Click-enabled heterotrifunctional template for sequential bioconjugations

A heterotrifunctional template was developed that utilizes thiol-maleimide and click chemistries (both copper-free and copper-mediated) to effect sequential biomolecule conjugations in a one-pot process. The breadth of compatible substrates was illustrated through highly efficient conjugations of protein, peptide, sugar, lipid, fluoroalkane, biotin and fluorophore molecules. This template should be useful for the creation of chemically-enhanced/enabled biotherapeutics, especially through the expression of discontinuous (and heterogeneous) epitopes.     

新型含异噁唑环的苯腙基吡唑酮与芳偶氮基吡唑酮衍生物的合成

以乙酰乙酸乙酯为起始原料,经四步反应制备了关键中间体3-甲基-5-苯基异嗯唑甲酰肼(2);2分别与取代苯腙基乙酰乙酸乙酯和取代苯腙基乙酰丙酮反应合成了一系列新型的1.(3′-甲基-5′-苯基-异噁唑4′-甲酰基)-3-甲基4-苯腙基吡唑酮和1-(3′-甲基-5′-苯基-异噁唑-4′-甲酰基)-3,5-二甲基4-芳偶氮基...     

New Furopyridines Containing Pyridoxal and Pyrazolone Fragments

Reactions of pyridoxal hydrochloride with 5-pyrazolone derivatives in alcohol medium in the presence of concentrated hydrochloric acid led to the formation of new pyrazolones with pyridoxal fragments in the molecule. The corresponding diarylmethanes were formed when using pyridoxal and pyrazolone in a 1: 2 ratio.     

A versatile synthesis of fused triazolo derivatives by sequential Ugi/alkyne-azide cycloaddition reactions

We report a facile synthesis of fused dihydrotriazolo[1,5-a]pyrazinones and triazolobenzodiazepines by an Ugi/alkyne-azide cycloaddition synthetic sequence. The coupling of the Ugi multi-component reaction with the intramolecular alkyne-azide cycloaddition provides access to highly functionalized heterocyclic ring systems in two steps from easily available starting materials in excellent overall yields.     

Dissolving capability difference based sequential extraction: A versatile tool for in-depth membrane proteome analysis

Profiling membrane proteins would facilitate revealing disease mechanism and discovering new drug targets as they play essential roles in cellular signaling, substrate transport, and cell adhesion. However, the analysis of membrane proteins still remains a challenge due to their high hydrophobicity, as well as the suppression effect of high abundant soluble proteins. In this work, to achieve a membrane proteome profiling, a sample preparation strategy based on sequential extraction at the protein level assisted by a range of extraction reagents with different dissolving capabilities, followed by nano-RPLC-ESI-MS/MS analysis was developed and applied for HeLa cell line analysis. It was found that with progressively harsher extraction reagents (i.e., 2 M NaCl, 4 M urea, 0.1 M Na₂CO₃, and 10% 1-dodecyl-3- methyl-imidazolium chloride (C12ImCl) performed, much more high hydrophobic proteins and low abundant proteins were identified. With our developed strategy, 5553 of the identified proteins (4419 gene products) were annotated to be membrane proteins and 2573 proteins (2183 gene products) have at least one transmembrane domain, to our best knowledge, which is the most comprehensive membrane proteome dataset for HeLa cell line. Notably, 110 of the identified membrane proteins were discovered in the “missing proteins” list referred to those in the neXtProt database. All above results indicated that our strategy has great potential to tackle the difficult but relevant task of identifying and profiling membrane proteins.     

吡咯酰胺催化合成吡唑啉酮衍生物

探究了绿色高效合成医药价值较高的吡唑啉酮衍生物的方法,即：以吡咯酰胺催化吡唑啉酮与硝基烯进行Michael反应,高收率地合成了系列吡唑啉酮衍生物,其结构经¹H NMR和¹³C NMR确证。并考察了催化剂及其用量、溶剂和温度对反应的影响。结果表明;在室温下,CH₂Cl₂体系中,在10 mmol%催化剂E存在下,吡唑啉酮与硝基烯烃能有效进行Michael反应,收率80%~91%。     

吡唑酮化合物在催化不对称反应中的应用

吡唑-5-酮类化合物在具有生物活性化合物中占有重要地位,该类化合物得到化学家们的广泛关注。吡唑-5-酮及其常见衍生物具有多个反应位点,可参与多种类型的不对称反应(如不对称加成反应、不对称环化反应和其他不对称反应类型)。本文主要从吡唑-5-酮类化合物参与的不对称催化反应类型进行分类,阐述了各类底物参与的反应类型及其主要反应位点,对近年来吡唑酮及其常见衍生物参与的不对称反应研究进展进行总结,并对其未来发展方向进行展望。     

新型吡唑啉酮稀土配合物的合成及荧光性能

通过分子设计,以吡啶-2,6-二甲酸为起始原料,合成了一种新型双吡唑啉酮吡啶配体:2,6-二(1-苯基4-乙氧羰基-5-吡唑啉酮-3-基)吡啶(H2L)。配体与稀土Eu(Ⅲ)和Tb(Ⅲ)离子成功螯合形成配合物。配体和配合物经FT-IR,1H NMR和元素分析进行表征,并确定配合物组成为RE2L3.4H2O。对配合物的紫外吸收和光致发光性能进行了检测,结果显示Eu(Ⅲ)和Tb(Ⅲ)离子能够有效地被有机配体敏化,发射出高亮、半峰宽狭窄的单色光。研究表明目标配合物能够成为优秀的发光材料。     

色酮吡唑啉酮类衍生物的合成及抗白血病细胞活性

以色酮-吡唑啉酮作为C1合成子, 在5 mol% 的DBU催化下,与α,β-不饱和酮发生Michael加成反应, 获得了10个色酮吡唑啉酮类衍生物3a~3j,产率76%~90%, dr值为4/1~9/1, 其结构经¹H NMR, ¹³C NMR和HR-MS（ESI-TOF）表征,通过单晶进一步进行了确定化合物3b的相对构型。该类化合物包含有连续两个立体中心,包括一个季碳中心,可以为生物活性筛选提供物质基础。采用MTT法研究了3a~3f对人白血病细胞(K562)的体外抗增殖活性。结果表明：化合物3a, 3c, 3d和3i对K562增殖具有一定的抑制活性。     

吡唑啉酮类稀土配合物的发光性质研究

合成了一系列吡唑啉酮类稀土铽、铕、钐、钆、镝的配合物, 并采用元素分析、红外光谱和紫外-可见光谱对其进行了表征, 解析了铕配合物的晶体结构. 测定了配体的三重态能级, 研究了这4种配合物的发光性质. 并通过研究配体到稀土离子的能量传递过程, 合理地解释了这些稀土配合物发光性质的差异.     

Synthesis of aldehyde-linked nucleotides and DNA and their bioconjugations with lysine and peptides through reductive amination

5-(5-Formylthienyl)-, 5-(4-formylphenyl)- and 5-(2-fluoro-5-formylphenyl)cytosine 2'-deoxyribonucleoside mono- (dC(R)MP) and triphosphates (dC(R)TP) were prepared by aqueous Suzuki-Miyaura cross-coupling of 5-iodocytosine nucleotides with the corresponding formylarylboronic acids. The dC(R)TPs were excellent substrates for DNA polymerases and were incorporated into DNA by primer extension or PCR. Reductive aminations of the model dC(R)MPs with lysine or lysine-containing tripeptide were studied and optimized. In aqueous phosphate buffer (pH?6.7) the yields of the reductive aminations with tripeptide?III were up to 25?%. Bioconjugation of an aldehyde-containing DNA with a lysine-containing tripeptide was achieved through reductive amination in yields of up to 90?% in aqueous phosphate buffer.     

A versatile stereocontrolled approach to chiral tetrahydrofuran and tetrahydropyran derivatives by use of sequential asymmetric Horner-Wadsworth-Emmons and ring-closure reactions

An approach to chiral tetrahydrofuran and tetrahydropyran derivatives based on the sequential use of an asymmetric Horner-Wadsworth-Emmons reaction and a cyclization step is presented. The approach is both stereochemically and structurally versatile since three different cyclization methods can be employed starting from the same HWE product: (i) palladium-catalyzed substitution, (ii) hetero-Michael addition, or (iii) epoxide opening. The asymmetric HWE reaction controls the absolute configuration of the ultimate product, whereas the relative configuration is controlled by the combined influence of the geometric selectivity in the HWE reaction and the stereochemistry of the respective cyclization method.     

Synthesis and Application of Some Azo and Azomethine Dyes Containing Pyrazolone Moiety

3-Amino-1-phenyl-4,5-dihydro-1H-pyrazol-5-one (1) was used as starting material for the synthesis of a number of azo compounds 3a—3c and azomethine derivative 4. The deblocking of 3a—3c and 4 gave rise to 5a—5c and 6 in which a free amino was revealed. The diazonium salts of 5a—5c and 6 were coupled with several phenols to produce a number of bis azo compounds 7a—7c and 8a—8c with azomethine in position 4 and azoic group in position 3. The prepared dyes were structurally confirmed by elemental analysis, spectral methods and applied to different fibers (wool, polyester and blend of wool/polyester) as disperse dyes and their fastness properties were measured.     

A versatile stereocontrolled approach to chiral tetrahydrofuran and tetrahydropyran derivatives via sequential asymmetric Horner-Wadsworth-Emmons and palladium-catalyzed ring closure reactions

[reaction: see text]An approach to chiral tetrahydrofuran and tetrahydropyran derivatives is reported which is based on the sequential use of an asymmetric Horner-Wadsworth-Emmons desymmetrization of a meso-dialdehyde and a palladium-catalyzed intramolecular allylic substitution. The strategy is versatile in that either a cis- or a trans-relation between the stereocenters adjacent to the ring oxygen can be obtained.     

Palladium/Imidazolium salt as a versatile catalyst for sequential coupling reactions of aryl dihalides to unsymmetrically substituted arenes

A simple method for one-pot sequential Heck/Suzuki coupling reactions of a range of substituted aryl dihalides has been described. The Pd(OAc)₂/imidazolium system catalyzed double coupling reactions proceed without isolation of the intermediates giving unsymmetrically polysubstituted biphenyls in good to excellent yields. Further couplings of the resultant products bearing additional C-Cl bonds with substituted arylboronic acids or amines lead to unsymmetrical terphenyls and aminobiphenyl derivatives.     

Evaluation of bicinchoninic acid as a ligand for copper(i)-catalyzed azide-alkyne bioconjugations

The Cu(i)-catalyzed cycloaddition of terminal azides and alkynes (click chemistry) represents a highly specific reaction for the functionalization of biomolecules with chemical moieties such as dyes or polymer matrices. In this study we evaluate the use of bicinchoninic acid (BCA) as a ligand for Cu(i) under physiological reaction conditions. We demonstrate that the BCA-Cu(i)-complex represents an efficient catalyst for the conjugation of fluorophores or biotin to alkyne- or azide-functionalized proteins resulting in increased or at least equal reaction yields compared to commonly used catalysts like Cu(i) in complex with TBTA (tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine) or BPAA (bathophenanthroline disulfonic acid). The stabilization of Cu(i) with BCA represents a new strategy for achieving highly efficient bioconjugation reactions under physiological conditions in many application fields.     

Synthesis and Antioxidant Activity of Some New Thiazolyl–Pyrazolone Derivatives

3‐Methyl‐1‐thiocarbamoyl‐2‐pyrazolin‐5‐one has been utilized as a core for the synthesis of some 1‐(thiazol‐2‐yl)‐pyrazolin‐5‐one derivatives through diazo‐coupling reaction and/or Knoevenagel condensation followed by heterocyclization with some α‐halogenated reagents such as bromoacetone, phenacyl bromide, and ethyl bromoacetate. Base prompted addition of the core compound to an equimolar amount of phenyl isothiocyanate furnished 3‐methyl‐4‐phenylthiocarbamoyl‐1‐thiocarbamoyl‐2‐pyrazolin‐5‐one which undergoes heterocyclization with α‐halogenated reagents at the more reactive phenylthiocarbamoyl moiety to afford the corresponding 4‐(thiazol‐2‐yl)‐1‐thiocarbamoyl‐2‐pyrazolin‐5‐ones. The new synthesized thiazolyl–pyrazolone compounds were evaluated for their potential antioxidant activity by using (ABTS Radical Cation Decolorization Assay).     

Facile and versatile annulation of the imidazole ring: Single and sequential cyclization reactions of Fischer carbene complexes with 1,4-diazafulvenes

We examined the reactivity of dimethylaminodiazafulvene 1 toward Fischer alkenylcarbene 2 and alkynylcarbene 3 complexes. Diazafulvene 1 reacts with alkenylcarbenes 2 through a formal [6+3] heterocyclization in a regio- and stereoselective manner to afford dihydroimidazo[1,2-a]pyridines 4. Acid-promoted dimethylamine elimination in compound 4 c gives rise to the aromatic imidazo pyridine 5. A likely mechanism for this reaction is a 1,2-nucleophilic addition/[1,2]-shift metal-promoted cyclization sequence. On the other hand, diazafulvene 1 and alkynyl carbenes 3 undergo a [6+2] cyclization to afford pyrrolo[1,2-a]imidazole carbene complex 6 that can be readily oxidized to the corresponding esters 7. When enynylcarbenes 3 e-i are treated with diazafulvene 1, consecutive and diastereoselective [6+2]/cyclopentannulation cyclization reactions take place affording new polycyclic complex systems 8, 9, and 12 that can be appropriately demetallated to the corresponding imidazole-based polyfused systems 10, 11, and 13 respectively. Finally, enynylcarbenes 3 d,f undergo consecutive [6+2]/[5+1] cyclization reactions with diazafulvene 1 and tBuNC, respectively, to yield tetracyclic adducts 14 and 15. All these processes result in high yields and provide a route to the preparation of imidazopyridines and pyrroloimidazoles as well as other polycyclic molecules that contain imidazole groups, which are interesting from a pharmacological and biological point of view.     

含萘酰亚胺光功能基元的吡唑啉酮席夫碱的合成及其光谱性质

以4-溴-1,8-萘酐为原料,经亚胺化、取代和还原反应合成了中间体N-对氨基苯基-4-哌啶-1,8-萘酰亚胺(4),4与1-苯基-3-甲基-4-苯甲酰基-吡唑啉酮-5缩合得到一种含萘酰亚胺光功能基元的的新型吡唑啉酮席夫碱——1-苯基-3-甲基-4-苯甲酰基-吡唑啉酮-5缩N-对氨基苯基-4-哌啶-1,8-萘酰亚胺(6)。4和6的结构经1H NMR和IR确证。研究了6在不同溶剂中的光谱性质,发现其吸收光谱和荧光光谱随溶剂的极性不同而表现出不同的光谱特性。进一步研究表明6在不同溶剂中可能以不同的互变异构体存在。