二价HIV-1融合抑制剂的设计、合成与活性评价

针对人免疫缺陷病毒跨膜糖蛋白(HIV-1 gp41)N末端重复序列靶标设计二价融合抑制剂, 以C肽为模板, 通过共价交联形成类似发夹结构的相互平行的2条肽链, 研究了二价C肽分子不同连接位点与不同连接臂对抗HIV融合活性的影响. 细胞-细胞融合活性测试表明, 与单价分子相比, 所设计的基于N末端交联的C34或T20的二价分子在前体共价交联后, 活性明显提升. 基于C34或T20的N末端与C末端均存在发生协同效应的可能性, 在C34的N末端设计中β-丙氨酸为最适连接臂, 而在C末端的设计中C34C的融合活性提高最大. 单价分子CβAC34经过氧化形成二硫键连接的二价分子BiCβAC34, 融合活性从43.7 nmol/L提高到6.4 nmol/L, 表明二价抑制剂中2条C肽链间具有良好的协同效应. 本文结果表明, 针对gp41靶标设计的二价融合抑制剂能够相互协同.     

基于α螺旋肽与多酚缀合的HIV-1融合抑制剂的设计、合成及活性初筛

将α螺旋多肽与羟基酪醇等多酚类化合物通过共价键缀合,期望二者在发挥各自生物学作用的同时产生协同效应,据此设计了HIV-1融合抑制多肽.圆二色光谱表征结果表明,所设计的缀合多肽呈典型的α螺旋结构特征,且可以与靶标N36相互作用.HIV-1包膜糖蛋白(Env)介导的细胞-细胞融合活性测试结果表明,这些具有α螺旋结构的缀合多肽可以在低微摩尔水平抑制病毒融合.     

促性腺激素释放激素类似物-紫杉醇靶向抗肿瘤缀合物的合成及评价

以促性腺激素释放激素类似物(GnRHa)为靶向配体, 以紫杉醇为抗癌因子, 分别以硫醚键和二硫键为连接臂, 设计合成了2个靶向抗肿瘤缀合物. 研究了缀合物的肿瘤细胞增殖抑制活性和GnRH受体结合活性, 结果表明, 2个缀合物均具有较强的抗肿瘤活性和GnRH受体亲和力; 另外, 血浆稳定性实验结果显示, 以硫醚键偶联的缀合物1在血浆中孵育24 h, 原型保留仍在50%以上, 具有较高的稳定性.     

新型饱和脂肪酸胆酸缀合物的合成及抗胆结石活性研究

胆结石是常见多发病, 但临床缺乏有效的治疗药物. 饱和脂肪酸与胆酸的缀合物能有效预防胆固醇结晶、溶解体内胆固醇结石. 以胆酸或熊去氧胆酸24位羧基为连接位点, 以氨基酸为连接子, 通过酰胺键将载体与具有溶石活性的饱和脂肪酸偶联, 设计合成了一系列新型脂肪酸胆酸缀合物, 其结构经元素分析, IR, 1H NMR和MS光谱分析确证. 通过测定化合物对模型胆汁溶液胆固醇结晶及模型小鼠胆结石的溶解活性, 研究了其体内外溶石活性.     

新型槲皮素缀合物的合成与降糖活性研究

经过五步反应以15%~46%的总收率成功合成了8个新型的槲皮素缀合物20~27.以芦丁为起始原料,经O-苄基化、酸催化糖苷水解、烷基化等步骤,获得重要中间体5,7,3',4'-四苄氧基-3-O-炔丙基槲皮素;再经过Click反应,得到槲皮素缀合物中间体12~19,最后经催化氢化得到系列糖基、聚乙二醇(PEG)或寡聚乙二醇(OEG)与槲皮素偶联的新型缀合物.经体外3T3-L1脂肪细胞水平降糖活性测试,结果显示缀合物24,26和27具有较好的降糖活性.     

环状多聚硫醚化合物的合成及生物活性研究

通过二硫醇化合物与二氯代物缩合,再酰化的方法合成了14个具有环状结构的新颖多聚硫醚化合物,其中12个为新化合物,得到的化合物经1H NMR,13C NMR和HREIMS确证其结构,部分化合物还经晶体X衍射方法确证.通过对II型糖尿病靶标蛋白酪氨酸磷酸酯酶(PTP1B)抑制活性的分析,发现一些化合物具有一定的PTP1B抑制活性.     

小分子靶标的核酸适配体筛选的研究进展

核酸适配体(aptamer)是通过指数富集配体系统进化(SELEX)技术筛选得到的核糖核酸(RNA)或单链脱氧核糖核酸(ssDNA)。核酸适配体通过高亲和力特异性地识别小分子、蛋白质、细胞、微生物等多种靶标,在生物、医药、食品和环境检测等领域的应用日渐增多。但目前实际可用的核酸适配体有限,其筛选过程复杂,筛选难度大,制约了其应用。与生物大分子、细胞和微生物等靶标不同,小分子靶标与核酸分子的结合位点少、亲和力弱,且靶标通常需要固定在载体上。此外,小分子靶标结合核酸形成的复合物与核酸自身的大小、质量、电荷性质等方面差异较小,二者的分离难度大。故小分子靶标的核酸适配体筛选过程与大分子和细胞等复合靶标相比有明显差异,筛选难度更大。因此需要根据其自身结构特点和核酸适配体的应用目的选定靶标或核酸库的固定方法,优化靶标核酸复合物的分离方法。本文介绍了不同类型小分子(具有基团差异的单分子、含相同基团分子和手性分子等)靶标的选择及其核酸适配体的筛选方法,并对核酸库的设计、与靶标结合的核酸的分离方法和亲和作用表征方法进行了介绍,列出了自2008年以来报道的40余种小分子靶标的核酸适配体序列和复合物的平衡解离常数(K_d)。     

N-4-羟基苯基维甲酰胺与呋咱氮氧化物偶联物的合成及抗肿瘤活性研究

为了寻找治疗乳腺癌的药物, 将N-4-羟基苯基维甲酰胺(4-HPR)以乙酸为连接基团通过酯键或酰胺键与NO供体呋咱氮氧化物缀合, 合成了NO供体型维甲酸类化合物, 共11个新的目标化合物, 其结构经IR, MS, ¹H NMR和元素分析表征, 总收率为8.8%～12.9%. 对目标物进行体外抗乳腺癌活性测试, 结果表明, 所有目标物均具有不同程度的抗肿瘤活性, 其中8g抗肿瘤活性和对照药阿霉素相当.     

胆固醇修饰的非天然HR序列肽类HIV-1融合抑制剂的合成及活性初筛

将胆固醇分子通过1个半胱氨酸侧链硫醚键和1个β-丙氨酸连接臂引入到所设计的非天然HR序列抗HIV融合活性多肽的C端和N端,合成了与天然C肽序列同源性很低的非天然序列的类肽抗HIV融合分子,以考察胆固醇修饰对非天然HR序列活性的影响,探讨克服耐药性的新思路.生物活性评价结果表明,胆固醇与HR肽C端结合物抑制HIV融合活性显著提高,而连接到N端的序列则完全失去了抗病毒活性,表明所设计的非天然序列确实具有与天然序列类似的作用机制.     

10-羟基喜树碱氨基酸缀合物的合成及抗肿瘤活性研究

以10-羟基喜树碱为原料,通过两碳边链链接,合成了一系列10-羟基喜树碱氨基酸缀合物和9-硝基-10-羟基喜树碱氨基酸缀合物.采用CCK-8法测试了合成化合物体外对人口腔鳞癌细胞KB、人肝癌细胞HepG2和小鼠结肠癌细胞C26三组细胞株的增殖抑制活性,结果表明部分目标化合物对所选肿瘤细胞株显示了潜在的抑制活性,其中10-羟基喜树碱氨基酸缀合物的体外活性明显优于9-硝基-10-羟基喜树碱氨基酸缀合物的体外活性.     

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.     

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.     

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.     

Highly regioselective Buchwald–Hartwig amination at C-2 of 2,4-dichloropyridine enabling a novel approach to 2,4-bisanilinopyridine (BAPyd) libraries

The highly regioselective Buchwald–Hartwig amination at C-2 of the cheap and readily accessible reagent, 2,4-dichloropyridine with a range of anilines and heterocyclic amines is described. This new methodology is robust and provides a facile access to 4-chloro-N-phenylpyridin-2-amines on 0.25 mol scale. These intermediates undergo a further Buchwald–Hartwig amination at higher temperature to enable rapid exploration of the chemical space at C-4 and to provide a library of 2,4-bisaminopyridines.     

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.     

Chemistry of heterocyclic compounds at the A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, over 50 years (Review)

The review contains a concise historical account and information on the most significant researches undertaken by the staff at the A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences on the Chemistry of Heterocyclic Compounds. Dedicated to Academician of the Russian Academy of Sciences B. A. Trofimov on his 70th jubilee. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1443–1502, October, 2008.     

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.     

Sulfur-directed metal-free and regiospecific methyl C(sp3)–H imidation of thioanisoles

Regiospecific and direct imidation of the methyl C(sp³)–H bond of thioanisoles is realized under mild and metal-free conditions with N-fluorobis(benzenesulfonyl)imide as an oxidant and nitrogen source. Proposed mechanism suggests that thionium ion intermediates and a Pummerer-type reaction are involved. The imidation has advantages such as high step-economy, excellent functionality tolerance, and regiospecificity, giving structurally diverse imidation products.     

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.