4-(N-乙酰氨基)-3-(4-芳基噻唑-2-氨基)苯甲酸乙酯的合成与生物活性

以3-氨基-4-乙酰氨基苯甲酸乙酯为原料设计合成了18种4-(N-乙酰氨基)-3-(4-芳基噻唑-2-基)-苯甲酸乙酯新化合物.化合物结构经质谱,元素分析,1H NMR和13C NMR确证.生物活性实验结果表明,化合物3d,3h,3p(40μg/mL)对神经氨酸酶(NA)的抑制率分别为36.02%,33.40%,42.05%;化合物3g,3h(500mg/L)对纹枯病菌的抑制率为50%.     

神经氨酸酶与3-(3-戊氧基)安息香酸作用机制的理论研究

运用柔性分子对接和分子动力学方法, 深入研究了4-(氮乙酰氨基)-5-胍基-3-(3-戊氧基)安息香酸(BA)与各类型神经氨酸酶(N1, N2, N9亚型和B型)间的作用机制. 结果显示, BA与各类型神经氨酸酶结合模式存在差异, 但作用机制比较相似: 与它们的活性腔均匹配良好, 并形成稳定的复合体系, 最大结合能分别等于－1233.62, －1385.72, －663.11, －1058.87 kJ•mol^－1. 这表明BA对各类型神经氨酸酶均有良好的抑制效果. 进一步分析发现, BA与各类型神经氨酸酶活性腔内保守关键氨基酸残基发生较强的静电和氢键作用, 而与易突变氨基酸残基作用较弱, 表明了活性腔内易突变氨基酸残基发生突变也不会对抑制效果造成明显影响. 因此, BA是一种极具应用前景的新型抗流感病毒药物. 结合以前的研究结果, 我们提出了以BA为底物的抗流感病毒药物的修饰方向.     

1,2,4-三唑-3-硫醚衍生物的合成、晶体结构与神经氨酸酶抑制活性

设计并合成了一系列1,2,4-三唑-3-硫醚衍生物,目标化合物的化学结构经~1H NMR、~(13)C NMR、质谱和元素分析确证;采用单晶X射线衍射法测定了(E)-4-(4-羟基-3-甲氧基苯基亚甲氨基)-5-乙基-4H-1,2,4-三唑-3-丙硫醚(1c)的晶体结构.目标化合物体外神经氨酸酶(Neuraminidase, NA, H1N1)抑制活性测试结果表明,大部分化合物1具有较好的NA抑制活性,其中(E)-4-(4-羟基-3-甲氧基苯基亚甲氨基)-5-乙基-4H-1,2,4-三唑-3-乙硫醚(1b)和1c的NA抑制活性最佳,其IC50值分别为(6.86±2.08)和(9.1±1.56)μg/m L.     

含脲砌块的4-氨基喹唑啉衍生物的设计、合成及抗肿瘤活性研究（英文）

为了寻找新的具有靶向治疗作用的抗肿瘤药物,设计并合成了一系列新型的含脲砌块的4-氨基喹唑啉类衍生物,并采用噻唑蓝(MTT)法测定目标化合物对MCF-7(人乳腺癌细胞)、MGC-803(人胃癌细胞)、SW620(人结肠癌细胞)、A549(人肺癌细胞)四种肿瘤细胞的抗肿瘤活性.结果显示大部分化合物具有较好的抗肿瘤活性,其中2-((4-((3,4,5-三甲氧基苯基)-氨基)喹唑啉-2-基)-硫代)-N-((3,4,5-三甲氧基苯基)氨基甲酰基)乙酰胺(10p)对MGC-803、SW620和A549三种细胞显示出最好的抗肿瘤活性, IC_(50)值分别为(7.02±0.46)、(6.00±0.78)和(7.04±1.11)μmol·L~(-1),其抗肿瘤活性和阳性对照品吉非替尼相当.分子对接结果显示,化合物10p能与EGFR很好地结合,有可能成为潜在的抗肿瘤药物.     

新型含咔唑环和芳环/芳稠杂环的N-酰腙衍生物的合成及蛋白酪氨酸磷酸酶1B(PTP1B)抑制活性评价

为寻找高效、低毒的新型蛋白酪氨酸磷酸酶1B(PTP1B)抑制剂,设计并合成出了一系列新型含咔唑环和芳环/芳稠杂环的N-酰腙衍生物6～8和11.利用IR、1H NMR、13C NMR和2D NMR(包括1H-1H COSY和NOESY)谱及元素分析确定了其结构和构型.评价了目标化合物对PTP1B的抑制活性.实验结果表明,目标化合物对PTP1B均有较强的抑制活性,除了化合物N'-[9-(2-氯噻唑-5-甲基)咔唑-3-亚甲基]-2-苯氨基乙酰肼(6a)、N'-[9-(2-氯噻唑-5-甲基)咔唑-3-亚甲基]-2-(4-甲基苯氨基)乙酰肼(6b)、N'-[9-(2-氯噻唑-5-甲基)咔唑-3-亚甲基]-2-(3-硝基苯氨基)乙酰肼(6g)和N'-[9-(2-氯噻唑-5-甲基)咔唑-3-亚甲基]-2-(4-硝基苯氨基)乙酰肼(6h)外,其它化合物的活性均高于阳性对照药物齐墩果酸,其中N,N'-[(9-丁基咔唑基)-3,6-二亚甲基]-2,2'-[二(4-硝基苯氨基)]双乙酰肼(11b)的活性最高,IC50=(0.89±0.06)μmol/L.利用分子对接分别研究了代表目标化合物N'-[9-(2-氯噻唑-5-甲基)咔唑-3-亚甲基]-2-(4-溴苯氨基)乙酰肼(6d)、N'-[9-(2-氯噻唑-5-甲基)咔唑-3-亚甲基]-2-((2-(1-萘氧基)甲基)苯并咪唑-1-基)乙酰肼(7f)和11b与PTP1B酶的结合模式.     

新型含氟酰胺化羟甲香豆素衍生物的合成及生物活性

以羟甲香豆素为先导,利用活性亚结构拼接原理,通过引入三氟甲基及酰胺基,设计、合成了系列新型含氟酰胺化羟甲香豆素衍生物,其结构用~1H NMR、~(13)C NMR、HRMS表征,N-正丁酰基-N-间氟苄基-6-氨基-7-甲氧基-4-三氟甲基香豆素(f1)及N-对甲苯甲酰基-N-间氟苄基-6-氨基-7-甲氧基-4-三氟甲基香豆素(f9)的结构经X射线单晶衍射进一步确证.除草活性初筛表明,化合物f1、N-苯乙酰基-N-间氟苄基-6-氨基-7-甲氧基-4-三氟甲基香豆素(f13)、N-甲基丙烯酰基-N-间氟苄基-6-氨基-7-甲氧基-4-三氟甲基香豆素(f5)、N-环丙甲酰基-N-间氟苄基-6-氨基-7-甲氧基-4-三氟甲基香豆素(f7)及N-(6-氯烟酰基)-N-间氟苄基-6-氨基-7-甲氧基-4-三氟甲基香豆素(f20)对马唐幼茎的生长具有强烈抑制作用,f9、f7及N-(萘-2-甲酰基)-N-间氟苄基-6-氨基-7-甲氧基-4-三氟甲基香豆素(f17)对灰藜幼茎生长具有良好抑制作用,其抑制率高于对照药剂乙草胺.作物安全评价结果表明,化合物f1、f9及f13对双子叶作物白菜及油菜比较安全,对单子叶作物小麦及高粱比较敏感.抑菌活性评价表明,N-间溴苯甲酰基-N-间氟苄基-6-氨基-7-甲氧基-4-三氟甲基香豆(f12)、f7及f9对番茄灰霉病菌具有较好抑制作用,N-氢化肉桂酰基-N-间氟苄基-6-氨基-7-甲氧基-4-三氟甲基香豆素(f14)对苹果腐烂病菌具有较好抑制作用.     

南瓜子化学成分的研究——Ⅱ.南瓜子氨酸的合成与旋光異构体的拆开

1,3-双(乙氧甲酰基)氮戊环-4-酮与羟胺作用,变为肟,后者经催化氢化,并再与酸作用,得到4-氨基-3-羧基氮戊环(Ⅰ)。1-乙氧甲酰基氮戊环-3-酮与氯化铵及氰化钾作用,继用氢溴酸水解,制成(±)-3-氨基-3-羧基氮戊环(Ⅱ)。动物试验中Ⅱ有抑制血吸虫童虫生长的作用,Ⅰ则无效,红外吸收光谱及纸上层析的R_f值观察中,Ⅱ均与天然南瓜子氨酸一致。于是,将Ⅱ制成( )-樟脑酸盐,以水及丙酮混合剂纯化拆开,获得(一)-3-氨基-3-羧基氮戊环( )-樟脑酸盐,并制成相应游离碱及高氯酸盐,又酰化成二苯甲酰及二对硝基苯甲酰衍生物。以上各化合物的比旋光度及熔点与天然南瓜子氨酸相应衍化物一致,证明天然南瓜子氨酸是(一)-3-氨基-3-羧基氮戊环。左旋体樟脑酸盐分去后,从母液中又得到右旋体。动物试验中左旋体对日本血吸虫童虫有明显抑制作用,右旋体则无效。     

((吡啶-3-基)甲氧基)芳酸衍生物的合成及抗血小板聚集活性

以具有活血化瘀作用的中药有效成分阿魏酸为先导物,按生物电子等排原理,设计合成了6个((吡啶-3-基)甲氧基)芳酸衍生物,其结构经IR,1H NMR,13C NMR及MS确证.体外药效筛选结果显示,部分((吡啶-3-基)甲氧基)芳酸衍生物对二磷酸腺苷(ADP)诱导的血小板聚集具有较好的抑制活性,其中化合物1a的抑制作用明...     

含丙烯酰胺结构的喹唑啉衍生物的合成及抗肿瘤活性研究（英文）

为了寻找高效低毒的抗肿瘤药物,设计并合成了一系列新型的含N-(3-丙烯酰胺苯基)乙酰胺结构的喹唑啉类衍生物,并采用噻唑蓝(MTT)法测定了目标化合物对H1975(人肺腺癌细胞系),PC-3(人前列腺癌细胞系),MGC-803(人胃癌细胞系)三种肿瘤细胞的抗增殖活性.结果显示大部分化合物具有较好的抗肿瘤活性,其中N-(3-(2-(((4-((4-氯苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)乙酰氨基)苯基)丙烯酰胺(13j)对H1975,MGC-803两种细胞显示出最好的抗增殖活性,IC50值分别为(6.77±0.65)和(4.06±0.34)μmol/L,其活性均优于阳性对照品吉非替尼,为抗肿瘤药物的研究提供了线索.     

新型含咔唑环芳氨基乙酰腙衍生物的合成及其蛋白酪氨酸磷酸酶1B(PTP1B)抑制活性评价

为寻找新型蛋白酪氨酸磷酸酶1B (PTP1B)抑制剂,设计并合成了一系列新型含咔唑环芳氨基乙酰腙衍生物.其结构和构型用IR、~1H NMR、~(13)C NMR和2D NMR(包括~1H-~1H COSY、~1H-~(13)C HMBC和NOESY)谱及元素分析进行了确证.通过对PTP1B抑制活性的测试发现,目标化合物对PTP1B有较强的抑制作用,且大多数化合物的IC_(50)值低于阳性对照药物齐墩果酸,其中N'-(9-辛基咔唑-3-亚甲基)-2-(4-硝基苯氨基)乙酰肼(3t)活性最高,IC_(50)=(2.78±0.04)μmol/L.利用分子对接研究了化合物3t与PTP1B酶的结合情况.     

新型神经氨酸酶抑制剂的设计合成及抗流感病毒活性

对上市药物扎那米韦、 奥司他韦和帕拉米韦进行结构修饰, 对化合物相应的氨基进行磷酰化, 设计合成了10个新化合物. 新化合物在酶水平和细胞水平均具有一定的抗流感病毒活性, 化合物I-8在酶水平、 化合物I-6在细胞水平具有和阳性对照药奥司他韦相当的活性.     

Enthalpies of formation of monoderivatives of hydrocarbons: Interaction of polar groups with an alkyl group

Energies of hydrocarbon monoderivatives CH(3)X, C(2)H(5)X, n-C(4)H(9)X, and n-C(5)H(11)X with 16 different substituents X were calculated at the levels B3LYP/6-311+G(d,p) and B3LYP/AUG-cc-pVTZ//B3LYP/6-311+G(d,p). The results were used to test the validity of the additive rule that has served commonly for estimating the enthalpies of formation Delta(f)H(T). The exact additivity corresponds to zero reaction energy DeltaE of the isodesmic reaction, in which the substituent X is transferred from one alkyl group R to another. Additivity is approximately fulfilled for butyl and pentyl derivatives with the differences less than 0.3 kJ mol(-1) (except charged groups X). Methyl derivatives deviated from the additive rule up to 22 kJ mol(-1) for dipolar groups X and 45 kJ mol(-1) for charged group, in agreement with the available experiments and with the anticipation of all suggested empirical schemes. In addition, smaller deviations of ethyl derivatives (3 or 20 kJ mol(-1), respectively) were observed here for the first time. There is no correlation between the deviations of methyl and ethyl derivatives; they are also not related to steric effects, and only partly to polarization. Deviations of methyl derivatives are proportional to the electronegativity of the first atom of the substituent; even when the definition of electronegativity is somewhat questionable, one can say in any case that it is controlled by the first atom.     

Substituent effects on heats of formation, group interactions, and detonation properties of polyazidocubanes

We have calculated the heats of formation (HOFs) for a series of polyazidocubanes by using the density functional theory (DFT), Hartree-Fock, and MP2 methods with 6-31G* basis set as well as semiempirical methods. The cubane skeleton was chosen for a reference compound, that is, the cubane skeleton was not broken in the process of designing isodesmic reactions. There exists group additivity for the HOF with respect to the azido group. The semiempirical AM1 method also produced reliable results for the HOFs of the title compounds, but the semiempirical MINDO3 did not. The relationship between HOFs and molecular structures was discussed. It was found that the HOF increases 330-360 kJ/mol for each additional number of the azido group being added to the cubane skeleton. The distance between azido groups slightly influences the values of HOFs. The interacting energies of neighbor azido groups in polyazidocubanes are in the range of 2.3 approximately 6.6 kJ/mol, which are so small and less related to the substituent numbers. The average interaction energy between nearest neighbor --N3 groups in the most stable conformer of octaazidocubane is 2.29 kJ/mol at the B3LYP/6-31G* level. The relative stability related to the number of azido groups of the title compounds was assessed based on the calculated HOFs, the energy gaps between the frontier orbitals, and the bond orders of the C--N3 and C--C bonds. The predicted detonation velocity of hepta- and octa-derivatives is over 9 km/s, and the detonation pressure of them is ca. 40 GPa or over.     

基于支撑向量机方法的有机化合物的生成Gibbs自由能的预测

基于支撑向量机方法的有机化合物的生成Gibbs自由能的预测;支撑向量机;多元线形回归;吉布斯自由能     

Density functional computations of proton affinity and gas-phase basicity of proline

The proton affinity and gas-phase basicity of proline were evaluated by using density functional theory coupling the B3-LYP hybrid functional with the extended 6--311++G** basis set. Cis and trans conformations of the carboxyl moiety for both exo and endo ring structures were considered for the neutral proline. The results show that the most stable structure of proline has the endo ring conformation with the carboxyl group in the cis position. The structure at the global minimum is stabilized by an intramolecular hydrogen bond. The nitrogen of the ring in the exo form is the preferred protonation site. The calculated proton affinity (924.3 kJ mol(-1)) and gas-phase basicity (894.4 kJ mol(-1)) are in very good agreement with the experimental counterparts.     

Effects of internal hydrogen bonds between amide groups: protonation of alicyclic diamides

The proton affinity (PA) of cyclopentane carboxamide 1, cyclohexane carboxamide 2 and their secondary and tertiary amide derivatives S1, S2, T1 and T2, was determined by the thermokinetic method and the kinetic method [PA(1) = 888 +/- 5 kJ mol(1); PA(2) = 892 +/- 5 kJ mol(1); PA(S1) = 920 +/- 6 kJ mol(1); PA(S2) = 920 +/- 6 kJ mol(1); PA(T1) = 938 +/- 6 kJ mol(1); PA(T2) = 938 +/- 6 kJ mol(1)]. Special entropy effects are not observed. Additionally, the effects of protonation have been studied using an advanced kinetic method for all isomers 37 of cyclopentane dicarboxamides and cyclohexane dicarboxamides (with the exception of cis-cyclopentane-1,2-dicarboxamide) and their bis-tertiary derivatives T3T7 by estimating the PA and the apparent entropy of protonation Delta(DeltaS(app)). Finally, the study was extended to bicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxamide 8 and its bis-tertiary derivative T8, to all stereoisomers of bicyclo[2.2.1]heptane-2,3-dicarboxamide 9, their secondary and tertiary amide derivatives S9 and T9, and to endoendobicyclo[2.2.1]heptane-2,5-dicarboxamide 10 and the corresponding secondary and tertiary derivatives S10 and T10. Compared with 1 and 2, all alicyclic diamides exhibit a significant increase of the PA (DeltaPA) and special entropy effects on protonation. For alicyclic diamides, which can not accommodate a conformation appropriate for building a proton bridge, the values of DeltaPA and Delta(DeltaS(app)) are small to moderate. This is explained by ion / dipole interactions between the protonated and neutral amide group which stabilize the protonated species but hinder the free rotation of the amide groups. If any of the conformations of the alicyclic diamide allows formation of a proton bridge, DeltaPA and Delta(DeltaS(app)) increase considerably. A spectacular case is cis-cyclohexane-1,4-dicarboxamide 7c which is the most basic monocyclic diamide, although generation of the proton bridge requires the unfavorable boat conformation with both amide substituents at a flagpole position. A pre-orientation of the two amide groups in such a 1,4-position in 10 results in a particularly large PA of < 1000 kJ mol(1). The observation of comparable values for Delta(DeltaS(app)) for linear and monocyclic diamides indicates that a major part of the entropy effects originates from freezing the free rotation of the amide groups by formation of the proton bridge. This is corroborated by observing corresponding effects during the protonation of dicarboxamides containing the rigid bicyclo[2.2.1]heptane carbon skeleton, where the only internal movements of the molecules corresponds to rotation of the amide substituents.     

DFT Study of the Group Interactions in 1,3,5‐Triamino‐2,4,6‐Trinitrobenzene and 1,3,5‐Triamino‐2,4,6‐Tridifluoroaminobenzene

Density functional calculations on isodesmic disproportionation reactions of 1,3,5‐triamino‐2,4,6‐trinitrobenzene (TATB) and 1,3,5‐triamino‐2,4,6‐tridifluoroaminobenzene (TATDB) indicate that the interaction between nitro groups on meta carbons of TATB, which brings about unstability to the molecule, is surprisingly larger than that between difluroamino groups in TATDB. The electron‐withdrawing and electron‐donating groups generate large positive and very small negative values of E_{disproportion}, respectively. When both electron‐withdrawing and electron‐donating groups are attached to the benzene skeleton at the same time, large negative disproportionation energy is produced, which stabilizes the derivatives. The values of E_{disproportion} for TATB and TATDB are predicted to be ‐48.03 kJ/mol and ‐63.54 kJ/mol, respectively, indicating that the total interaction among groups with stabilization effects in TATDB is larger than that in TATB. The large difference of the E_{disproportion} values between TATB and TATDB is derived from the large difference between the interactions of the meta‐nitro group and those of meta‐difluoroamino groups. The energy barriers for the C‐N internal rotation of NO₂ group and NF₂ groups are 74.7 kJ/mol and 185.8 kJ/mol for TATB and TATDB, respectively. The large energy barrier for the rotation of the NF₂ group is caused by its stabilization interaction with neighbor amino groups, instead of steric effects. When the number of pairs of amino‐nitro or amino‐difluoroamino groups increases, there are more negative charges on the NO₂/NF₂ groups and on the O/F atoms.     

Conformations of protonated gas-phase bradykinin ions: evidence for intramolecular hydrogen bonding

The post-source decay of bradykinin, Lys1-bradykinin, des-Arg1-bradykinin, des-Arg9-bradykinin and [D-Phe7]-bradykinin [M + H]+ ions was examined in order to assertain the influence of secondary structure on peptide ion dissociation. Fragment ions corresponding to the elimination of H2O and HN=C=NH are observed in the product ion mass spectra of Lys1-bradykinin and des-Arg1-bradykinin but not in the spectra of bradykinin or des-Arg9-bradykinin. Cleavage reactions at the Phe-Ser and/or Ser-Pro bonds are observed for all peptide [M + H]+ ions with the exception of des-Arg9-bradykinin. The product ions arising from the processes described above are rationalized in terms of the intramolecular solvation of the protonated guanidino groups of the arginines. The strongest intramolecular interaction appears to be a proton bridge between the guanidino groups of the N- and C-terminal arginines in bradykinin. In addition, increased abundances of fragment ions in the vicinity of Ser-Pro may be attributed to intramolecular solvation of the protonated C-terminal guanidino group by the Ser-Pro portion of the molecule. This self-solvation of the ionizing proton leads to a gas-phase peptide conformation that is supported by solution-phase NMR studies at elevated temperatures and in non-polar solvents but which is different from the conformation in polar solvents.     

Gas-Chromatographic Studies of the Interaction between Water and Methanol Molecules and the Surface of Carbon Materials

The gas-chromatographic method is used to study the interaction of water and methanol molecules with active hydrophilic centres existing at the surface of thermally exfoliated graphite and graphitized thermal carbon black. The concentration of carboxyl and phenol hydroxyl groups at the surface of these sorbents is determined, and heats of adsorption of the studied molecules are shown to be and 28−25 kJ/mol, respectively. It is also shown that adsorption of water at the hydrophilic centres at lowest relative pressure values takes place with formation of clusters consisting of n = 2 water molecules.     

苏丹红Ⅱ与肌红蛋白相互作用的分子模拟与实验

用荧光光谱法研究了苏丹红Ⅱ与肌红蛋白(Mb)之间的相互作用, 实验结果表明,二者结合位点数近似为1, 结合常数K=3.84×107L/mol, 有很强的相互作用. 用分子柔性对接技术模拟确定了它们之间的作用位点、作用力类型及相互作用能. 理论计算的结果表明,苏丹红Ⅱ和Mb相互作用的势能为-9419.9 kJ/mol, 静电能为-7468.8 kJ/mol, 范德华能为-1951.0 kJ/mol. 苏丹红Ⅱ与Mb中His64残基形成氢键, 苏丹红Ⅱ也能与疏水氨基酸残基, 如能产生内源荧光的Phe33、Phe43、Phe106 和 Phe138等发生作用, 这与苏丹红Ⅱ能使Mb荧光猝灭的实验结果是一致的.