Medicinal Organometallic Chemistry: Designing Metal Arene Complexes as Anticancer Agents

The field of medicinal inorganic chemistry is rapidly advancing. In particular organometallic complexes have much potential as therapeutic and diagnostic agents. The carbon‐bound and other ligands allow the thermodynamic and kinetic reactivity of the metal ion to be controlled and also provide a scaffold for functionalization. The establishment of structure–activity relationships and elucidation of the speciation of complexes under conditions relevant to drug testing and formulation are crucial for the further development of promising medicinal applications of organometallic complexes. Specific examples involving the design of ruthenium and osmium arene complexes as anticancer agents are discussed.     

Rare-Earth Metal Complexes of the Antibacterial Drug Oxolinic Acid: Synthesis,Characterization, DNA/Protein Binding and Cytotoxicity Studies

“Drug repositioning” is a current trend which proved useful in the search for new applications for existing, failed, no longer in use or abandoned drugs, particularly when addressing issues such as bacterial or cancer cells resistance to current therapeutic approaches. In this context, six new complexes of the first-generation quinolone oxolinic acid with rare-earth metal cations (Y³⁺, La³⁺, Sm³⁺, Eu³⁺, Gd³⁺, Tb³⁺) have been synthesized and characterized. The experimental data suggest that the quinolone acts as a bidentate ligand, binding to the metal ion via the keto and carboxylate oxygen atoms; these findings are supported by DFT (density functional theory) calculations for the Sm³⁺ complex. The cytotoxic activity of the complexes, as well as the ligand, has been studied on MDA-MB 231 (human breast adenocarcinoma), LoVo (human colon adenocarcinoma) and HUVEC (normal human umbilical vein endothelial cells) cell lines. UV-Vis spectroscopy and competitive binding studies show that the complexes display binding affinities (K_b) towards double stranded DNA in the range of 9.33 × 10⁴ − 10.72 × 10⁵. Major and minor groove-binding most likely play a significant role in the interactions of the complexes with DNA. Moreover, the complexes bind human serum albumin more avidly than apo-transferrin.     

Interaction of Metal Complexes with G‐Quadruplex DNA

Guanine‐rich sequences of DNA can assemble into tetrastranded structures known as G‐quadruplexes. It has been suggested that these secondary DNA structures could be involved in the regulation of several key biological processes. In the human genome, guanine‐rich sequences with the potential to form G‐quadruplexes exist in the telomere as well as in promoter regions of certain oncogenes. The identification of these sequences as novel targets for the development of anticancer drugs has sparked great interest in the design of molecules that can interact with quadruplex DNA. While most reported quadruplex DNA binders are based on purely organic templates, numerous metal complexes have more recently been shown to interact effectively with this DNA secondary structure. This Review provides an overview of the important roles that metal complexes can play as quadruplex DNA binding molecules, highlighting the unique properties metals can confer to these molecules.     

From Intercalation to Groove Binding: Switching the DNA‐Binding Mode of Isostructural Transition‐Metal Complexes

The interaction with duplex DNA of a small library of structurally related complexes that all contain a d⁶‐metal ion coordinated to either the 2,2 ′ :4,4 ′′ :4 ′ ,4 ′′′ ‐quaterpyridyl ligand or its methylated derivative are reported. This library is made up of a mixture of newly synthesised and previously reported systems. Despite their structural similarities the complexes display an almost 20‐fold variation in binding affinities. Although effects due to the overall charge of the complexes are apparent, the differences in binding characteristics are deeper than this; indeed, in a number of cases, changes in overall charge have little effect on binding affinity. Intriguingly, despite interacting with DNA through unfused ring systems, although two of the complexes studied are groove binders, the majority are non‐classical intercalators. A rationale for these effects has been obtained through a combination of experimental and computational studies.     

高分子对酶、抗体、DNA的修饰、固定化及其生物医学应用

为发展适于生物医用的生物功能高分子材料,本实验室近年来研究了可溶性高分子对L-天冬酰胺酶的修饰、纳米磁性高分子微粒对酶或抗体的固定化、亚微米高分子微球固定化碱性磷酸酶及其在DNA检测中的应用、高分子微球固定化酶的合成与性能、酶在导电高分子膜上的固定化及生物传感器制备等. 本文对此进行简要总结.     

The Interactions of Low Oxidation State Transition Metal Clusters with DNA: Potential Applications in Cancer Therapy

A series of ruthenium and platinum clusters have been examined for DNA binding activity in methanol-water and water solutions. The clusters [H₄Ru₄(C₆H₆)₄]²⁺and Ru₃(CO)₉(PTA)₃(PTA=1,3,5-triaza-7-phosphatricyclo[3.3.1.1] decane) proved to be most effective; the former is believed to cross link DNA and the latter possibly intercalates. These clusters are highly water soluble and combined with their DNA damaging activity and size represent potential anticancer drugs.     

抗肿瘤多核铂配合物的研究

多核铂配合物作为非经典铂抗肿瘤药物,其抗肿瘤机制与现有铂类抗肿瘤药物不同,因而在克服现有铂类抗肿瘤药物耐药性方面有着巨大的潜力。本文综述了多核铂类抗肿瘤药物的研究进展,以连接铂原子的桥配体结构的不同,可分为六大类:以烷基二胺及其衍生物为桥的多核铂配合物、以含氮杂环为桥的多核铂配合物、以羧酸根为桥的多核铂配合物、以卤素离子为桥的多核铂配合物、以含硫配体为桥的多核铂配合物及以其他配体为桥的多核铂配合物。本文还介绍了这几类多核铂配合物的抗肿瘤机理及在克服顺铂耐药性机理方面的研究进展。     

高分子类型MONOLITH材料的制备技术及其作为亲和色谱固定相用于分离生物大分子的应用

高分子类型MONOLITH材料（也称整体柱,连续床）是近些年来发展迅速的一种新型的以高分子为基质的整体型多孔材料,由于其内部独特的三维连续相互贯通的多孔结构,在诸多应用领域越来越受到研究者的关注,尤其被认为是分离过滤领域的一个历史性突破。与硅基质MONOLITH材料相比,高分子类型的MONOLITH材料具有制备工艺简单、生物相容性好、化学稳定性高和表面化学性质易调控等特点,因此作为亲和色谱的固定相在生物大分子的分离分析上具有更大的优势。本综述重点总结了高分子类型MONOLITH材料的制备方法及其最新研究进展,并论述了近5年来其作为亲和色谱固定相用于分离生物大分子的应用进展。     

New Designs for Phototherapeutic Transition Metal Complexes

In this Minireview, we highlight recent advances in the design of transition metal complexes for photodynamic therapy (PDT) and photoactivated chemotherapy (PACT), and discuss the challenges and opportunities for the translation of such agents into clinical use. New designs for light‐activated transition metal complexes offer photoactivatable prodrugs with novel targeted mechanisms of action. Light irradiation can provide spatial and temporal control of drug activation, increasing selectivity and reducing side‐effects. The photophysical and photochemical properties of transition metal complexes can be controlled by the appropriate choice of the metal, its oxidation state, the number and types of ligands, and the coordination geometry.     

金属卟啉对杂环及DNA分子识别研究进展

介绍了近几年国内外关于组装金属卟啉对杂环分子、DNA碱基以及RNA的分子识别的研究进展, 并简述了本课题组对金属卟啉与杂环及药物分子复合物的理论研究工作. 金属卟啉广泛存在于自然界和生物体中, 此识别过程对研究和模拟生命体中各种细胞之间的相互作用具有重要意义. 组装后的金属卟啉可通过轴向配位、氢键及π-π堆积作用等识别杂环分子. 金属卟啉对DNA的识别主要有四种作用方式, 而金属卟啉对DNA以及RNA分子的识别主要靠疏水作用力、静电力以及自堆叠作用. 卟啉阳离子与DNA的结合位点受主体侧链取代基的空间结构影响. 金属卟啉对药物分子的识别靠配位键和氢键进行, 以配位键结合的复合物通常具有更高的结合能.     

钌配合物的电化学性质及其在电致化学发光中的应用

概述了近年来国内外对钌配合物的研究,主要介绍了它们的电化学性质及其在电致化学发光中的应用。     

Preparation and Structures of Several Complexes Containing Carbon-Rich Ligands Attached to Polynuclear Metal Carbonyls

Several new gold-containing cluster complexes have been prepared from the reactions of gold alkynyl complexes, L _n M-C _x -Au(PPh₃), (x = 3, 4, 6) with Ru₃(CO)₁₀(NCMe)₂. The bis-cluster complex 1,4-{AuRu₃(CO)₉(PPh₃)(μ₃-C₂)}₂C₆H₄ was obtained from Ru₃(CO)₁₀(NCMe)₂ and 1,4-{(Ph₃P)Au(C≡C)}₂C₆H₄. The complexes Ru₃(μ-H){μ₃-C₂C≡C[Ru(PP)Cp′]}(CO)₉ [PP = (PPh₃)₂, Cp′ = Cp; PP = dppe, Cp′ = Cp*] were also obtained as minor by-products and synthesised independently from Ru(C≡CC≡CH)(PP)Cp′. A reaction between Co₃{μ₃-CC≡CC≡CAu(PPh₃)}(μ-dppm)(CO)₇ and Ru₃(CO)₁₂ afforded {(Ph₃P)(OC)₉AuRu₃}C≡CC≡CC{Co₃(μ-dppm)(CO)₇} 7. Related complexes AuRu₃{μ₃-C₂C≡[M(CO)₂Tp]}(CO)₉(PPh₃) (M = Mo 8, W 9) were obtained from {Tp(OC)₂M}≡CC≡C{Au(PPh₃)}, while the mixed metal cluster complexes MoM₂(C₂Me)(CO)₈Tp (M = Ru 13, Fe 14) were obtained from M(≡CC≡CSiMe₃)(CO)₂Tp (M = Mo, W) with Fe₂(CO)₉ and Ru₃(CO)₁₂, respectively. Reactions of the Mo carbyne complex with Co₂(LL)(CO)₆ [LL = (CO)₂, μ-dppm] or nickelocene afforded complexes 15–17 in which Co₂ and Ni₂ fragments, respectively, had coordinated to the C≡C triple bond. XRD structural determinations of 7, 8, 14, 16 and {Tp(OC)₂W}≡CC≡CC≡{Co₃(μ-dppm)(CO)₇} (18-W) are reported. In memoriam: F. Albert Cotton (1930–2007).     

Dendritic Macromolecules as Inhibitors to Protein-Protein Binding

Summary: Our initial studies into protein binding using a series of dendrimers as size selective inhibitors have been described. Two different proteins, cytochromo-c and chymotrypsin have been selected for these binding experiments.     

液相脉冲激光烧蚀法制备高熔点的纳米金属粒子

采用液相脉冲激光烧蚀法成功地制备了高熔点的金属Pt、Ru与Ag纳米粒子. 采用SEM、TEM、ED和紫外-可见吸收光谱表征了纳米粒子的特征. 纳米粒子的粒径基本在数个到数十个纳米的大小范围内. 发现含适量PVP(poly(vinylpyrrolidone))的水溶液有利于纳米粒子的制备, 而且还能够提高纳米粒子悬浮液的稳定性. 该制备方法较简单, 在制备高熔点的纳米金属粒子方面有着其它方法所不能比拟的优势.     

Biological and Catalytic Applications of Pd(II)-Indenyl Complexes Bearing Phosphine and N-Heterocyclic Carbene Ligands

A general synthetic entryway into novel cationic Pd(II) indenyl complexes bearing one alkyl/aryl phosphine and one N-heterocyclic carbene is reported. All metal complexes have been exhaustively characterized by spectroscopic and structural analyses, highlighting that the indenyl fragment has an hapticity intermediate between η³ and η⁵. Most of the target complexes are stable in solid state and in solution for a long time. Two different applications of these organopalladium compounds are proposed. Firstly, they have been tested as antiproliferative agents towards three different ovarian cancer cell lines, showing a cytotoxicity significantly higher than that of cisplatin, with a clear dependence on the nature of the coordinated phosphine. Moreover, the similar cytotoxicity towards cisplatin-sensitive and cisplatin-resistant cell lines suggests that these new palladium derivatives act with a different mechanism of action with respect to classical platinum-based drugs. Finally, the water-soluble palladium complexes bearing 1,3,5-triaza-7-phosphaadamantane (PTA) have demonstrated interesting catalytic performances in Suzuki–Miyaura coupling in aqueous media, being, inter alia, readily and efficiently recyclable.     

钌配合物与G-四链体DNA的相互作用研究进展

人体端粒由富含鸟嘌呤(G)的DNA重复序列组成,该序列在一定条件下可以形成G-四链体DNA结构。小分子化合物诱导该结构的形成并使之稳定,可以抑制端粒酶活性而达到抗肿瘤的目的。因此,G-四链体DNA稳定剂的设计和筛选是近年来生物无机化学的重要前沿研究领域之一。在金属配合物中,钌配合物由于具有丰富的光化学、光物理特性以及生物活性,其作为G-四链体DNA稳定剂引起人们的高度关注。本文以近年一些代表性的研究工作为例,对钌配合物与G-四链体DNA相互作用方面的研究进展进行了综述。     

Metal segregation in bimetallic clusters and its possible role in synergism and bifunctional catalysis

Aspects of the reactivity of segregated bimetallic compounds and their unusual catalytic properties are reviewed with an emphasis on the author's own studies of platinum—ruthenium mixed-metal cluster complexes and their ability to produce hydrogenation and hydrosilylation of alkynes, catalytically.     

噻吩基钌配合物与酵母RNA的相互作用研究

通过紫外-可见吸收光谱和荧光光谱滴定、稳态荧光猝灭以及盐效应实验研究了噻吩基钌配合物[Ru(bpy)2(Htip)]Cl2(1)、[Ru(Htip)2(dppz)]Cl2(2)、[Ru(Htip)3]Cl2(3)和[Ru2(bpy)4(H2bipt)]Cl4(4){bpy=2,2'-联吡啶;Htip=2-噻吩咪唑[4,5-f][1,10]邻菲咯啉;H2bipt=2,5-二(2-咪唑[4,5-f][1,10]邻菲咯啉)噻吩;dppz=二吡啶并[3,2-a:2',3'-c]吩嗪}与酵母RNA(yeast-RNA)的相互作用,并比较了该类配合物与yeast-RNA和小牛胸腺DNA(ct-DNA)的键合性质。结果表明,该类噻吩基钌配合物是较强的RNA嵌入试剂,其中配合物2和3的RNA键合强度大于其DNA键合强度;此系列配合物在低盐和高盐浓度时均能与RNA较强地结合,即使在100 mmol/L Na Cl条件下仍具有较大的RNA键合常数;配合物1与RNA键合时荧光强度下降,配合物2在水溶液中以及与RNA键合时几乎无荧光,而它们与DNA作用时荧光强度明显增大,显示出良好的区分RNA和DNA的荧光特性。