肽基模拟酶、催化糖苷键水解的肽基模拟酶。本文主要分析了具有水解酶活性的肽基模拟酶的活性来源、构建方法及微观结构、催化反应类型、催化影响因素、活性改善方法、作用机理及未来潜在应用等;以期为构建具有高效水解催化活性的模拟酶提供借鉴,推进肽基水解模拟酶的研究发展及实际应用。     

HLA-A*0201限制性CTL表位肽的三维定量构效关系的研究

运用比较分子力场(CoMFA)和比较分子相似性指数分析(CoMFA)方法研究了50个HLA-A^*0201限制性CTL表位九肽结构与亲和性间的关系,另外15个表位九肽作为预测集用于检验模型的预测能力.结果表明采用CoMSIA得到的构效关系模型(q^2=0.628,r^2=0.997,F=840.419)要明显优于采用CoMFA得到的构效关系模型.在CoMSIA计算中,当引入疏水场时,三维构效关系模型得到明显改善,通过该三维构效关系模型,可较精确地估算预测集中15个CTL表位肽与HLA-A^*0201间的亲和力(r^2pred=0.743).通过分析分子场等值面图在空间的分布,可以观察到表位肽分子周围的立体及疏水特征对表位肽与HLA-A^*0201间结合亲和力的影响,从而为进一步对CTL表位肽进行结构改造并基于此进行治疗性疫苗分子设计提供理论基础.     

非蛋白氨基酸对生物活性多肽的修饰及其构效关系的研究进展

简述了非蛋白氨基酸的结构特征和生理活性。介绍了某些天然存在的含非蛋白氨基酸的生物活性肽及非蛋白氨基酸残基在相应活性肽中的重要作用。着重总结了非蛋白氨基酸对生物活性肽进行修饰的方式和构效关系研究的进展。     

二氧化碳和丙烯直接合成甲基丙烯酸的NiPMo/TiO2催化剂的研究

用溶胶-凝胶法以磷钼酸(MPA)的镍盐溶液水解钛酸四丁酯制备了NiPMo/TiO2催化剂.使用ICP、 XRD、 TG-DTA、 IR、 TPD-MS和微反应技术研究了催化剂的化学组成、热稳定性、化学吸附性质和催化反应性能.杂多钼酸盐与TiO2通过O2-在TiO2表面发生了键合.在623 K下,杂多阴离子仍保持原有的Keggin结构.CO2在Lewis酸位Ni(Ⅱ)和Lewis碱位Ni-O-Mo的桥氧协同作用下生成CO2卧式吸附态Ni(Ⅱ)←O-(CO)←(O--Ni).丙烯有多种吸附态在催化剂上吸附.在563 K、 1 MPa和空速1500 h-1的反应条件下,丙烯的摩尔转化率为3.2%,产物MAA选择性为95%.     

Synthesis of 1-benzyloxypyrazin-2(1H)-one derivatives

Different approaches for the synthesis of 1-benzyloxypyrazin-2(1H)-one derivatives from simple amino acids have been investigated. A library of 33 precursors for the preparation of N-hydroxy pyrazinones was obtained in moderate to good yields.     

A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in amidoalkylation of hydrogen,heteroatom, and carbon nucleophiles

A general synthesis of previously unknown semicarbazone-based α-amidoalkylating reagents, 4-(tosylmethyl)semicarbazones, has been developed. The synthesis involved three-component condensation of semicarbazones of aliphatic or aromatic aldehydes with the same or other aldehydes and p-toluenesulfinic acid. The scope and limitations of this reaction were investigated. The compounds obtained were demonstrated to be an efficient α-(4-semicarbazono)alkylating agents. They were reacted with H- (sodium borohydride), O- (sodium methylate), S- (sodium phenylthiolate), N- (pyrrolidine, sodium succinimide), P- (trialkyl phosphites), and C-nucleophiles (sodium diethyl malonate) to give the corresponding products of the tosyl group substitution, 4-substituted semicarbazones, including analogues of nitrofurazone. Among the prepared compounds tested in vitro for antibacterial and antifungal activity, three nitrofuryl-containing semicarbazones exhibited high biological activities with minimum inhibitory concentration (MIC) values of 8–32 μg/mL.     

Toward new camptothecins. Part 6: Synthesis of crucial ketones and their use in Friedländer reaction

In the context of the preparation of camptothecin and luotonin A analogs, the synthesis of some key keto-precursors and their use in Friedländer condensation are described. This paper also focuses on the stability of these keto intermediates and emphasizes the major differences between indolizinones and pyrroloquinazolinones series. Noteworthy is also the report of some original structures isolated as by-products of some experiments.     

Synthesis of novel chiral bidentate hydroxyalkyl-N-heterocyclic carbene ligands and their application in palladium-catalyzed Mizoroki–Heck couplings and asymmetric addition of diethylzinc to benzaldehyde

A small library of new chiral bidentate hydroxyalkyl-imidazolium salts 1 is conveniently synthesized on multi-gram scale from inexpensive and commercially available chiral pool amino acids. The corresponding carbenes, generated by deprotonation of imidazolium salts 1, in combination with palladium(II) chloride were tested in the Mizoroki–Heck coupling reaction. The most significant results in terms of yields and reactivities were achieved with low catalyst loading. The catalytic activities of these imidazolium salts were also investigated in the asymmetric addition of diethylzinc to benzaldehyde. The use of MgO nanoparticles as an additive in conjunction with these ligands played a crucial role in increasing the efficiency of these reactions.     

α-Amino acid derived enaminones and their application in the synthesis of N-protected methyl 5-substituted-4-hydroxypyrrole-3-carboxylates and other heterocycles

A new and simple synthesis of novel N-protected methyl 5-substituted-4-hydroxypyrrole-3-carboxylates, which exist in equilibrium with their 4-oxo tautomers, has been developed in two steps starting from N-protected α-amino acids. The key intermediates are enaminones, which can also be isolated, characterized, and used for the construction of other functionalized heterocycles, before they spontaneously decompose to pyrrole products. 4-Hydroxypyrroles are prone to partial aerial oxidation but can be efficiently alkylated or reduced to stable polysubstituted pyrrolidine derivatives.     

Specific intramolecular aromatic CH insertion of diazosulfonamides

The chemoselectivity in the intramolecular CH insertion of various diazosulfonamides has been experimentally studied. The results reveal that the aliphatic 1,4-, 1,5-, or 1,6-C(sp³)?H insertions of diazosulfonamides are not accessible, while the aromatic 1,5-C(sp²)?H insertion can be realized specifically by adjusting the diazo-adjacent group. In addition, the general chemoselectivities in the intramolecular CH insertions of diazosulfonyl compounds are summarized. Generally, diazosulfones undergo both aromatic 1,5-C(sp²)?H and aliphatic 1,5- and 1,6-C(sp³)?H insertions, while diazosulfonates undergo aliphatic 1,5- and 1,6-C(sp³)?H insertions. However, diazosulfonamides only undergo aromatic 1,5-C(sp²)?H insertion.     

CoFe2O4自形成磁性液体场致结构化对磁化的影响

The Langevin paramagnetic theory can’t describe the relation between magnetization of ferrofluids and applied magnetic field. The structuralization of ferrofluids, which is considered the main influence factor of the magnetization, is regarded. The part of magnetization works is deposited when the structure is forming. This action influences the magnetization of ferrofluids directly or indirectly. On the base of the “compressing” model, the Langevin function that usually describes the magnetization of ferrofluid is modified, and a well-fitted curve is obtained. An equation of the relation between the equivalent volume fraction after being “compressed” and the intensity of magnetic field is discovered, which approximately describes the process of magnetization. The relation between the approximate initial susceptibility and the volume fraction can be obtained from modified formula.     

KMnO4-mediated oxidative CN bond cleavage of tertiary amines: Synthesis of amides and sulfonamides

KMnO₄-mediated oxidative CN bond cleavage of tertiary amines producing secondary amine was introduced, which was trapped by electrophiles (acyl chloride and sulfonyl chloride) to form amides and sulfonamides. The reaction could take place at mild condition, tolerating a wide range of function groups and affording products in moderate to excellent yields.     

Microwave-assisted copper-catalyzed stereoselective ring expansion of three-membered heterocycles with α-diazo-β-dicarbonyl compounds

Microwave-assisted copper-catalyzed ring expansions of three-membered heterocycles with α-diazo-β-dicarbonyl compounds were investigated. Thiiranes generated 3-acyl-5,6-dihydro-1,4-oxathiines in the presence of copper sulfate and trans-3-acyl-5,6-dihydro-1,4-oxathiines as stereospecific products for 1,2-disubstituted cis-thiiranes through an intramolecular S_N2 process. Oxiranes gave rise to 2-acyl-5,6-dihydro-1,4-dioxines under the catalysis of copper hexafluoroacetylacetonate and cis-3-acyl-5,6-dihydro-1,4-dioxines as stereospecific products for 1,2-disubstituted cis-oxiranes via an intimate ion-pair mechanism. The current method provides a direct and simple strategy in efficient preparation of 3-acyl-5,6-dihydro-1,4-oxathiines and 2-acyl-5,6-dihydro-1,4-dioxines, important agents in medicinal and agricultural chemistry, from readily available thiiranes and oxiranes, respectively.