生物小分子钒配合物抑制蛋白酪氨酸磷酸酶活性研究

钒化合物治疗糖尿病机理研究表明其与蛋白酪氨酸磷酸酶的酶活抑制有一定关系。本文分别研究了生物小分子配体与氧钒离子在20:1配比条件下形成的生物小分子钒配合物及其对蛋白酪氨酸磷酸酶的抑制作用和选择性。结果表明氨基酸与氧钒离子配合形成2:1的配合物, 而抗坏血酸及多羧酸与氧钒离子配合形成1:1的配合物。它们对蛋白酪氨酸磷酸酶抑制作用显示, 大部分生物小分子氧钒配合物对PTP1B表现强烈的抑制作用, IC₅₀值在0.12~0.63 μmol·L^-1之间。化合物[VO(Phe)₂]表现最强的抑制作用, IC₅₀值为0.07 μmol·L^-1。而[VO(Arg)₂]、[VO(Oxalate)]、[VO(Nitrilotriacetate)]和[VO(Citrate)]则呈现较弱的抑制, IC₅₀值分别为1.05、1.41、9.90和21.5 μmol·L^-1。对PTP1B, TCPTP, HePTP以及SHP-1的抑制作用表明配体的结构不仅影响氧钒配合物对蛋白酪氨酸磷酸酶的抑制效率同时也影响其选择性。     

含氮杂环氧钒配合物对PTP1B和ALP的抑制活性研究

蛋白酪氨酸磷酸酶1B (protein tyrosine phosphatase 1B, PTP1B)是当前开发治疗糖尿病药物的优秀靶标, 也是钒配合物抗糖尿病作用相关的重要靶蛋白. 研究了三种含氮平面杂环螯合配体2,2’-联咪唑(L1), 2,2’-联吡啶(L2), 1,10-邻菲咯啉(L3)的氧钒配合物对PTP1B以及碱性磷酸酶(alkaline phosphatase, ALP)的体外抑制作用. 结果表明, 1∶1和2∶1型配位的氧钒化合物均表现出对PTP1B较强的抑制活性, IC50值在120～260 nmol/L间, 抑制能力接近双麦芽酚氧钒配合物(BMOV). 抑制动力学实验表明这些氧钒配合物对PTP1B的抑制模式均为竞争性抑制, 抑制常数在20～160 nmol/L. 其对PTP1B抑制活性较ALP高103倍, 表明氧钒配合物对两种磷酸酶的抑制具有一定的选择性.     

芳酰胺类衍生物的合成及蛋白酪氨酸磷酸酶1B和含SH2结构域蛋白酪氨酸磷酸酶2抑制活性研究

为拓展含串联二芳酰胺结构的蛋白酪氨酸磷酸酶1B(PTP1B)抑制剂的化学空间,将其中的联苯二胺结构单元简化为芳基酰胺结构单元,设计并合成了18个芳酰胺类化合物.活性测试结果表明,部分芳酰胺衍生物对PTP1B和含SH2结构域蛋白酪氨酸磷酸酶2(SHP2)显示了一定强度的抑制活性.其中化合物3c[IC_(50)=(5.13±0.21)μmol/L]对PTP1B显示了中等强度的抑制活性,并且对其他亚型[T细胞蛋白酪氨酸磷酸酶(TCPTP)、含SH2结构域蛋白酪氨酸磷酸酶1(SHP1)和SHP2]显示了一定的选择性.有意思的是,化合物12对SHP2显示了中等强度的抑制活性[IC50=(7.47±1.26)μmol/L],对PTP1B、TCPTP以及SHP1显示了2倍的选择性,为发现新型选择性SHP2抑制剂提供了新的骨架类型.     

酰腙氧钒(Ⅴ)配合物的合成、结构及其抑制幽门螺旋杆菌脲酶研究

为了探索新型高效脲酶抑制剂,本文合成了2个新的酰腙氧钒(V)配合物,[VOL1(OCH3)(CH3OH)](1)和[VOL2(μ-OCH3)]2(2)(H2L1=N′-(5-氯-2-羟基苯亚甲基)-3-硝基苯甲酰肼;H2L2=N′-(5-氯-2-羟基苯亚甲基)-4-氯苯甲酰肼),并通过物理化学方法和单晶X-射线衍射表征了它们的结构。化合物1是一个单核配合物,而化合物2是由两个甲氧基配体桥连的具有中心对称性的双核配合物。在每个配合物中,V原子都采取八面体配位构型。本文还研究了这两个配合物的热稳定性和它们对幽门螺旋杆菌脲酶的抑制活性。在浓度为100μmol.L-1时,配合物1和2对脲酶的抑制率分别为71.4%和73.3%,其IC50值分别为63.6和37.7μmol.L-1。     

两个含吡咯环酰腙配体的Cu(Ⅱ)配合物的合成、晶体结构和生物活性（英文）

合成并通过元素分析,红外和X-射线单晶衍射表征了2个酰腙铜配合物[Cu(L)2(THF](1)和[Cu(L)(CH3OH)Cl](2)[HL=3,4-二甲基-2-乙氧羰基-吡咯-5-甲醛苯甲酰腙]。结果表明在每个配合物中,HL脱质子作为阴离子配体,通过烯醇化的氧和亚氨基的氮与中心铜(Ⅱ)离子配位。中心铜(Ⅱ)离子在配合物1和2中的配位构型分别为扭曲的四方锥和平面正方形。配合物2对金黄色葡萄球菌有明显的抑制作用(MIC=1.98μg·m L-1),而配合物1则对肝癌细胞Hep G2展现出显著的抗肿瘤活性(IC50=9.1μmol·L-1)。     

4-(2-羟基-3-氯)苯基-2,2':6',2"-三联吡啶Cu(Ⅱ)配合物的合成、结构表征及抗肿瘤活性

以4-(2-羟基-3-氯)苯基-2,2′∶6′,2″-三联吡啶(HL)为配体,合成了一种新的铜(Ⅱ)配合物[Cu2(μ-L-κO,O)2Cl2](1),并通过红外光谱、电喷雾质谱、元素分析及单晶X射线衍射分析等方法对配合物1进行结构表征。配合物1为双核结构,中心铜(Ⅱ)离子为五配位扭曲四方锥几何构型,每个铜离子与1个Cl-以及来自配体(L-)的2个N原子和2个羟基O原子配位,2个铜(Ⅱ)离子通过羟基的桥联形成双核结构。MTT实验结果表明:配合物1对所选5种癌细胞株表现出不同的抑制活性,尤其是对MGC80-3细胞的抑制作用最明显,抑制率高达(84.30±1.28)%,其IC50值为(3.36±0.43)μmol·L-1。流式细胞术分析结果显示:配合物1能诱导MGC80-3细胞凋亡。在配合物1浓度为4.5μmol·L-1时,MGC80-3的凋亡百分数为41.4%。此外,配合物1将MGC80-3细胞阻滞于G1期,从而抑制肿瘤细胞的生长。     

(E)-1-取代苯基-3-[4-((E)-(2-(4-苯基噻唑-2-基)腙)甲基)苯基]-2-丙烯-1-酮的合成及PTP1B抑制活性研究

蛋白酪氨酸磷酸酶1B(PTP1B)作为胰岛素和瘦素信号转导通路的负调节因子,已成为治疗糖尿病和肥胖症的潜在靶标.为了寻找非磷酸酯类PTP1B抑制剂,设计、合成了一系列(E)-1-取代苯基-3-[4-((E)-(2-(4-苯基噻唑-2-基)腙)甲基)苯基]-2-丙烯-1-酮(4a～4n),并对化合物进行了PTP1B抑制活性测定.结果显示,所有化合物对PTP1B均显示出较强的抑制活性,其中化合物4h活性最佳,IC50为(2.57±0.50)μmol L-1.     

含乙酰氧肟酸配体的席夫碱钒配合物的合成、结构及其抑制幽门螺旋杆菌脲酶研究(英文)

本文合成了2个新的含乙酰氧肟酸配体的席夫碱钒配合物,[VⅢL1(HAHA)](1)和[VⅤOL2(AHA)](2),其中L1为N,N′-二(5-甲基水杨基)乙烷-1,2-二胺的二价阴离子,L2为2-{[2-(2-羟乙基氨基)乙亚胺基]甲基}-6-甲基苯酚的一价阴离子,HAHA和AHA分别为乙酰氧肟酸的一价和二价阴离子,通过物理-化学方法以及单晶X-射线衍射表征了它们的结构。在每个化合物中,V原子都采取八面体配位构型。本文还研究了配合物的热稳定性以及其对幽门螺旋杆菌脲酶的抑制活性。在浓度为100μmol·L-1时,配合物1和2对脲酶的抑制率分别为37.2%和81.5%,其中配合物2的IC50值为21.5μmol·L-1。分子对接研究表明配合物2与脲酶活性中心存在有效的作用力。     

水杨醛缩芳胺席夫碱铜(Ⅱ)配合物抑制蛋白酪氨酸磷酸酶活性研究

为了探讨席夫碱配体上取代基变化对其配合物抑制蛋白酪氨酸磷酸酶(PTPs)活性的影响,合成表征了水杨醛缩芳胺席夫碱铜(Ⅱ)配合物[Cu(X-pimp)₂](X=Cl,Br和Acetyl),用紫外光谱滴定和pH电位滴定研究了[Cu(Cl-pimp)₂]的溶液结构,并测定了3个配合物抑制4种PTPs活性的IC₅₀值。结果表明它们都能够有效抑制PTP1B和TCPTP(0.20μmol·L^-1< IC₅₀< 0.31μmol·L^-1),但对SHP-1的抑制较弱且对SHP-2几乎无抑制作用。分析并与文献结果比较发现,席夫碱配体上苯胺对位取代基类型的改变不会显著影响其抑制作用,但取代基位置的改变可能会影响其选择性。稳态动力学研究表明[Cu(Cl-pimp)₂]能够非竞争性抑制PTP1B活性,而荧光光谱实验表明二者形成了键合常数为9.3×10⁶L·mol^-1的1:1复合物。我们推测,配合物可能结合在PTP1B非活性区域,间接导致活性中心结构变化,从而抑制其活性。     

拟热带灵芝中杂萜类化学成分及其蛋白酪氨酸磷酸酶1B抑制活性

利用硅胶柱层析和半制备高效液相色谱(HPLC)等色谱分离技术对拟热带灵芝的化学成分进行分离纯化,从中分离得到了3个新的酚酸杂萜类化合物(ganoduriporols C～E).运用NMR和HRESIMS等多种波谱技术鉴定了它们的结构.对所分离的化合物进行体外PTP1B抑制活性测试,结果显示所得化合物具有明显的蛋白酪氨酸磷酸酶1B (PTP1B)抑制活性,其IC50值分别为19.1, 17.8和29.6μmol·L~(-1).     

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%.     

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.     

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.     

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.     

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.     

N-Heterocyclic carbene-palladacyclic complexes: synthesis,characterization and their applications in the C-N coupling and α-arylation of ketones using aryl chlorides

N-Heterocyclic carbene-palladacyclic complexes 3 were successfully achieved in a one-pot procedure under mild conditions. The structure of 3a was unambiguously confirmed by X-ray single crystal diffraction and it was an active catalyst in the Buchwald-Hartwig amination and α-arylation of ketones even at very low catalyst loadings (0.01?mol%).     

Iodine-mediated oxidative Pictet-Spengler reaction using terminal alkyne as the 2-oxoaldehyde surrogate for the synthesis of 1-aroyl-β-carbolines and fused-nitrogen heterocycles

An efficient iodine-mediated oxidative Pictet-Spengler reaction in dimethyl sulphoxide (DMSO) using terminal alkynes as the 2-oxoaldehyde surrogate for the synthesis of aryl (9H-pyrido[3,4-b]indol-1-yl)methanones is described. The scope of the protocol includes the total synthesis of Fascaplysin, Eudistomins Y₁ and Y₂. The methodology is extended for preparing pyrrolo[1,2-a]-quinoxaline and indolo[1,5-a]quinoxaline derivatives. The utility of 1-aroyl-β-carbolines was demonstrated by performing palladium-catalyzed β-carboline directed ortho-C(sp2)-H functionalization of the phenyl ring with thiomethyl (SMe) group using DMSO as source and for accessing 4-aryl-canthin-6-ones.