新型双核铂(Ⅱ)配合物通过p53-Bak途径诱导人乳腺癌MCF-7细胞凋亡

新型双核铂(Ⅱ)配合物{［cis-Pt(NH3)2Cl］2L}(NO3)2（L=4,4′-methylenedianiline)对多种肿瘤细胞有一定的抑制作用,但作用机制不明。本研究以顺铂为对照,探讨了该双核铂(Ⅱ)配合物对MCF-7细胞增殖抑制、细胞周期、细胞凋亡及凋亡相关因子p53、P-p53(ser15)、p21、Bcl-2、Bak、Cleaved- caspase-3、cPARP（cleavage of poly(ADP-ribose)polymerase）的影响。MTT法检测配合物或顺铂在不同浓度或不同作用时间后对MCF-7增殖的影响,其中作用48 h后配合物对MCF-7的IC50为1.59 μmol/L,顺铂为7.95 μmol/L。原位移植瘤实验显示,配合物组肿瘤抑制率为54.1%,高于顺铂组（36.2%）。同等条件下,配合物处理的MCF-7细胞,经Hoechst33342染色后出现明显细胞体积缩小和染色质固缩现象。流式细胞检测技术分析显示,经该配合物处理后,大部分MCF-7细胞停滞在S期,并出现了细胞膜外表面的磷脂酰丝氨酸外翻与线粒体内膜急剧下降等典型的细胞凋亡现象。Western 印迹结果显示,随着配合物浓度增加,Cleaved-caspase-3、p53、P-p53(ser15)、cPARP、Bak蛋白表达增强,而p21、Bcl-2表达水平下调。上述结果表明,该配合物可能通过p53-Bak途径诱导DNA损伤,进而导致MCF-7细胞发生凋亡。     

顺,反铂配合物诱导生物合成金属硫蛋白的研究

给家兔皮下注射不同结构的铂配合物溶液、对肝、肾组织的可溶性组分进行凝胶和离子交换层析分离,研究了它们诱导金属硫蛋白合成的性质,发现顺铂只选择性地诱导肝脏合成ＭＴ,反铂对肝,肾都不诱导,Ｋ２ＰｔＣｌ４同时可在肝和肾脏中诱导ＭＴ的合成。并通过用Ｚｎ（ＮＯ３）２预先诱导肝和肾中合成ＭＴ,然后每日以２、４、４和８ｍｇＰｔ／ｋｇ的剂量连续皮下注射４天顺铂或反铂溶液后,在肝和肾中分离出大量的铂化硫蛋白,且用反     

氨基酸schiff碱及其金属配合物的性能研究进展

氨基酸Sch iff碱及其金属配合物具有良好的抗炎、抗菌、抗癌等生物活性而有望成为高效、低毒、可供临床使用的新药物而引起人们的极大关注。本文综述了氨基酸sch iff碱及其金属配合物的生物活性、测定金属含量、催化、载氧等性能的研究情况(特别是在生物活性方面),并分析总结了其在研究方面存在的问题。     

稀土Ho-吲哚-3-乙酸配合物的合成及其生物活性的研究

以吲哚-3-乙酸为配体,合成了稀土钬的配合物。利用元素分析、红外光谱(IR)、热重-差热分析(TG-DTG)和荧光光谱(FS)等分析手段对配合物的组成和光学等性质进行了分析与表征,推测配合物的通式为Ho(L)3.2H2O;通过对荧光光谱的研究表明,稀土钬配合物具有较好的荧光性能;通过对其生物活性的表征说明吲哚乙酸与稀土硝酸盐在形成稀土配合物后,对植物的生长起到了协同促进作用。     

壳聚糖金属配合物的抑菌特性及机理研究（英文）

制备了壳聚糖(CS)与金属离子Zn(II)、Ni(II)和Co(II)的配合物,通过红外光谱和紫外-可见吸收光谱进行了结构性能的表征。体外抑菌法研究了壳聚糖金属配合物对细菌S.aureu和E.coli的抑菌活性。结果表明:壳聚糖金属配合物的抑菌活性较壳聚糖增强,且与所含的金属离子种类有关,其中CS-Zn体现出更强的抑菌活性。因此,选CS-Zn为代表通过测定细胞内溶物的OD260nm判断细胞膜的完整性、荧光探针1-N-苯萘胺(NPN)的荧光变化来判断细胞外膜的渗透性,以研究其对大肠杆菌(E.coli.)的抑菌机理。透射电镜(TEM)结果表明CS-Zn能够破坏细菌细胞膜,使细胞内溶物溢出。     

黄芩苷镧(Ⅲ)、钇(Ⅲ)配合物的合成及生物活性研究

改进以往反应条件,合成了黄芩苷镧(Ⅲ)、黄芩苷钇(Ⅲ)配合物,利用IR、UV、LC-MS和金属元素含量测定对配合物进行了表征。采用MTT法分别考察了两种新化合物的抑菌活性(金黄色葡萄球菌、大肠杆菌、枯草芽孢杆菌、沙门氏菌、白色念珠菌)和抗肿瘤活性(A549、HepG2),采用灌胃法考察化合物对小鼠的急性毒性。结果表明:黄芩苷在与金属配合后,结构表征发生了一定的变化,配合物无金属离子毒性反应,并且其抑菌、抗肿瘤作用均显示出黄芩苷镧>黄芩苷钇>黄芩苷。     

β-二酮亚胺-铁(Ⅱ)羰基配合物的合成及其表征

β-二酮亚胺配体(ArN(R)CCH(R)NAr,R=CH_3,H,Ar=2,6-二异丙基苯胺,苯胺,2,6-二甲基苯胺等等)可与不同金属配位形成多种配合物,上述配合物因其特殊的反应性能引起了研究者的广泛关注。本文以环戊二烯氯代羰基铁与β-二酮亚胺配体(ArN (R)CCH(R)NAr,R=CH_3,Ar=2,6-二甲基苯胺)反应生成铁的金属配合物,并对其产物进行了IR,1HNMR表征。     

表没食子儿茶素没食子酸酯（EGCG）锗（IV）配合物的研究

研究了以绿茶中表没食子儿茶素没食子酸酯(EGCG)为配体制备有机储配合物的反应。结果表明:EGCG[2.00％(w/w)]与Ge(Ⅳ)按摩尔比3:1,在pH6.50～7.00的缓冲溶液中,于40℃恒温水浴中反应30分钟,生成EGCG-Ge(Ⅳ)金属配合物,产物产率61.81％。按等摩尔连续变换法及摩尔比法测定EGCG-Ge(Ⅳ)配合物组成为[EGCG][Ge(Ⅳ)]=2:1(mol/mol),配合物不稳定常数2.570×10~(-11)。在温度≤40℃的中性溶液中,配合物对光的稳定性较好。此外,对配合物的结构进行了红外、紫外及高效液相分析。 茶多酚粗品、EGCG及EGCG-Ge(Ⅳ)配合物对艾氏腹水肿瘤均表现出一定的抗癌效果。     

氨基酸Schiff碱及其金属配合物的抑菌抗癌活性的研究进展

氨基酸Ｓｃｈｉｆｆ碱及其金属配合物具有良好的生理、生物活性,本文就近年来国内外在氨基酸Ｓｃｈｉｆ碱及其金属配合的抑菌抗癌活性的研究进展方面进行了综述     

光动力过程中线粒体膜电位和细胞存活关系

以1-anilionaphthalene-8-sulfonate(ANS)作荧光探针,通过其荧光光谱研究了苯硫基酞菁锌PcS)、苯硫基铝酞菁(AIPcS)和烷氧基铝酞菁(AIPc)这三种金属酞菁配合物作为光敏剂的光动力作用对癌细胞线粒体膜表面电位的影响．研究表明,光动力作用后线粒体膜表面电位降低,表面电荷数面密度增加．ZnPcS的影响最大,这与酶联免疫检测光动力作用后对癌细胞的杀伤效果相一致,提示细胞线粒体膜可能是金属酞菁配合物在光动力过程中的作用位点。通过比较细胞线粒体膜表面电位以及表面电荷数面密度与细胞存活之间的关系,阐述了光动力作用的物理学机制．同时,由于线粒体膜电位与细胞凋亡的密切关系,金属酞菁配合物对线粒体膜表面电位的影响提供了一个衡量药物疗效的判据。     

Beyond mere DNA damage: Recent progress in platinum(IV) anticancer complexes containing multi-functional axial ligands

The clinical application of Pt-based anticancer drugs has inspired the development of novel chemotherapeutic metallodrugs with improved efficacies. Pt(IV) prodrugs are one of the most promising successors of Pt(II) drugs and have displayed great anticancer performance. In particular, judicious modification of axial ligands endows Pt(IV) complexes with unique properties that enable them to overcome the limitations of conventional Pt(II) drugs. Herein, we summarize recent developments in Pt(IV) anticancer complexes, with a focus on their axial functionalization with other anticancer agents, immunotherapeutic agents, photosensitive ligands, peptides, and theranostic agents. We hope that this concise view of recently reported Pt(IV) coordination complexes will help researchers to design next-generation multi-functional anticancer agents based on a comprehensive Pt(IV) platform.     

Application of natural products derivatization method in the design of targeted anticancer agents from 2000 to 2018

A concept, natural products derivatization method (NPDM), was introduced to assess the influence of natural products on the discovery of targeted anticancer agents. Subsequently, 106 new molecular entities (NMEs) for targeted anticancer agents from 2000 to 2018 were categorized and sorted into four types: ND (Natural Product Derivative), SND (Synthetic Natural Derived), B (Biological Macromolecule), S (Totally synthetic in origin). Furthermore, by setting molecular targeted agents (MTA), cellular targeted agents (CTA), vascular targeted agents (VTA) and immuno targeted agents (ITA) as study subject, ND category and SND category were reviewed from aspects including natural products source, action mechanism and their share in all NMEs in order to comprehensively evaluate the significance of NPDM in the design and development of targeted anticancer agents, and the prospects of this method was also put forward.     

Unique platinum-DNA interactions may lead to more effective platinum-based antitumor drugs

Platinum coordination compounds are among the most utilized anticancer agents, even though platinum has not been determined to be an essential trace element in any living organism. The success of platinum-based drugs has catalyzed research on other metal-containing agents that can be used to achieve therapeutic goals that cannot be achieved with organic compounds. The antitumor activities of recently reported platinum(ii) complexes indicate that further modification of platinum coordination compounds will lead to the development of anticancer agents with higher efficacies against chemotherapy-insensitive tumors.     

Perspective: the potential of pyrazole-based compounds in medicine

Pyrazoles are widely used as core motifs for a large number of compounds for various applications such as catalysis, agro-chemicals, building blocks of other compounds and in medicine. The attractiveness of pyrazole and its derivatives is their versatility that allows for synthesis of a series of analogues with different moieties in them, thus affecting the electronics and by extension the properties of the resultant compounds. In medicine pyrazole is found as a pharmacophore in some of the active biological molecules. While pyrazole derivatives have been extensively studied for many applications including anticancer, antimicrobial, anti-inflammatory, antiglycemic, anti-allergy and antiviral, much less has been reported on their metal counterparts in spite of the fact that metals have been shown to impart activity to ligands. Thus this perspective is intended to demonstrate the potential of pyrazole and pyrazolyl metal complexes in the areas of drug discovery and development. Several examples, that include palladium, platinum, copper, gold, zinc, cobalt, nickel, iron, copper, silver and gallium complexes, are used to bolster the above point. For the purposes of this review three areas are discussed, that is pyrazole metal complexes as: (i) anticancer, (ii) antibacterial/parasitic and (iii) antiviral agents.     

Synthesis and biological evaluation of novel coumarin-based inhibitors of Cdc25 phosphatases

The cell division cycle 25 (Cdc25) family of proteins are dual specificity phosphatases that activate cyclin-dependent kinase (CDK) complexes, which in turn regulate progression through the cell division cycle. Overexpression of Cdc25 proteins has been reported in a wide variety of cancers; their inhibition may thus represent a novel approach for the development of anticancer therapeutics. Herein we report new coumarin-based scaffolds endowed with a selective inhibition against Cdc25A and Cdc25C, being 6a and 6d the most efficient inhibitors and worthy of further investigation as anticancer agents.     

Polyether ionophores—promising bioactive molecules for cancer therapy

The natural polyether ionophore antibiotics might be important chemotherapeutic agents for the treatment of cancer. In this article, the pharmacology and anticancer activity of the polyether ionophores undergoing pre-clinical evaluation are reviewed. Most of polyether ionophores have shown potent activity against the proliferation of various cancer cells, including those that display multidrug resistance (MDR) and cancer stem cells (CSC). The mechanism underlying the anticancer activity of ionophore agents can be related to their ability to form complexes with metal cations and transport them across cellular and subcellular membranes. Increasing evidence shows that the anticancer activity of polyether ionophores may be a consequence of the induction of apoptosis leading to apoptotic cell death, arresting cell cycle progression, induction of the cell oxidative stress, loss of mitochondrial membrane potential, reversion of MDR, synergistic anticancer effect with other anticancer drugs, etc. Continued investigation of the mechanisms of action and development of new polyether ionophores and their derivatives may provide more effective therapeutic drugs for cancer treatments.     

Meeting report on 8th International Symposium on Platinum and Other Metal Coordination Compounds in Cancer Chemotherapy

The platinum-based drugs, cisplatin and carboplatin, represent major agents in the chemotherapeutic treatment of a variety of types of cancer. Novel, "third-generation" agents aimed at broadening the clinical activity of this class of drug are currently undergoing clinical evaluation. These include oxaliplatin, ZD0473 and BBR3464. Clinical trials and preclinical studies are also being conducted with liposomal (SPI-077 and L-NDDP) and polymeric platinum complexes (linked to HPMA or albumin). Combination studies of cisplatin/carboplatin with other anticancer drugs such as gemcitabine and UCN-01 (7-hydroxystaurosporine) and agents designed to reduce platinum drug toxicities (e.g., BNP-7787, DIMESNA) are ongoing. Preclinically, there is interest in trans platinum complexes, terpyridine platinum(II) complexes and other metal-containing agents (ruthenium and gold).     

Copper(II) complexes containing N,N-donor ligands and dipeptides act as hydrolytic DNA-cleavage agents

Copper(II) complexes are known to play a significant role in both naturally occurring biological systems and pharmaceutical agents. Recently, Cu(II) complexes have gained importance in DNA cleavage essential for the development of anticancer drugs and chemotherapeutic agents. Therefore, we have designed small molecules, consisting of a metal ion, N,N-donor ligands, and dipeptides, to probe their DNA-cleaving potential. Accordingly, the interaction of Cu(II) with ethylenediamine, histamine and the dipeptides histidylglycine, histidylalanine, and histidylleucine has been investigated. The binding modes, stabilities, and geometries of these complexes were determined by various physicochemical techniques. Their DNA-binding abilities were probed by absorption and fluorescence spectroscopy, and their DNA-cleavage potential was tested by electrophoresis.     

MicroRNAs and drug modulation in cancer: an intertwined new story

MicroRNAs (miRNAs) are endogenous small non-coding RNAs (ncRNAs) which play important regulatory roles in physiological processes such as cellular differentiation, proliferation, development, apoptosis and stem cell self-renewal. An increasing number of papers have clearly claimed their involvement in cancer, providing, in some cases, also the molecular mechanisms implicated. Several studies led to the conclusion that miRNAs can be effectively used as anticancer agents alone or in combination with existing anticancer drugs. In particular, miRNAs can be effectively used to overcome drug resistance, one of the main factors responsible for anticancer treatment insuccess. One of the main questions remains how to modulate the expression of miRNAs in cancer cells. Interestingly, a few studies have shown that the expression of miRNAs is affected by drugs (including some drugs currently used as anticancer agents), therefore providing the rationale for an intertwined scenario in which miRNAs can be modulated by drugs and, in turn, can affect drug sensitivity of cancer cells.     

Supramolecular platinum complexes for cancer therapy

The rise of supramolecular chemistry offers new tools to design therapeutics and delivery platforms for biomedical applications. This review aims to highlight the recent developments that harness host-guest interactions and self-assembly to design novel supramolecular Pt complexes as anticancer agents and drug delivery systems. These complexes range from small host-guest structures to large metallosupramolecules and nanoparticles. These supramolecular complexes integrate the biological properties of Pt compounds and novel supramolecular structures, which inspires new designs of anticancer approaches that overcome problems in conventional Pt drugs. Based on the differences in Pt cores and supramolecular structures, this review focuses on five different types of supramolecular Pt complexes, and they include host-guest complexes of the FDA-approved Pt(II) drugs, supramolecular complexes of nonclassical Pt(II) metallodrugs, supramolecular complexes of fatty acid-like Pt(IV) prodrugs, self-assembled nanotherapeutics of Pt(IV) prodrugs, and self-assembled Pt-based metallosupramolecules.