4-(1H)-喹诺酮及甲氧基和溴代衍生物的合成研究

提出了一种4-(1H)-喹诺酮衍生物合成方法.以3,3-二乙氧基丙酸乙酯和苯胺为原料,生成中间体3-(苯基亚氨基)丙酸乙酯,再经热环化或微波促进环化两步反应制备4-(1H)-喹诺酮,并以此方法合成了7个溴代或甲氧基取代的4-(1H)-喹诺酮衍生物.     

氨基-3-氰基丙酸衍生物的合成

以廉价易得的2,5-二溴吡啶为原料,经取代、氧化、R-(+)-叔丁基亚磺酰胺手性诱导、氨基化、氨基酸缩合等反应,合成了氨基-3-氰基丙酸衍生物,其结构经¹H-NMR, ¹³C-NMR和LC-MS确证。同时对吡啶环5位取代反应机理进行探讨,并且采用ELISA法研究了氨基-3-氰基丙酸衍生物对炎症细胞（BMDM）Caspase-1活性的影响。结果表明：经11步合成的氨基-3-氰基丙酸衍生物结构新颖,并且对Caspase-1的抑制活性具有剂量依赖性。      

氨甲酰基硅烷作为氨酰基源合成3-羟基-3-杂环丁基甲酰胺衍生物

几种氨甲酰基硅烷与四元环氧-3-酮和四元环硫-3-酮在无催化剂甲苯作溶剂的温和条件下,发生亲核加成反应,直接制备了3-羟基-3-杂环丁基酰胺衍生物,收率为56%～85%,为合成含无手性中心的四元杂环药物提供了一种有效途径.通过不同氨甲酰基硅烷的选择,用此方法可合成3-羟基-3-杂环丁基叔酰胺、仲酰胺和伯酰胺衍生物,以及酰氨基带手性中心的3-取代杂环丁基酰胺.通过研究反应的影响因素发现,氨甲酰基硅烷的酰氨基所带基团旳大小是影响反应的重要因素,它既影响反应完成的时间,又影响产物的产率.该反应具有条件温和、副产物少、产物得率高和后处理简单等优点,是有效合成3-羟基-3-杂环丁基甲酰胺的新方法.     

D-(R)-酪氨酸的不对称催化氢化合成及其在药物合成中的应用

以最近开发的双膦-铑配合物[Rh((R,R)-QuinoxP*)(cod)]SbF6作为催化剂,利用不对称催化氢化方法合成了一系列D-(R)-酪氨酸衍生物,在S/C=10000条件下获得了99%ee的对映选择性.并将所得的氢化产物成功应用于具有重要生理活性的化合物(R)-2-羟基-3-(3,4-二羟基苯基)丙酸钠的合成.相比于已报道的方法,该工艺路线产率更高而且不需要柱层析分离,因而非常具有工业化应用前景.     

水杨酸丙酮叉衍生物的合成研究

以取代水杨酸和丙酮为原料,4-二甲氨基吡啶为催化剂,在二氯亚砜作用下以较高的收率合成得到一系列水杨酸丙酮叉衍生物(1a-1f).并采用¹H NMR、¹³C NMR、ESI-MS以及X射线单晶衍射对其结构进行表征.同时,通过对反应条件研究确定最佳反应工艺.以1a为例对产物在有机合成中的应用进行研究,发现产物1a经四氢铝锂还原可以得到2-(羟甲基)苯-1,3-二醇(3),而经过DIBAL-H还原可以制备2,6-二羟基苯甲醛(4).     

3-氨基-7,8-二甲氧基香豆素及其衍生物的合成及抗氧化活性

合成了3-氨基-7,8-二甲氧基香豆素及其衍生物共11个化合物,其中3个化合物(2b、2d、2e)为新型香豆素芳酰胺类化合物。 通过猝灭1,1-二苯基-2-三硝基苯肼(DPPH)、2,2'-联氮二(3-乙基苯并噻唑-6-磺酸)二铵盐阳离子自由基(ABTS^+·)和羟自由基实验考察了所合成化合物的抗氧化活性,结果表明化合物2b对DPPH自由基、羟自由基的清除能力超出或接近对照品维生素C,而衍生物2a、2b和2c的抗氧化活性优于母体。 故酰化可提高3-氨基-7,8-二甲氧基香豆素的抗氧化性能,尤其是普遍提高了羟基自由基的清除能力。     

氨甲酰基硅烷作氨酰基源与邻位二酮选择性氨酰化反应合成α-羟基-β-羰基仲(伯)酰胺衍生物

几种氨甲酰基硅烷与邻位二酮在无催化剂和氧化剂的温和条件下直接发生选择性氨酰化反应,制备了α-硅氧基-β-羰基仲(伯)酰胺衍生物,收率为62%～90%.氨甲酰基硅烷和邻位二酮的结构的空间位阻都影响在两个羰基上的反应选择性.氨基保护基甲氧甲基和苄基容易脱保护基转化成氢原子,得到α-羟基-β-羰基仲(伯)酰胺衍生物.通过选择不同氨甲酰基硅烷进行反应发现,此方法是选择性合成α-羟基-β-羰基叔酰胺、仲酰胺和伯酰胺衍生物的简易方法.该反应具有条件温和、副产物少、选择性強、产物得率高和后处理简单等优点,是有效合成α-羟基-β-羰基酰胺衍生物的新方法.     

芳香型螺双内酯二胺的合成

以对硝基甲苯和多聚甲醛为原料,经过两种途径合成了二氨基芳香型螺双内酯--6,6′-二氨基-3,3′-螺双苯酞.发现二(2-甲基-5-硝基苯基)甲烷在酸性体系中经氧化反应可高收率地得到二硝基螺双内酯,还原二硝基螺双内酯时发现,在低极性溶剂中主要生成一种稳定的芳香型羟胺类化合物--6,6′-二羟氨基-3,3′-螺双苯酞,在高极性溶剂中主要生成6,6′-二氨基-3,3′-螺双苯酞.通过¹HNMR,¹³CNMR,IR,MS及元素分析确证了二氨基螺双内酯及其中间产物的结构     

新型4-羟基香豆素衍生物的微波合成及其光谱性质

以4-羟基香豆素(a)为原料微波辐射合成了具有独特的生理活性和荧光性能的3,3′,3″,3′″-亚乙四基-4-羟基香豆素(b)、3,3′-苯亚甲基-双-4-羟基香豆素(c)和4-羟基香豆素-1,4-萘醌(d)系列4-羟基香豆素衍生物, 采用元素分析、红外光谱、核磁共振及质谱表征了产物的结构, 并对其紫外-可见吸收光谱及荧光光谱性质进行了研究, 探索了化合物的微观结构与其光学性能之间的关系. 研究结果表明, 具有“近平面”、大π共轭和对称型结构的化合物b具有较大的摩尔吸光系数及强荧光特性, 且浓度在0.50~1.50×10^-4 mol/L范围时, 其荧光强度随着浓度的降低而呈线性增加; 在pH=1.81~6.09时, 荧光强度随pH降低而减弱, 在pH 8.36~11.98时, 荧光强度随pH升高而减弱. 此外, 牛血清白蛋白(BSA)及脱氧核糖核酸(DNA)可与该化合物发生相互作用, 进而敏化增强该分子的内源荧光.     

手性联二萘酚衍生物催化的苯乙炔与苯甲醛不对称加成反应

以手性联二萘酚为原料,合成了3,3′位取代的手性联二萘酚衍生物,研究了该衍生物配体在二乙基锌存在下,催化苯乙炔与苯甲醛的不对称加成反应,产物的产率为73%,e.e.值为40%。 研究结果表明,手性联二萘酚衍生物结构的微小变化导致催化产物构型的改变。     

Tandem mass spectrometry of kahalalides: identification of two new cyclic depsipeptides, kahalalide R and S from Elysia grandifolia

Spectra obtained using electrospray ionization mass spectrometry (ESI-MS) of the mollusk Elysia grandifolia showed a cluster of molecular ion peaks centered at a molecular mass of 1478 Da (kahalalide F, an anticancer agent). Two new molecules, kahalalide R (m/z 1464) and S (m/z 1492) were characterized using tandem mass spectrometry. The mass differences of 14 Da suggest that they are homologous molecules. In addition, previously identified kahalalide D and kahalalide G are also reported. However, the ESI-MS of the mollusk's algal diet Bryopsis plumosa showed the presence of only kahalalide F. The amino acid sequences of kahalalide R and S are proposed using collision-induced dissociation (CID) experiments of singly and doubly charged molecular ions and by comparison with the amino acid sequence of kahalalide F. The pathway is presented for the loss of amino acid residues in kahalalide F. It is observed that there is sequential loss of amino acids in the linear peptide chain, but in the cyclic part the ring opens at the amide bond rather than at the lactone linkage, and the loss of amino acid residues is not sequential. The CID experiment of the alkali-metal-cationized molecular ions shows that the sodium and potassium ions coordinate to the amide nitrogen/oxygen in the linear peptide chain of the molecule and not to the lactone oxygen of the lactone. In the case of kahalalide D, CID of the protonated peptide opens the depsipeptide ring to form a linear peptide with acylium ion, and fragment ion signals indicate losses of amino acids in sequential order. In this study, tandem mass spectrometry has provided the detailed information required to fully characterize the new peptides.     

Mass spectral characterization of phloroglucinol derivatives hyperforin and adhyperforin

Active phloroglucinol constituents of Hypericum perforatum (St. John's wort) extracts, hyperforin and adhyperforin, have been studied following ion activation using tandem mass spectrometry (MS/MS) and complemented by accurate mass measurements. These two compounds were readily analyzed as protonated and deprotonated molecules with electrospray ionization. MS/MS and MS3 data from a quadrupole-linear ion trap tandem mass spectrometer were employed to elucidate fragmentation pathways. Fourier transform ion cyclotron resonance measurements afforded excellent mass accuracies for the confirmation of elemental formulae of product ions formed via infrared multiphoton dissociation and sustained off-resonance irradiation collision-induced dissociation. Fragmentation schemes have been devised for the dissociation of hyperforin and adhyperforin in negative and positive ion modes. This information is expected to be especially valuable for the characterization of related compounds, such as degradation products, metabolites and novel synthetic analogs of hyperforin.     

Determination of the site of glucuronidation in an N-(3,5-dichlorophenyl)succinimide metabolite by electrospray ionization tandem mass spectrometry following derivatization to picolinyl esters

Derivatization using 3-pyridylcarbinol coupled with liquid chromatography electrospray ionization tandem mass spectrometry (LC/MS/MS) was used to characterize a novel Phase II metabolite of the nephrotoxic agricultural fungicide, N-(3,5-dichlorophenyl)succinimide (NDPS). A glucuronide conjugate of N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA) was identified in the urine from a rat dosed with [14C]NDPS. However, 2-NDHSA contains an aliphatic hydroxyl group and a carboxylic acid group, both of which are potential sites for glucuronidation. Mass spectrometry alone was unable to distinguish between these possibilities. Since the position of glucuronidation may be important in the mechanism of NDPS-induced nephrotoxicity, chemical derivatization in conjunction with mass spectrometry was used to characterize the glucuronide. The 2-NDHSA glucuronide conjugate was isolated from rat urine, derivatized with 3-pyridylcarbinol, and the derivatized metabolite was then analyzed by LC/MS/MS. Two known NDPS metabolites, 2-NDHSA and N-(3,5-dichlorophenyl)succinamic acid (NDPSA), were also isolated from rat urine and derivatized similarly. 3-Pyridinylcarbinol reacted rapidly with the carboxylic acid groups and formation of the picolinyl esters increased the ionization potential under positive ion conditions. The urinary glucuronide of 2-NDHSA was identified as an alcohol-linked glucuronide by examination of the molecular ions and the collision-induced dissociation (CID) product ion spectra of the derivatized products. When used in combination with mass spectrometry, derivatization of carboxylic acids with 3-pyridylcarbinol provided useful mass fragmentations and is a rapid way to obtain structural information about the position of glucuronidation of NDPS metabolites.     

Cyclopolycondensations

Fully aromatic polyquinazolinediones of high molecular weight were prepared by the cyclopolycondensation reaction of 4,4′-diamino-3,3′-biphenyldicarboxylic acid with aromatic diisocyanates. The poly(phosphoric acid) solution polymerization techniques yielded tractable poly(urea acid), which was converted to polyquinazolinediones by thermal cyclodehydration at 300–400°C. under reduced pressure. The polyquinazolinediones thus obtained have excellent thermal stability both in nitrogen and in air. The poly(urea acid) is soluble in dimethyl sulfoxide, and films can be cast from the polymer solution of poly(urea acid) (η_inh = 0.8 to 1.8). The films are made tough by being heated in nitrogen or under reduced pressure at 300–400°C. The polymerization mechanism of the cyclopolycondensation reaction was studied, and it was established that the polymerization proceeded through the formation of tractable poly(urea acid), Structure (I), of high molecular weight, followed by cyclodehydration, yielding poly(1,2-dihydro-2-imino-4H-3,1-benzoxazin-4-one), Structure (II). On subsequently being heated this undergoes intramolecular rearrangement along the polymer chain, giving the thermodynamically stable polyquinazolinedione, Structure (III).     

Analysis of post-translational modification and characterization of the domain structure of dynamin A from Dictyostelium discoideum

The post-translational modifications of the 96 kDa protein dynamin A from Dictyostelium discoideum were analyzed using Q-TOF mass spectrometry. The accurate molecular mass of the intact protein revealed a covalent modification causing an additional mass of 42 Da. The modification could be identified as N-terminal acetylation by tandem mass spectrometry. Extracted ion chromatograms for the a(1) and b(1) ion of the tryptic T1 peptide were used to detect the acetylated peptide within 54 nanoelectrospray ionization tandem mass spectra. Owing to the accurate molecular mass of the intact protein, additional covalent modifications could be excluded. In addition to the covalent modification, the domain structure of dynamin A was determined by applying a combination of limited proteolysis, sodium dodecylsulfate polyacrylamide gel electrophoresis, automated tandem mass spectrometry and protein database searching.     

纳升电喷雾串联质谱"序列对接法"确定多肽的加钠位点

用QuattroM icro三级四极串联质谱分析常见的20种氨基酸的加钠效果。结果表明,绝大多数氨基酸与钠离子的非共价键结合力很弱甚至没有,但脯氨酸和苯丙氨酸很容易形成加钠离子峰。采用“序列对接法”测出重组人酸性纤维细胞生长因子(rh-a FGF)C-端肽段的全序列,并确定钠离子的加成位点为该肽段的第6位脯氨酸(6Pro)。通过酸化样品溶液获得无加钠、无序列间隙的该肽全序列,与加钠肽段的序列一致。     

Characterization of metabolites of Celecoxib in rabbits by liquid chromatography/tandem mass spectrometry

The metabolism of the anti-inflammatory drug Celecoxib in rabbits was characterized using liquid chromatography (LC)/tandem mass spectrometry (MS/MS) with precursor ion and constant neutral loss scans followed by product ion scans. After separation by on-line liquid chromatography, the crude urine samples and plasma and fecal extracts were analyzed with turbo-ionspray ionization in negative ion mode using a precursor ion scan of m/z 69 (CF(3)) and a neutral loss scan of 176 (dehydroglucuronic acid). The subsequent product ion scans of the [M - H] ions of these metabolites yielded the identification of three phase I and four phase II metabolites. The phase I metabolites had hydroxylations at the methyl group or on the phenyl ring of Celecoxib, and the subsequent oxidation product of the hydroxymethyl metabolite formed the carboxylic acid metabolite. The phase II metabolites included four positional isomers of acyl glucuronide conjugates of the carboxylic acid metabolite. These positional isomers were caused by the alkaline pH of the rabbit urine and were not found in rabbit plasma. The chemical structures of the metabolites were characterized by interpretation of their product ion spectra and comparison of their LC retention times and the product ion spectra with those of the authentic synthesized standards.     

Comparison of the isomeric α-amino acyl adenylates and amino acid phosphoramidates of adenosine by electrospray ionization tandem mass spectrometry

The isomeric α-amino acyl adenylates and amino acid phosphoramidates of adenosine were synthesized and analyzed in detail by electrospray ionization tandem mass spectrometry (ESI-MS(n)). In ESI-MS/MS of α-amino acyl adenylates, the novel rearrangement ion [cAMP-H](-) observed as the most intense signal was formed through the pentacoordinate phosphorus intermediate with a six-membered ring by nucleophilic attack of the 3'-hydroxyl group on the phosphorus atom. In contrast, for the amino acid phosphoramidate of adenosine, the phosphorus atom could be attacked not only by the carboxylic group to form the cyclic aminoacyl phosphoramidates (CAPAs), but also by the nitrogen atom on the nucleobase leading to intramolecular phosphoryl group migration. It was found that the sodium ion having multidentate binding ability played an essential role in this characteristic rearrangement. The proposed mechanisms were supported by the MS/MS study, deuterium-labeled experiments, high-resolution tandem mass spectrometry and moderate calculations at the B3LYP/6-31G* level. The characteristic fragmentation patterns of α-amino acyl phosphates and amino acid phosphoramidates allows identification of stereoisomers when either the phosphorylation is at the N-terminus or C-terminus of amino acids.     

Electrospray Ionization Mass Spectra of Amino Acid Methyl Ester 5 ＇-Phosphoramidates of 2＇, 3＇-Isopropylideneuridine

Amino acid methyl ester phosphates were synthesized and determined by using positive-ion mode dectrospmy ionization mass spectrometry（ESIMS） in combination with multistage tandem mass spectrometry. The fragmentation pathways were investigated, and it was observed that most fragment ions contained the phosphoryl group. It was interesting to observe that the fragmentation pathways of the protonated molecule show some differences when compared with those of the sodium ion adduct. The methoxy group of amino acid methyl ester can migrate from the carbonyl group to the phosphoryl group in the sodium ion adduct.     

Characterization of phosphatidylethanolamine as a lithiated adduct by triple quadrupole tandem mass spectrometry with electrospray ionization

Structural characterization of the glycerophosphoethanolamine (GPE) molecule as a lithiated adduct ion by collisionally activated dissociation (CAD) tandem mass spectrometry with electrospray ionization is described. Abundant fragment ions reflecting polar head group and fatty acid constituents were observed in the product ion spectrum of GPE, which permits an unambiguous structural determination, including the regiospecificity of fatty acyl substituents. The pathways leading to the formation of fragment ions are proposed. The suggested mechanisms are supported by the tandem mass spectra of various deuterated analogs and source CAD of GPE followed by CAD tandem mass spectrometry. Identification of GPE molecular species and specific GPE subclasses in a biological mixture by tandem mass spectrometry with various constant neutral loss scannings is also described.