金属氮杂环卡宾配合物的抗肿瘤活性研究进展

自1978年顺铂成功地被开发成癌症临床治疗药物以来,金属配合物作为小分子抗癌药物的开发成为人们的研究热点。其中,氮杂环卡宾能与多种过渡金属中心形成稳定的共价键,这种特殊的稳定性使得金属氮杂环卡宾配合物具有被开发成药物的潜能。近年来,金属氮杂环卡宾配合物被发现具有良好的抗癌活性,激发了广大无机药物化学研究者的研究热情。综合笔者课题组在金属氮杂环卡宾抗肿瘤配合物方面的前期研究,本文将对银、金、铑和铂氮杂环卡宾配合物的抗肿瘤活性及作用机制进行综述,以期为新型金属氮杂环卡宾抗肿瘤化合物的设计合成提供参考。     

钌多吡啶配合物的合成、表征及其与DNA相互作用的研究

二十世纪七十年代,顺铂作为抗肿瘤药物在临床上的广泛使用,使无机过渡金属配合物的抗肿瘤活性成为生物医药领域的研究热点之一;随后研究者在数千个铂系金属配合物中又筛选出了毒性相对较低的广谱抗肿瘤药物卡铂和环硫铂[1].但是临床上化疗药物的疗效、毒副作用和肿瘤细胞的耐药性等问题仍是生物医药领域亟待解决的关键问题之一.钌和钌配合物在生物体内易于吸收和代谢,属于低毒性的化合物;而且钌配合物具有与铂配合物相似的分子结构,能够以插入方式、沟结合方式和静电作用方式与DNA分子交联,干扰核酸的生物功能.国际上已普遍认为,钌配合物将成为最有前途的抗肿瘤药物之一[2].     

镧(Ⅲ)-氧氟沙星配合物与DNA的相互作用

氧氟沙星(Ofloxacia)是第三代喹诺酮抗菌素代表药物之一,具有抗菌谱广,活性强,毒副作用低及临床疗效高等特点.近年来,稀土无机盐及其配合物的抗菌作用、抗肿瘤活性开始受到人们的重视~([1]).脱氧核糖核酸是所有生物的基本遗传物质,许多分子能与DNA分子发生相互作用进而影响DNA的复制.为了进一步探索和认识DNA的性质,人们研究了大量金属配合物与DNA的反应~([3]).本研究合成了La(Ⅲ)-氧氟沙星的配合物,采用荧光光谱法,热变性法,黏度测定法,盐效应法,研究了La(Ⅲ)-氧氟沙星与DNA的相互作用模式.     

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。     

稀土配合物抗肿瘤活性研究进展

大量研究表明,稀土具有一定的抗肿瘤活性,稀土与配体形成配合物后其抗肿瘤活性强于配体。目前,国内外研究安全、有效、可控的稀土配合物的抗肿瘤药物已经成为热点,已研究出多种稀土配合物并对其进行抗肿瘤机制分析。本文对已研究出的多种稀土配合物如邻香兰醛缩氨基酸Schiff碱稀土配合物、氧氟沙星稀土配合物、嘧啶类稀土配合物和芦丁素稀土配合物等进行分类,并对其抗肿瘤机制进行归纳、总结。     

铑配合物的抗肿瘤活性及其作用机制研究

自从Rosenberg等人发现顺铂具有抗肿瘤活性以来，金属配合物的抗肿瘤活性引起了人们的广泛关注。本文综述了近年来铑配合物抗肿瘤活性的研究进展，并对铑配合物的抗肿瘤机制和构效关系进行了探讨，为进一步寻找高效低毒和抗肿瘤谱广的新药物揭示了可循的途径。     

质谱在金属抗肿瘤化合物分子作用机理研究中的应用

软电离质谱,包括电喷雾质谱(ESI-MS)和基质辅助激光解吸电离质谱(MALDI-MS)已成为研究金属抗肿瘤药物与蛋白质、DNA等生物大分子相互作用最强有力的工具.质谱成像技术在组织、细胞水平上探索金属抗肿瘤化合物作用机理研究上的应用也方兴未艾.本文基于在金属抗肿瘤配合物分子作用机理研究中的工作进展,系统地总结、评述质谱在铂基和钌基金属抗肿瘤配合物分子作用机理研究中的应用,介绍质谱研究金属抗肿瘤配合物与蛋白质和DNA相互作用及作用位点的最新研究成果,并展望质谱在这一前沿交叉领域的应用前景和趋势.     

磷光环金属化铱(Ⅲ)配合物在癌症治疗方面的应用

配位饱和且取代惰性的环金属化铱（Ⅲ）配合物由于优秀的磷光特性,在生物成像和生物传感等方面有着广泛的应用。近年来,该类铱配合物由于有效的抗肿瘤效力和新颖的抗肿瘤机制,在抗肿瘤方面的应用也引起了广泛关注。本文主要对磷光环金属化铱（Ⅲ）配合物（结构通式为[Ir（C^N）₂（N^N）]⁺）在抗癌化疗和光动力治疗两方面的最新研究进展进行了综述;分类总结了靶向不同细胞器,作为蛋白-蛋白相互作用抑制剂,以及应用于单光子和双光子光动力治疗的环金属化铱（Ⅲ）配合物,为开发新型金属抗肿瘤药物提供参考。最后,对环金属化铱（Ⅲ）配合物在抗癌应用方面的前景进行了展望。     

桑色素及其配合物与DNA作用的研究

桑色素 (Morin)是黄酮类化合物 ,具有一定的抗肿瘤活性 [1] .前文 [2 ] 以桑色素为配体合成了 6种过渡金属的配合物 ,并研究了这些配合物与配体对超氧阴离子自由基的清除作用和抗肿瘤活性 .研究表明 ,配合物对超氧阴离子自由基的清除作用明显高于配体 ,桑色素合铜 ( )和桑色素合锌 ( )配合物对 Hep- 2 ,BHK- 2 1和 HL - 6 0癌细胞瘤株的抑制作用强于配体 .配合物具有比单一有效成分更显著的药效 [3 ,4 ] .本文采用荧光方法和电化学方法研究了桑色素和抗肿瘤活性较强的桑色素合铜 ( )、桑色素合锌 ( )与 DNA在生理条件下的相互作用 ,试图…     

钼系杂多,同多配合物抗肿瘤活性（Ⅱ）

钼系杂多、同多配合物抗肿瘤活性（Ⅱ）刘术侠，刘彦勇，刘杰，李白涛，王恩波（东北师范大学化学系长春１３００２４）关键词ＭＴＴ法，钼系杂多配合物，抗肿瘤活性多阴离子是一类多核配合物，可望成为新型的抗肿瘤药物，迄今发现，钼系同多配合物具有较优秀的抗肿瘤活性...     

钒酰腙配合物的合成、结构及生物活性

以酰腙为配体钒的单核、双核配合物因其结构丰富、生物活性多样而引起广泛关注。目前该领域新配合物的合成、表征和生物活性的研究甚为活跃。本文回顾了近年来钒酰腙配合物的研究状况,主要从以下三个方面进行综述：(1)钒酰腙配合物的合成方法;(2)此类配合物的配位模式;(3)一些单、双核钒酰腙配合物抗变形虫,抗肿瘤,类胰岛素,抑制Na⁺, K⁺-ATP酶,与DNA作用的生物活性。文中着重阐述了钒酰腙化合物的结构和生物活性之间的关系。此外,还提出了钒酰腙配合物研究领域的不足之处并对其今后发展方向进行了展望。     

钌配合物抗肿瘤研究新进展*

钌配合物作为抗癌药物的研究已受到广泛关注,成为无机药物化学的重要研究内容之一。本文简要评述了近年来钌配合物的抗肿瘤活性研究进展,包括作为细胞毒药物的钌配合物设计与筛选、钌配合物以端粒酶、DNA拓扑异构酶及蛋白激酶作为抗肿瘤作用新靶点等。     

基于中药活性成分的金属基抗肿瘤药物前期研究*

本文综述了近年来中药活性成分的金属基抗肿瘤药物前期研究概况。介绍了中药活性成分生物碱、黄酮、醌类化合物以及斑蝥素、香豆素、白花丹素等金属配合物合成、结构和抗肿瘤活性、与DNA作用的研究进展,对基于中药活性成分金属基抗肿瘤药物研究进行展望。     

硝基四唑及其高氮化合物*

硝基四唑及其高氮化合物是指分子中含有5-硝基四唑结构的一类高氮化合物,优越的性能和突出的特点使其成为含能材料领域的研究热点之一,在起爆药、推进剂及其燃速催化剂、高能炸药、气体发生剂等领域有着广泛的应用前景。本文对硝基四唑的结构与热分解机理进行了分析介绍;全面系统地综述评价了硝基四唑及其盐类和配合物类衍生物的合成、性能表征与应用前景。根据其成盐阳离子的不同,硝基四唑盐类主要包括碱金属盐、碱土金属盐、过渡金属盐、胺盐和高氮杂环阳离子盐。根据配位方式的不同,其配合物可分为配阴离子型和配阳离子型。在此基础上,对硝基四唑及其高氮化合物的未来发展及应用提出了展望。     

Promising anticancer mono- and dinuclear ruthenium(III) dithiocarbamato complexes: systematic solution studies

During the last decade, our research group has prepared a number of metal dithiocarbamato derivatives of Pt, Pd and Au that were expected to resemble the main features of cisplatin together with higher activity, improved selectivity and bioavailability, and lower side-effects. Furthermore, we have already published the synthesis, characterization and in vitro cytotoxicity studies of novel ruthenium(III) dithiocarbamato complexes such as [RuL(3)] monomers (11) and α-[Ru(2)L(5)]Cl dimers (12) with five different dithiocarbamate ligands. As both the monomer and the dinuclear complexes have shown significant antitumor activity in different human tumor cell lines, we decided to widen the characterization studies and to analyse thoroughly their behavior in physiological-like medium by UV-visible and CD spectroscopy. In the present paper we report on the crystal structure of [Ru(DMDT)(3)], [Ru(PDT)(3)] and [Ru(ESDT)(3)] complexes and we determine the spin state of the paramagnetic Ru(III) by means of Evans' method. Then, we discuss in detail the UV-visible spectral data of the complexes in different medium. All the studied complexes are stable in dimethyl sulfoxide, and show low solubility in phosphate buffered saline solution, particularly the monomer species, even at low concentration, while increased solubility for both types of complexes have been found in the presence of bovine serum albumin (BSA). Moreover, no changes on the coordination sphere of the metal, as well as no direct interaction between the BSA protein and the complex have been identified by UV-visible spectroscopy. However, some conformational changes on the BSA structure, induced by the ruthenium(III) complexes have been confirmed by CD spectroscopy, indicating a probable secondary electrostatic interaction between the metal complex and the peptide. In addition, no significant interaction has been demonstrated with the components of Dulbecco's Modified Eagle's Medium, used for the in vitro assays.     

Kinetics and mechanism of the reactions of Au(III) complexes with some biologically relevant molecules

The kinetics of the substitution reactions between the mono-functional Au(III) complexes, [Au(dien)Cl](2+) and [Au(terpy)Cl](2+) (dien = 3-azapentane-1,5-diamine, terpy = 2,2';6',2'-terpyridine) and bi-functional Au(III) complexes, [Au(bipy)Cl(2)](+) and [Au(dach)Cl(2)](+) (bipy = 2.2'-bipyridine, dach = (1R,2R)-1,2-diaminocyclohexane) and biologically relevant ligands such as l-histidine (l-His), inosine (Ino), inosine-5'-monophosphate (5'-IMP) and guanosine-5'-monophosphate (5'-GMP), were studied in detail. All kinetic studies were performed in 25 mM Hepes buffer (pH = 7.2) in the presence of NaCl to prevent the spontaneous hydrolysis of the chloride complexes. The reactions were followed under pseudo-first order conditions as a function of ligand concentration and temperature using stopped-flow UV-vis spectrophotometry. The results showed that the mono-functional complexes react faster than the bi-functional complexes in all studied reactions. The [Au(terpy)Cl](2+) complex is more reactive than the [Au(dien)Cl](2+) complex, which was confirmed by quantum chemical (DFT) calculations. A more than 50% lower activation energy for the terpy than for the dien based complex was found. The bi-functional [Au(bipy)Cl(2)](+) complex is more reactive than the [Au(dach)Cl(2)](+) complex. The reactivity of the studied nucleophiles follows the same order for all studied systems, viz. l-His > 5'-GMP > 5'-IMP > Ino. According to the measured activation parameters, all studied reactions follow an associative substitution mechanism. Quantum chemical calculations (B3LYP/LANL2DZp) suggest that ligand substitution in [Au(terpy)Cl](2+) and [Au(dien)Cl](2+) by imidazole follows an interchange mechanism with a significant degree of associative character. The results demonstrate the strong connection between the reactivity of the complexes toward biologically relevant ligands and their structural and electronic characteristics. Therefore, the binding of gold(III) complexes to 5'-GMP, constituent of DNA, is of particular interest since this interaction is thought to be responsible for their anti-tumour activity.     

Luminescent Bimetallic IrIII/AuI Peptide Bioconjugates as Potential Theranostic Agents

Diverse iridium peptide bioconjugates and the corresponding iridium/gold bimetallic complexes have been synthesized starting from a cyclometallated carboxylic acid substituted Ir^III complex [Ir(ppy)₂(Phen-5-COO)] by solid phase peptide synthesis (SPPS). The selected peptide sequences were an enkephalin derivative Tyr-Gly-Gly-Phe-Leu together with the propargyl-substituted species Tyr-Gly-Pgl-Phe-Leu to allow gold coordination (Pgl: propyrgyl-glycine, HC≡C-Gly), and a specific short peptide, Ala-Cys-Ala-Phen, containing a cysteine residue. Introduction of the gold center has been achieved via a click reaction with the alkynyl group leading to an organometallic Au−C(triazole) species, or by direct coordination to the sulfur atom of the cysteine. The photophysical properties of these species revealed predominantly an emission originating from the Ir complex, using mixed metal-to-ligand and ligand-to-ligand charge transfer excited states of triplet multiplicity. The formation of the peptide bioconjugates caused a systematic redshift of the emission profiles. Lysosomal accumulation was observed for all the complexes, in contrast to the expected mitochondrial accumulation triggered by the gold complexes. Only the cysteine-containing Ir/Au bioconjugate displayed cytotoxic activity. The absence of activity may be related to the lack of endosomal/lysosomal escape for the cationic peptide conjugates. Interestingly, the different coordination sphere of the gold atom may play a crucial role, as the Au−S(cysteine) bond may be more readily cleaved in a biological environment than the Au−C(triazole) bond, and thus the Au fragment could be released from or trapped in the lysosomes, respectively. This work represents a starting point in the development of bimetallic peptide bioconjugates as theranostics and in the knowledge of factors that contribute to anti-proliferative activity.     

金属配位化合物在生物分析、成像以及染色方面的应用

由于优越的光物理和光化学特性,很多金属配合物长期以来被用于生物传感器、生物探针和医学诊断等领域。本文综述了近年来已经或有望成功应用于生命科学基础研究和临床医学诊断众多领域中的多种金属配位化合物,包括几种在成功商业化的体外诊断系统中作为分子探针、生物标记物或蛋白染色剂而广泛应用的金属钌配位化合物和稀土金属配位化合物,在核磁共振成像技术中作为造影剂或影像增强剂的系列金属钆配位化合物,以及在细胞成像、生物标记和蛋白质分析应用中极具商业化应用前景的一些新型环金属铱配位化合物等。此外,本文还对金属配合物结合纳米结构及技术在生物医学领域中的应用作了简单介绍和展望。     

Study on carbon-hydrogen activation of ketones by Gold(III) complexes and the synthesis and characterization of two ketonylgold(III) complexes

The acetonylgold(III) compound [Au(ppy)(CH₂COCH₃)Cl] (1) (ppy = 2-phenylpyridine) was unexpectedly obtained during the crystallization process of Au(III) lactate complex [Au(ppy)(CH₃CHOHCOO⁻)Cl]. This new structure prompted us to further study the role of Au(III) complexes on the carbon-hydrogen activation of ketones. Complex [Au(ppy)(CH₂COCH₃)NO₃] (2) was synthesized by reacting [Au(ppy)(NO₃)₂] with acetone while the ketonyl Au(III) complex [Au(apd)Cl₂] (3) (Hapd = 2-acetylpyridine) was obtained through carbon-hydrogen bond activation of the acetyl group. The crystal structures of 1 and 2 have common features: a square-planar Au(III) centre coordinated by one five-membered chelate ring, one acetonyl ligand and one anion (chloride or nitrate). Both structures show that carbon-hydrogen activation of acetone by 2-phenylpyridine-Au(III) complexes leads to the formation of acetonyl-Au(III) complexes. The Au-CH₂ bond lengths (2.067(7) Å, 1 and 2.059(5) Å, 2) are similar to each other but longer than the Au-C (phenyl) bond lengths. The two softest ligands (carbanion) are also cis to each other in the thermodynamically most stable isomer. In complex 3, the σ-bonded acetyl group is confirmed by ¹³C DEPT NMR spectroscopy.     

Properties and X-ray structural study of volatile dimethylgold(III) β-iminoketonates

Three complexes of dimethylgold(III) of a general formula of (CH₃)₂Au(R¹-CNH-CH-CO-R²) involving β-imino-derivatives of acetylacetone (k-acac), trifluoroacetylacetone (k-tfa), and pivaloyltrifluoroacetone (k-pta) are studied for the first time with single crystal X-ray diffraction. Synthesis and properties of these compounds are presented along with thermal properties determined by the DTA technique. The structures of the compounds in question are based on monomeric complexes. Gold atoms have a slightly distorted square-planar coordination involving oxygen and nitrogen atoms of the β-iminoketonate ligand and two methyl groups. Geometrical characteristics of the coordination cores are the following: bond lengths of Au-C_Me fall within 2.008–2.050 Å; average Au-O and Au-N distances are 2.094 Å and 2.068 Å respectively. In the structure of (CH₃)₂Au(k-acac) gold complexes are joined by hydrogen bonds to give infinite chains with the shortest Au...Au separation of 5.396 Å. In the crystals of the fluorinated compounds coplanar molecules make infinite stacks. The shortest intra-stack Au...Au separation of 3.416 Å is observed for the complex of (CH₃)₂Au(k-pta) that possesses the largest thermal stability among the investigated compounds.