细胞研究中的金属配合物-核酸相互作用

金属配合物与核酸相互作用的探讨对新型抗癌金属药物的设计、核酸结构的特异识别和核酸水解断裂的研究一直起着巨大的推动作用。不仅如此,配合物与核酸的相互作用已被引入细胞生物学研究中。本文利用一些典型的研究结果,对配合物与核酸相互作用应用于胞内DNA定位成像,对胞内信号转导和表观遗传的影响,以及金属配合物作为非病毒基因载体进行了总结。     

脱氧核糖核酸电化学研究进展

本文首先介绍了DNA与电极的相互作用、DNA的电化学反应、DNA与过渡金属配合物相互作用的电化学研究及技术， 然后重点对过渡金属配合物在DNA的长程电子转移、DNA的电致化学发光标记分析、DNA电化学传感器、DNA损伤与修复等方面应用的研究现状作了归纳和评述。提出了今后研究工作的方向。     

钌(II)多吡啶配合物与DNA相互作用研究*

DNA是遗传信息的携带者和基因表达的物质基础,金属配合物与DNA的相互作用研究已受到广泛关注,成为生物无机化学的重要研究内容之一。本文简要评述了钌(II)多吡啶配合物在DNA识别、断裂及拓扑异构酶抑制方面的研究情况。     

钌、铑金属配合物在DNA中介的电子传递与错配碱基识别中的应用

化学家设计合成了一系列能通过插入方式与DNA结合的金属配合物,应用于研究有关以DNA为中介的电子传递,发现碱基对不仅是电子传递的媒介,而且自身能作为电子受体,形成长程氧化损坏.本文总结了近年来该领域的研究进展,同时也介绍了金属配合物对错配碱基识别的研究成果.     

金属有机配合物对DNA的断链作用

过渡金属配合物催化DNA、RNA的断链反应研究是近年来最为活跃的前沿研究领域之一,因某些金属配合物具有核酸酶特异性催化DNA、RNA断链的功能,因而该研究对新型抗肿瘤、抗艾滋病化学药物的定向设计及其基因治疗和分子生物学研究中DNA、RNA的高度专一性定点断裂、染色体图谱分析及DNA定位诱变、基因工程中足迹技术(footprinting)以及DNA构象识别等方面均具有重要意义和应用前景,文献已报道了一些具有断裂DNA、RNA功能的金属配合物,但其中很少有含金属-碳σ键的金属有机化合物,本文首次报道了二茂铁鎓离子三氯乙酸盐和二氯二茂钛对DNA的断链作用。     

多吡啶钴(Ⅲ)配合物与Zn2+形成的新型“关-开”荧光探针

近十几年来,对小分子过渡金属配合物与大分子DNA键合与识别机理的研究一直是国际上生物无机化学领域十分活跃的研究课题[1￣3],已发展了一系列具有特定功能的配合物,如DNA结构探针和DNA荧光探针等。与其他类型的金属配合物相比,八面体过渡金属多吡啶配合物具有丰富的光化学和光物理信息,当这些配合物与DNA相互作用时,由于结构匹配或微环境的差异,配合物的光谱特征会出现不同程度的改变,从而达到对DNA的检测。传统的DNA荧光探针有[Ru(bpy)2dppz]2 和[Ru(phen)2dppz]2 (bpy=2,2′-联吡啶,phen=1,10-菲咯啉,dppz=二吡啶[3,2-a∶2′,3′…     

新型的DNA切割试剂制备与应用

将具有DNA选择性识别的小分子与具有DNA切割活性的小分子缀合,合成对DNA具有定点切割效果的试剂是化学生物学研究领域具有挑战性的研究之一,它为化学、药学和生物学在生命科学中的相互渗透开辟了又一个广阔的空间.设计了具有切割系统和识别系统的定点切割试剂,识别系统由寡聚酰胺组成,含有N-甲基吡咯的寡聚酰胺能够穿透细胞膜与特定的碱基序列高亲和力地结合,并控制基因表达,是一类十分重要的化学物质;切割系统由大环多胺和它的金属配合物构成,大环多胺的金属配合物可作为仿酶催化剂.化合物1的锌配合物对pBR322DNA的切割见下图,此结果为进一步研究DNA特异识别及切割分子提供一个良好的基础.     

咔咯及其金属配合物与DNA的作用和抗肿瘤活性

咔咯及其金属配合物与DNA相互作用和它们的抗肿瘤活性研究已成为咔咯大环化学前沿课题之一。本文综述了咔咯及其金属配合物与DNA相互作用和关于这类化合物在抗肿瘤方面的研究进展,系统介绍了咔咯及其金属配合物与DNA结合模式、在氧化剂存在或光照条件下的核酸酶活性、与G-四链体DNA相互作用以及这类化合物抗肿瘤活性。     

稀土手性配合物在核酸识别及调控方面的研究

通过小分子选择性靶向特殊基因,进而调节该基因所参与的生物学功能一直是生物无机化学领域十分活跃的研究课题。其中,DNA的手性识别引起了人们的高度重视,因为越来越多的研究表明,DNA的手性转化以及DNA构象的多样性与一系列重要的生命过程密切相关。此外,DNA的手性识别对于药物的合成以及DNA构象探针的设计也非常重要。在过去的几十年里,人们合成了大量的手性小分子和金属配合物,能够对B-DNA,Z-DNA以及G-四链DNA表现出特异性识别。由于独特的4fn的电子结构,稀土配合物已经广泛地应用于生物荧光探针以及磁共振成像。另外,作为人工核酸酶,稀土配合物表现出高效的促进DNA和RNA的水解能力,并且不会造成氧化损伤。近年来,人们正努力发现能够选择性靶向DNA进而调制DNA性质的稀土手性配合物,并已经取得了显著的成果。本文总结了目前关于稀土手性配合物对核酸的手性识别及选择性调控等方面的研究进展。     

微量热法研究 [Cu(phen)2]~(2 )、[Cu(bpy)_2]~(2 )与DNA的作用

用微量热法对菲咯啉合铜（ [Cu(phen)2]2＋）和联吡啶合铜（ [Cu(bpy)2]2＋）与小牛胸腺 DNA的相互作用进行了研究,依据 McGhee-Von Hippel邻近排斥方程确定了结合反应的平衡常数 K、结合位点距离 n及热力学参数Δ rHm、Δ rGm和Δ rSm。结果表明这两种铜的配合物与 DNA之间均可形成稳定的三元配合物,且反应为熵驱动过程, DNA与这些配合物的键合过程中同时存在插入和静电作用两种模式,插入作用的强弱与金属配合物中配体的平面性质有关。     

Mechanistic aspects of the interaction of intercalating metal complexes with nucleic acids

Since the discovery of the intercalative binding mode, almost half a century ago, intense efforts have been devoted to design, synthesize and test new small molecules that can bind nucleic acids with improved recognition and affinity. Among them, metal bearing compounds play a principal role. Despite the plethora of different metal complexes which have been designed to react with DNA and which have been tested, the binding mechanisms have often not been analysed. This is unfortunate, considering the importance of understanding of the binding features in depth in order to optimise their biological effects. This review covers articles where an analysis of the kinetic aspects of the interaction between the target metal compound and nucleic acids has been carried out and details of the reaction mechanism are provided. Flat metal complexes (porphyrins), spherical complexes with protruding intercalating residues, azamacrocycle metallo-intercalators and intercalators with metal bearing pendant arms are the classes of molecules that have been taken into account. The limits of the SDS method, employed to measure the rates of drug dissociation from polynucleotides, are also discussed.     

Reactivity of ferrocenylcarbodiimide with DNA duplex containing single-mismatched base pairs.

Ferrocenylcarbodiimide (1), which is known to react with a guanine (G) or thymine (T) base of single stranded DNA, was allowed to react with DNA duplex having a single mismatched base pair of G-T, T-T, or T-cytosine (C). Electrophoreograms of the reaction mixture showed that 1 could react with G or T base of the mismatched sites on the DNA duplex. However, 1 also reacted with the G base of the terminal site on the DNA duplex. This showed that 1 can react with an unpaired base or unstable base pair such as a terminal or mismatched base on the DNA duplex. Electrochemical mismatch detection could be achieved after hybridization of the ferrocenylated mismatched DNA duplex with a selected DNA probe-immobilized electrode. These results revealed that 1 has a potentiality of serving as a labeling reagent of mismatched bases on the DNA duplex, which is important in the search for heterozygous single nucleotide polymorphisms (SNPs).     

A warning on the use of radical traps as a test for radical mechanisms: they react with palladium hydrido complexes

Typical radical traps (galvinoxyl, TEMPO, DPPH) react with palladium hydrides, sometimes at rates competitive with those of palladium hydride catalyzed reactions that follow an insertion mechanism (for example, alkene isomerization). Thus, positive results for radical reaction tests can be misleading. The complexes with more polarizable (neutral complexes rather than cationic) and more accessible hydrides, and the less sterically protected radical traps, react faster.     

极具潜在应用价值的催化剂——N-杂环卡宾金属配合物

N杂环卡宾的反应性能较高,与周期表中几乎所有的金属都能发生反应形成稳定的配合物.主要阐述了N杂环卡宾的结构与类型,其金属配合物的合成方法及在化学反应中的催化作用和应用前景.     

Metallo-intercalators and metallo-insertors

Since the elucidation of the structure of double helical DNA, the construction of small molecules that recognize and react at specific DNA sites has been an area of considerable interest. In particular, the study of transition metal complexes that bind DNA with specificity has been a burgeoning field. This growth has been due in large part to the useful properties of metal complexes, which possess a wide array of photophysical attributes and allow for the modular assembly of an ensemble of recognition elements. Here we review recent experiments in our laboratory aimed at the design and study of octahedral metal complexes that bind DNA non-covalently and target reactions to specific sites. Emphasis is placed both on the variety of methods employed to confer site-specificity and upon the many applications for these complexes. Particular attention is given to the family of complexes recently designed that target single base mismatches in duplex DNA through metallo-insertion.     

Metallation of ethylenediamine based Schiff base with biologically active Cu(II), Ni(II) and Zn(II) ions: synthesis, spectroscopic characterization, electrochemical behaviour, DNA binding, photonuclease activity and in vitro antimicrobial efficacy

A new ligand [C28H20N6O8] (L2) has been synthesized by the condensation reaction of 3-hydroxy-4-nitrobenzaldehydenephenylhydrazine (L1) with diethyloxalate. This ligand L2 is allowed to react with bis(ethylenediamine)Cu(II)/Ni(II)/Zn(II) complexes. It affords [(L2)Cu(en)2]Cl2(1)/[(L2)Ni(en)2]Cl2(2)/[(L2)Zn(en)2]Cl2(3) complexes, respectively. These complexes (1-3) have been characterized by the spectral and analytical techniques. The interaction of these complexes with calf thymus (CT) DNA is characterized by the absorption spectra which exhibit a slight red shift with hypochromic effect. Electrochemical analyses and viscosity measurements have also been carried out to determine the mode of binding. The shift in ΔEp, E1/2 and Ipc values explores the interaction of CT DNA with the above metal complexes. The slight increase in the viscosity of CT DNA indicates that these complexes bind to CT DNA through a partial non-classical intercalative mode. Cleavage experiments using pBR322 DNA in presence of H2O2 indicate that these complexes behave as efficient artificial chemical nucleases in the order of 1>2>3. Moreover, the antibacterial and antifungal studies reveal that complex 1 is highly active against the bacterial and fungal growth.     

Mild synthesis of organophosphorus compounds: reaction of phosphorus-containing carbenoids with organoboranes

Organoboranes react with phosphorus-containing carbenoids to produce a variety of functionalized organophosphorus compounds under mild conditions. In some cases, selective migration of one group attached to boron can be observed. Phosphonite-borane complexes are introduced as novel synthons for the synthesis of phosphinic esters.     

Synthesis of poly(beta-amino ester)s with thiol-reactive side chains for DNA delivery

The safe and efficient delivery of DNA remains the major barrier to the clinical application of non-viral gene therapy. Here, we present novel, biodegradable polymers for gene delivery that are capable of simple graft modification and demonstrate the ability to respond to intracellular conditions. We synthesized poly(beta-amino ester)s using a new amine monomer, 2-(pyridyldithio)-ethylamine (PDA). These cationic, degradable polymers contain pyridyldithio functionalities in the side chains that react with high specificity toward thiol ligands. This reactivity is demonstrated using both mercaptoethylamine (MEA) and the thiol peptide RGDC, a ligand that binds with high affinity to certain integrin receptors. These two polymer derivatives displayed strong DNA binding as determined using electrophoresis and dye exclusion assays. In addition, the MEA-based polymer and plasmid DNA were shown to self-assemble into cationic complexes with effective diameters as low as 100 nm. Furthermore, this DNA binding ability was substantially reduced in response to intracellular glutathione concentrations, which may aid in DNA unpackaging inside the cell. These complexes also displayed low cellular toxicity and were able to mediate transfection at levels comparable to PEI in human hepatocellular carcinoma cells. These results suggest that PDA-based poly(beta-amino ester)s may serve as a modular platform for polymer-mediated gene delivery.     

The reaction of isocyanide—mercuric chloride complexes with amines. Preparation of guanidines

Isocyanide—mercuric chloride complexes react readily with an excess of primary and secondary amines to give guanidines and metallic mercury in high yields through a redox decomposition reaction. In the presence of triethylamine, isocyanide—mercuric chloride complexes react with an equimolar amount of a primary amine to give a carbodiimide and metallic mercury. An intermediate organomercuric compound was isolated in the reaction of the isocyanide—mercuric chloride complex with pyrrolidone.     

大环多胺及其金属配合物与DNA的相互作用*

本文综述了近年来基于大环多胺及其金属配合物与DNA相互作用的研究进展,着重介绍本课题组在有关单双核、多核以及功能化大环多胺衍生物及其金属配合物与DNA相互作用方面的研究和发现,并对其在化学核酸酶方面的应用进行了讨论。在单双核大环多胺衍生物方面,我们分别合成了以吡啶、苯环、咪唑、三氮唑为侧臂的单核大环多胺金属配合物,同时合成了以刚性桥相连的双核配合物和以柔性链相连的双核配合物。并研究这些单双核大环多胺与DNA的相互作用,发现以刚性链相连的双核大环多胺金属配合物具有很好的切割DNA的性质,可以在低浓度、短时间内切断DNA。在功能化大环多胺方面,我们合成了含有碱基、PNA单体、咪唑鎓盐、冠醚、二茂铁等功能化基团的大环多胺衍生物及金属配合物,并研究了其与DNA的相互作用。在多核大环多胺方面,我们合成了基于大环多胺的寡聚物,研究发现该类物质可与DNA形成复合物,从而有效地保护DNA免于酶解。