靶向抑制拓扑异构酶和端粒酶的钌配合物研究进展

金属配合物抗肿瘤研究,尤其是铂类药物,已取得了相对令人瞩目的成功,但同时也面临着包括耐药性和毒副作用等诸多问题。近年来钌配合物作为新的抗癌药物引起了人们的注意。在非铂系药物中,金钌配合物;拓扑异构酶;G-四链体;端粒酶属钌配合物是最有前途的抗癌药物之一,国际上普遍认为钌和钌的配合物属于低毒性,容易吸收并在体内很快排泄。本文将着重介绍钌配合物与DNA结合后进一步引发的细胞内核酶活性抑制研究,从新的角度来诠释钌配合物的抗肿瘤研究最新进展。     

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].     

钌配合物诱导肿瘤细胞凋亡的信号通路及其作用机制

钌配合物作为抗癌药物的研究已经受到了国际研究者的广泛关注.近年来,新型结构钌配合物的设计合成;钌配合物在细胞凋亡、信号传递、基因、蛋白表达等过程中的调控作用成为新的研究热点,金属钌配合物抗癌活性机制得到进一步的阐释.本文主要对钌配合物诱导肿瘤细胞凋亡及其信号通路以及蛋白调控等抗肿瘤机制的研究进行评述.主要包括:已经进入...     

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。     

金属钌配合物的抗肿瘤活性及其作用机理

金属配合物在医药领域起着重要的作用,金属钌配合物在抗肿瘤活性研究方面取得了重要的进展.结合本组的研究工作,本文对金属钌配合物在抗肿瘤活性以及抗肿瘤作用机制方面的研究进展进行了综述.     

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。     

芳基钌抗癌化合物的研究进展

无机药物化学领域正在快速发展,尤其是有机金属配合物作为癌症的治疗和诊断试剂有很大的潜力.芳基钌配合物中芳基对抗癌活性有重要影响,并能调控配合物金属中心的热力学和动力学性能.配合物的构效关系研究,对进一步合理设计/合成具有潜在药用价值的有机金属配合物至关重要.本文选取钌芳基配合物作为抗癌药物的具体实例进行讨论,重点介绍了多种芳基钌配合物的构效关系及抗癌机理.     

钌配合物稳定端粒DNA的作用及其诱导细胞凋亡分子机制的研究

端粒酶在肿瘤细胞中高表达,已经成为抗肿瘤药物的重要靶点,由于很多肿瘤细胞中富含G4-DNA,通过稳定G-四链体DNA的形成来抑制端粒酶的活性已成为抗癌药物的一个新策略. 本文设计了两种钌配合物,调查了这两种钌配合物稳定G4-DNA的能力,发现配合物2稳定端粒 G4-DNA的能力强于配合物1,配合物2能够诱导端粒 G4-DNA发生构型的转化,而配合物1不能诱导G4-DNA发生构型的转化,这项研究结果证明,钌配合物与G4-DNA的作用能力与配体的平面性有关. 在抗肿瘤活性方面,配合物2表现出更强的抗肿瘤活性,尤其是对HepG2细胞具有较强的抑制作用,推测其是以端粒酶为靶点发挥的抗肿瘤作用. 配合物2能够诱导肿瘤细胞凋亡,能诱导G1期细胞阻滞和DNA碎片的形成（细胞凋亡的特征）. 据此推测本论文设计的钌配合物是一个潜在的抗肿瘤药物.     

8-羟基喹啉及其衍生物金属配合物抗肿瘤和抗菌活性研究进展

铂类抗癌药物在临床上的成功应用,极大推动了金属药物化学的发展.寻找新型作用机制金属药物已成为药物化学研究领域的热点之一.本文就8-羟基喹啉及其衍生物金属配合物在抗肿瘤和抗菌方面的研究进展进行综述,从金属配合物的合成、结构、活性、作用机制、构效关系等总结了8-羟基喹啉及其衍生物金属抗肿瘤配合物的最新研究进展.对8-羟基喹啉及其衍生物金属抗菌配合物的研究也进行了总结,从中发现了一些活性基团及卤代效应的趋势,为设计和开发具有应用前景的8-羟基喹啉及其衍生物金属抗肿瘤、抗菌药物提供了重要的参考.     

基于天然产物的铂类和芳基金属抗癌药物研究进展

临床使用的现代药物超过50%都来自于天然产物,它们不仅能够通过阻止细胞周期进程、抑制癌细胞存活信号通路以及调节免疫细胞等多种生物途径来阻止肿瘤生长及其进程,而且对正常组织表现出较低的毒性。虽然以顺铂为代表的金属抗肿瘤药物广泛用于临床,但是它们存在严重的耐药性和毒副作用,包括肾毒性、神经毒性等。因此,利用天然产物中的优势来改造铂类配合物,有望开发出新型铂类抗癌药物以克服铂药的缺陷。另一方面,芳基金属配合物因其良好的水溶性和对正常组织的低毒性受到了广泛关注,将天然产物与芳基金属配合物相结合,也为开发高效低毒的新型抗癌药物提供了更多可能。结合天然产物和金属各自优势开发基于天然产物的金属配合物作为抗癌剂已成为研究热点,开辟了抗癌的新途径。本文对已经报道的有关天然产物的铂类和芳基金属配合物的研究及作用机理进行了较为全面的综述,并对该领域的未来发展进行了展望。     

Dicarba-closo-dodecarborane-containing half-sandwich complexes of ruthenium, osmium, rhodium and iridium: biological relevance and synthetic strategies

This review describes how the incorporation of dicarba-closo-dodecarboranes into half-sandwich complexes of ruthenium, osmium, rhodium and iridium might lead to the development of a new class of compounds with applications in medicine. Such a combination not only has unexplored potential in traditional areas such as Boron Neutron Capture Therapy agents, but also as pharmacophores for the targeting of biologically important proteins and the development of targeted drugs. The synthetic pathways used for the syntheses of dicarba-closo-dodecarboranes-containing half-sandwich complexes of ruthenium, osmium, rhodium and iridium are also reviewed. Complexes with a wide variety of geometries and characteristics can be prepared. Examples of addition reactions on the metal centre, B-H activation, transmetalation reactions and/or direct formation of metal-metal bonds are discussed (103 references).     

Palladium complexes: new candidates for anti-cancer drugs

Platinum complexes which are most studied metal complexes due to their importance as adjuvant therapy of cancers aiming to induce tumor-cell-death. Some of the platinum-based antitumor drugs like cisplatin, carboplatin and oxaliplatin, have several disadvantages including side effects, cisplatin-resistant tumors, limited solubility in aqueous media, and so on. Thus, to achieve lower undesirable toxicity, enhanced solubility, and tumor selectivity, significant amount of work have been devoted to the preparation of modified platinum complexes. One of the ways to design the new anti-tumor agents related to cisplatin is to change the nature of central metal ion. Among the non-platinum metal complexes studied for cancer treatment, palladium(II) derivatives were readily chosen due to their structural analogy with those containing Pt(II) complexes. This review focuses on anti-tumor property of Pd(II) complexes and makes comparisons with similar property of cisplatin. Then, in the review, palladium(II) complexes have been classified according to their leaving ligands into palladium(II) complexes. In the last part, the most important factors affecting on the anti-tumor activity of the Pd(II) complexes were discussed. These factors are encouraging more researches in this field, for future applications.     

Functionalization of Alkynes by a (Salen)ruthenium(VI) Nitrido Complex

Exploring new reactivity of metal nitrides is of great interest because it can give insights to N₂ fixation chemistry and provide new methods for nitrogenation of organic substrates. In this work, reaction of a (salen)ruthenium(VI) nitrido complex with various alkynes results in the formation of novel (salen)ruthenium(III) imine complexes. Kinetic and computational studies suggest that the reactions go through an initial ruthenium(IV) aziro intermediate, followed by addition of nucleophiles to give the (salen)ruthenium(III) imine complexes. These unprecedented reactions provide a new pathway for nitrogenation of alkynes based on a metal nitride.     

Metals in Medicine

Not only the 24 or so essential elements , but also nonessential and even radioactive elements have enormous potential for applications in medicine. In the fight against cancer cisplatin, one of the world's best selling anticancer drugs, is being joined by other platinum, titanium, and ruthenium complexes. Gadolinium(III ) complexes can be safely injected as magnetic resonance imaging contrast agents, and ligand design allows targeting of paramagnetic ions as well as radiodiagnostic (e.g. ^99mTc) and radiotherapeutic isotopes (e.g. ¹⁸⁶Re). Manganese superoxide dismutase mimics, vanadium insulin mimics, ruthenium nitric oxide scavengers, lanthanide-based photosensitizers, and metal-targeted organic agents show exciting clinical potential.     

Targeted and multifunctional arene ruthenium chemotherapeutics

The introduction of multifunctionalities for tumour targeting is becoming a popular strategy toward the development of new therapeutic agents. In particular, the multifaceted potential of ruthenium(II)-arene complexes show great promise as chemotherapeutics. An ever-increasing number of papers dealing with the integration of ruthenium complexes with biologically active molecules to derive bioorganometallic molecules of chemotherapeutic significance have been published in recent years. This perspective review presents a short overview of multifunctional ruthenium-based drugs, especially those containing arene ruthenium complexes, with the emphasis on the combination of photosensitizers with ruthenium complexes for the preparation of novel multifunctional photodynamic therapy agents.     

Promising sensitizers for dye sensitized solar cells: A comparison of Ru(II) with other earth's scarce and abundant metal polypyridine complexes

There has recently been a growing interest in dye sensitized solar cells (DSSCs) based on ruthenium metal, but due to the scarcity and high price of ruthenium, design of better and cheaper light adsorbent dyes based on more abundant metal ions is one of the key issues for future development of the DSSCs. Using density functional theory (DFT) and time-dependent DFT we have studied the properties of new and abundant metal ion-based polypyridyl dyes for p-type DSSCs and compared with ruthenium and other scarce metal ions. Molecular geometries, electronic structures, and optical absorption spectra have been calculated using an implicit solvent corresponding to acetonitrile. The calculated fair light harvesting efficiency, high hole injection efficiency and Gibbs free energy for the hole injection and longer excited state lifetime (important for reflecting the efficiency of solar cells) for the new abundant metal ions (V³⁺ and Cr²⁺) based dyes could provide promising sensitizers for efficient next generation DSSC's for p-SC.     

Covalent Interaction of Ru(terpy)(tmephen)Cl+ with DNA: A Potential Ruthenium‐Based Anticancer Drug

The use of ruthenium complexes in antitumor therapy was launched two decades ago. In view of their low toxicity and good selectivity for solid tumor metastasis, ruthenium complexes have great potential as alternative drugs to cisplatin in cancer chemotherapy. A series of monochloro ruthenium complexes, Ru(terpy) (NN)Cl⁺ (NN, bidentate nitrogen ligand), containing different electron‐donating groups were prepared. The reactivity towards the formation of Ru‐DNA adduct were revealed by gel mobility shift assay. Their DNA binding sites of Ru(terpy)(tmephen)Cl⁺ were located predominantly at the purine residues i.e., guanine and adenine, by terminating DNA elongation in vitro using PCR and primer extension techniques. Surprisingly, the ability of Ru(terpy)(tmephen)Cl⁺ to inhibit cell growth was found to be approximately two times better than that of a known cross‐linking agent, Ru(bpy)₂Cl₂. Therefore, the increase in liability of the chloro ligand was demonstrated to improve the reactivity of these ruthenium complexes towards the covalent bond formation in Ru‐DNA adducts and result also in a significant inhibition of cell growth. Based on our results, these ruthenium complexes modified with electron‐rich groups provide new consideration in the tune of ruthenium‐based drugs in cancer chemotherapy.     

A comparison of the binding of metal complexes to duplex and quadruplex DNA

Electrospray ionisation mass spectrometry (ESI-MS) and circular dichroism (CD) spectroscopy were used to compare the binding of mononuclear nickel, ruthenium and platinum complexes to double stranded DNA (dsDNA) and quadruplex DNA (qDNA). CD studies provided evidence for the binding of intact complexes of all three metal ions to qDNA. ESI mass spectra of solutions containing platinum or ruthenium complexes and qDNA showed evidence for the formation of non-covalent complexes consisting of intact metal molecules bound to DNA. However, the corresponding spectra of solutions containing nickel complexes principally contained ions consisting of fragments of the initial nickel molecule bound to qDNA. In contrast ESI mass spectra of solutions containing nickel, ruthenium or platinum complexes and dsDNA only showed the presence of ions attributable to intact metal molecules bound to DNA. The fragmentation observed in mass spectral studies of solutions containing nickel complexes and qDNA is attributable to the lower thermodynamic stability of the former metal complexes relative to those containing platinum or ruthenium, as well as the slightly harsher instrumental conditions required to obtain spectra of qDNA. This conclusion is supported by the results of tandem mass spectral studies, which showed that ions consisting of intact nickel complexes bound to qDNA readily undergo fragmentation by loss of one of the ligands initially bound to the metal. The ESI-MS results also demonstrate that the binding affinity of each of the platinum and ruthenium complexes towards qDNA is significantly less than that towards dsDNA.