金属配合物抗癌活性的研究进展

自从发现顺铂具有抗癌活性以来,金属配合物作为新一类抗癌药物引起了人们的广泛关注。综述了近年来铂类配合物、钌类配合物和席夫碱配合物在抗癌药物中的研究进展,重点阐述了铂类配合物抗癌活性的研究现状及作用原理,并对金属配合物抗癌活性的研究进展进行总结,为金属配合物抗癌药物研究提供参考和依据。     

Pharmapolymers in the 21st century: Synthetic polymers in drug delivery applications

The administration of drugs, as a main challenge of pharmaceutical and medicinal applications, has certainly benefited from the application of synthetic polymers. However, despite an enormous effort to develop new materials for drug delivery applications, only few of them have entered the market due to the hurdles of regulation, production, cost efficiency and both industrial’s and patients’ acceptance. In this review, we summarize all these classes of synthetic polymers, which are on the market as well as the latest developments in clinical trials, and describe their application in polymer-drug conjugates, as excipients, in nano-/microscopic and macroscopic drug carriers, as polymeric coatings, or as polymeric drugs. Our intention is to create a link between the underlying chemical structures, the properties of the polymers, and their area of application, where they are often just known by their trade names or abbreviations. In addition selected types of synthetic polymers are highlighted that feature interesting properties and have the potential to make it to the market in future.     

G-quadruplexes: targets in anticancer drug design

G-quadruplexes are special secondary structures adopted in some guanine-rich DNA sequences. As guanine-rich sequences are present in important regions of the eukaryotic genome, such as telomeres and the regulatory regions of many genes, such structures may play important roles in the regulation of biological events in the body. G-quadruplexes have become valid targets for new anticancer drugs in the past few decades. Many leading compounds that target these structures have been reported, and a few of them have entered preclinical or clinical trials. Nonetheless, the selectivity of this kind of antitumor compound has yet to be improved in order to suppress the side effects caused by nonselective binding. As drug design targets, the topology and structural characteristics of quadruplexes, their possible biological roles, and the modes and sites of small-ligand binding to these structures should be understood clearly. Herein we provide a summary of published research that has set out to address the above problem to provide useful information on the design of small ligands that target G-quadruplexes. This review also covers research methodologies that have been developed to study the binding of ligands to G-quadruplexes.     

Designing Irreversible Inhibitors—Worth the Effort?

Despite the unquestionable success of numerous irreversible drugs that are currently in clinical use, such as acetylsalicylic acid (Aspirin) and penicillin, the number of such approved drugs is much lower than that of noncovalent drugs. Over the years, the potential off‐target effects of these types of compounds have been the primary concern that has hampered their development. However, their remarkable advantages over noncovalent drugs and a better analysis of the risks have decreased the widespread skepticism surrounding them. The design of irreversible inhibitors is a challenge, particularly considering that in some cases their efficacy is due to complex and unexpected mechanisms of action. In this review the main advantages of irreversible inhibition are summarized, and the complexity of certain covalent modification mechanisms is highlighted with selected examples.     

Metal Complexes of New Bioactive Pyrazolone Phenylhydrazones; Crystal Structure of 4-Acetyl-3-methyl-1-phenyl-2-pyrazoline-5-one phenylhydrazone Ampp-Ph

The condensation reaction of phenylhydrazine and dinitrophenylhydrazine with 4-acetyl and 4-benzoyl pyrazolone precipitated air-stable acetyldinitrophenylhydrazone Ampp-Dh, benzoylphenylhydrazone Bmpp-Ph and benzoyldinitrophenylhydrazone Bmpp-Dh in their keto imine form; a study inspired by the burning interest for the development of new bioactive materials with novel properties that may become alternative therapeutic agents. Elemental analysis, FTIR, ¹H, and ¹³C NMR, and mass spectroscopy have been used to justify their proposed chemical structures, which were in agreement with the single crystal structure of Bmpp-Dh earlier reported according to X-ray crystallography. The single crystal structure of 4-acetyl-3-methyl-1-phenyl--pyrazoline-5-one phenylhydrazone Ampp-Ph, which crystallizes in a triclinic crystal system with a P-1 (No. 2) space group is presented. Octahedral Mn(II), Ni(II), Co(II), and Cu(II) complexes of these respective ligands with two molecules each of the bidentate Schiff base, coordinating to the metal ion through the azomethine nitrogen C=N and the keto oxygen C=O, which were afforded by the reaction of aqueous solutions of the corresponding metal salts with the ligands are also reported. Their identity and proposed structures were according to elemental analysis, FTIR spectroscopy, UV-VIS spectrophotometry (electronic spectra) and Bohr magnetic moments, as well as thermogravimetric analysis (TGA) results. A look at the antibacterial and antioxidant activities of synthesized compounds using the methods of the disc diffusion against some selected bacterial isolates and 1,1-diphenyl-2-picryl-hydrazil (DPPH) respectively, showed biological activities in relation to employed standard medicinal drugs.     

Computational Analysis of the Crystal and Cryo-EM Structures of P-Loop Channels with Drugs

The superfamily of P-loop channels includes various potassium channels, voltage-gated sodium and calcium channels, transient receptor potential channels, and ionotropic glutamate receptors. Despite huge structural and functional diversity of the channels, their pore-forming domain has a conserved folding. In the past two decades, scores of atomic-scale structures of P-loop channels with medically important drugs in the inner pore have been published. High structural diversity of these complexes complicates the comparative analysis of these structures. Here we 3D-aligned structures of drug-bound P-loop channels, compared their geometric characteristics, and analyzed the energetics of ligand-channel interactions. In the superimposed structures drugs occupy most of the sterically available space in the inner pore and subunit/repeat interfaces. Cationic groups of some drugs occupy vacant binding sites of permeant ions in the inner pore and selectivity-filter region. Various electroneutral drugs, lipids, and detergent molecules are seen in the interfaces between subunits/repeats. In many structures the drugs strongly interact with lipid and detergent molecules, but physiological relevance of such interactions is unclear. Some eukaryotic sodium and calcium channels have state-dependent or drug-induced π-bulges in the inner helices, which would be difficult to predict. The drug-induced π-bulges may represent a novel mechanism of gating modulation.     

Thiourea and Guanidine Compounds and Their Iridium Complexes in Drug-Resistant Cancer Cell Lines: Structure-Activity Relationships and Direct Luminescent Imaging

Thiourea and guanidine units are found in nature, medicine, and materials. Their continued exploration in applications as diverse as cancer therapy, sensors, and electronics means that their toxicity is an important consideration. Iridium complexes present new opportunities for drug development and imaging in terms of structure and photoactivity. We have systematically synthesised a set of thiourea and guanidine compounds and iridium complexes thereof, and elucidated structure–activity relationships for cellular toxicity in three ovarian cancer cell lines and their cisplatin-resistant sub-lines. We have been able to use the intrinsic luminescence of iridium complexes to visualise the effect of both structure alteration and cellular resistance mechanisms. These findings provide starting points for the development of new drugs and consideration of safety issues for novel thiourea-, guanidine-, and iridium-based materials.     

meso-四(间烷氧基苯基)卟啉合银配合物的合成与表征

合成了未见文献报道的meso-四(间烷氧基苯基)卟啉合银配合物6个,研究了其合成、分离、纯化方法。用红外光谱、紫外-可见光谱、核磁共振氢谱、质谱和元素分析等分析测试方法对配合物的结构进行了表征,确证了该系列配合物的结构。     

Ir(III) and Ru(II) Complexes in Photoredox Catalysis and Photodynamic Therapy: A New Paradigm towards Anticancer Applications

Individually, photoredox catalysis (PC) and photodynamic therapy (PDT) are well-established concepts that have experienced a remarkable resurgence in recent years, leading to significant progress in organic synthesis for PC and clinical approval of anticancer drugs for PDT. But, very recently, new photoredox catalyst systems based on Ir(III) and Ru(II) complexes have garnered significant interest because they can simultaneously be used as PDT agents apart from their demonstrated PC activity. This highlight discusses the unique PC behavior of emerging Ir(III)- and Ru(II)-based systems while also examining their potential PDT activity in cancer treatment.     

Interaction of DNA with Simple and Mixed Ligand Copper(II) Complexes of 1,10-Phenanthrolines as Studied by DNA-Fiber EPR Spectroscopy

The interaction of simple and ternary Cu(II) complexes of 1,10-phenanthrolines with DNA has been studied extensively because of their various interesting and important functions such as DNA cleavage activity, cytotoxicity towards cancer cells, and DNA based asymmetric catalysis. Such functions are closely related to the DNA binding modes of the complexes such as intercalation, groove binding, and electrostatic surface binding. A variety of spectroscopic methods have been used to study the DNA binding mode of the Cu(II) complexes. Of all these methods, DNA-fiber electron paramagnetic resonance (EPR) spectroscopy affords unique information on the DNA binding structures of the complexes. In this review we summarize the results of our DNA-fiber EPR studies on the DNA binding structure of the complexes and discuss them together with the data accumulated by using other measurements.     

Interpolyelectrolyte complexes of diblock copolymers via interaction of complementary polyelectrolyte-surfactant complexes in chloroform

We have studied the interpolyelectrolyte complexation in chloroform between polystyrene-block-poly(cetyltrimethylammonium acrylate), (PA⁻ CTA⁺), and poly(2-(methacryloyloxy)ethyldimethylethyl-ammonium dodecyl sulfate) (quaternized poly(2-(dimethylamino)ethyl methacrylate) complexed with sodium dodecyl sulfate), (PDMAEMAQ⁺ DS⁻). Turbidimetry, dynamic/static light scattering, and transmission electron microscopy show the formation of large aggregated interpolyelectrolyte complex species, which are colloidally stable in chloroform or even chloroform-soluble if the certain conditions are met. We suggest such co-assemblies to be micellar species with a core assembled from electrostatically coupled fragments of the polymeric components. The corona is built up either from a mixture of polystyrene blocks and excessive fragments of (PDMAEMAQ⁺ DS⁻) chains or from a mixture of polystyrene blocks and excessive fragments of (PA⁻ CTA⁺) blocks, depending on which polymeric component was taken in excess for the interpolyelectrolyte complexation. However, their real structures may deviate from such idealized consideration because of the non-equilibrium character of interpolyelectrolyte complexation in organic media of low polarity.     

金属有机配位聚合物荧光及小分子识别

金属有机配位聚合物不仅结构多样,而且在光学、电学、磁学、气体储存和分离等领域有着巨大的应用前景。众所周知,配位聚合物的性能与结构有着紧密的联系。当前晶体工程学的重要任务是选择合适的有机配体和金属离子,根据晶体工程原理和自组装规律,通过调控影响反应过程的各种因素,从而获得结构新颖、性能独特金属有机配位聚合物。利用金属有机配位聚合物的荧光性质在小分子识别方面已进行了广泛的研究。本文综述了金属有机配位聚合物的荧光产生原理及小分子识别方面的应用。     

金属络合物不对称催化硫醚氧化研究现状

手性亚砜是重要的手性中间体和辅剂、手性配体和催化剂、手性药物。手性金属络合物催化硫醚的不对称氧化是合成手性亚砜最有效的方法。文章简要的介绍了钛,钒,铌,铁四种金属的络合物不对称催化硫醚氧化的一些最新的研究现状。     

Glycoconjugated Metal Complexes as Cancer Diagnostic and Therapeutic Agents

The possibility of selectively delivering metal complexes to a defined cohort of cells on the basis of their metabolic features is a highly challenging goal, which may be extremely useful for a series of purposes, including diagnosis and therapy of pathological states, such as cancer. Tumor cells display augmented requests for carbohydrates and, in particular, for glucose in order to sustain their high proliferation rate, which causes an increased glycolytic process (Warburg effect). Since several metal complexes display diagnostic and/or therapeutic properties, their conjugation to carbohydrate portions often induce their preferential accumulation in cancer cells, similarly to what is observed with fluorodeoxyglucose (FDG). In this review we have considered the latest developments of glycoconjugates containing metal complexes in their structures. These compounds are classified as diagnostic or therapeutic agents and are further systematically discussed on the basis of the metal atom they contain. Several diagnostic techniques are possible with these probes, since, depending on the metal species included in their structures, they may be employed in nuclear medicine (PET, SPECT), magnetic resonance imaging, luminescence and phosphorescence. At the same time, the lack of selective cytotoxicity displayed by several metal-based chemotherapeutic agents, may also be solved by the conjugation of these agents to carbohydrate portions. Overall, data so far available reveal the great potential of this chemical class in the early detection and in the cure of severe neoplastic diseases, which still needs to be fully explored in the clinic.     

Antiviral Effects of Animal Toxins: Is There a Way to Drugs?

Viruses infect all types of organisms, causing viral diseases, which are very common in humans. Since viruses use the metabolic pathways of their host cells to replicate, they are difficult to eradicate without affecting the cells. The most effective measures against viral infections are vaccinations and antiviral drugs, which selectively inhibit the viral replication cycle. Both methods have disadvantages, which requires the development of new approaches to the treatment of viral diseases. In the study of animal venoms, it was found that, in addition to toxicity, venoms exhibit other types of biological activity, including an antiviral one, the first mention of which dates back to middle of the last century, but detailed studies of their antiviral activity have been conducted over the past 15 years. The COVID-19 pandemic has reinforced these studies and several compounds with antiviral activity have been identified in venoms. Some of them are very active and can be considered as the basis for antiviral drugs. This review discusses recent antiviral studies, the found compounds with high antiviral activity, and the possible mechanisms of their action. The prospects for using the animal venom components to create antiviral drugs, and the expected problems and possible solutions are also considered.     

Applications of Isothermal Titration Calorimetry in Biophysical Studies of G-quadruplexes

G-quadruplexes are higher-order nucleic acids structures formed by G-rich sequences that are stabilized by tetrads of hydrogen-bonded guanine bases. Recently, there has been growing interest in the study of G-quadruplexes because of their possible involvement in many biological processes. Isothermal titration calorimetry (ITC) has been proven to be a useful tool to study the energetic aspects of G-quadruplex interactions. Particularly, ITC has been applied many times to determine the thermodynamic properties of drug-quadruplex interactions to screening among various drugs and to address drug design. In the present review, we will focus on the ITC studies of G-quadruplex structures and their interaction with proteins and drugs and the most significant results will be discussed.     

Polypyridyl CoII-Curcumin Complexes as Photoactivated Anticancer and Antibacterial Agents

Four new Co^II complexes, [Co(bpy)₂(acac)]Cl ( 1 ), [Co(phen)₂(acac)]Cl ( 2 ), [Co(bpy)₂(cur)]Cl ( 3 ), [Co(phen)₂(cur)]Cl ( 4 ), where bpy=2,2’-bipyridine ( 1 and 3 ), phen=1,10-phenanthroline ( 2 and 4 ), acac = acetylacetonate ( 1 and 2 ), cur=curcumin monoanion ( 3 and 4 ) have been designed, synthesized and fully characterized. The X-ray crystal structures of 1 and 2 indicated that the CoN₄O₂ core has a distorted octahedral geometry. The photoactivity of these complexes was tuned by varying the π conjugation in the ligands. Curcumin complexes 3 and 4 had an intense absorption band near 435 nm, which made them useful as visible-light photodynamic therapy agents; they also showed fluorescence with λ_em≈565 nm. This fluorescence was useful for studying their intracellular uptake and localization in MCF-7 breast cancer cells. The acetylacetonate complexes ( 1 and 2 ) were used as control complexes to understand the role of curcumin. The white-light-triggered anticancer profiles of the cytosol targeting complexes 3 and 4 were investigated in detail. These non-dark toxic complexes displayed significant apoptotic photo-cytotoxicity (under visible light) against MCF-7 cells through ROS generation. The control complexes 1 and 2 did not induce significant cell death in the light or dark. Interestingly, 1-4 produced a remarkable antibacterial response upon light exposure. Overall, the reported results here can increase the boundary of the Co^II-based anticancer and antibacterial drug development.     

A simple approach for protein structure discrimination based on the network pattern of conserved hydrophobic residues

Evolutionarily conserved hydrophobic residues at the core of protein structures are generally assumed to play a structural role in protein folding and stability. Recent studies have implicated that their importance to protein structures is uneven, with a few of them being crucial and the rest of them being secondary. In this work, we explored the possibility of employing this feature of native structures for discriminating non-native structures from native ones. First, we developed a network tool to quantitatively measure the structural contributions of individual amino acid residues. We systematically applied this method to diverse fold-type sets of native proteins. It was confirmed that this method could grasp the essential structural features of native proteins. Next, we applied it to a number of decoy sets of proteins. The results indicate that such an approach indeed identified non-native structures in most test cases. This finding should be of help for the investigation of the fundamental problem of protein structure prediction.     

Maleic anhydride copolymers with ability to bind metal ions. 1. polydentate amine derivatives for cr (III) ions' removal

New polymeric chelate structures derived from maleic anhydride–dicyclopentadiene copolymer (MA–DCPD) were synthesized by chemical modifications with triethylenetetramine (TETA), from Riedel De Haën AG Seelze, Hannover. Germany. Both amide and imide forms of these new polymers have been tested in the retention process of Cr (III) ions. Experimental results referring mainly to the retention capacity and retention efficiency, for different values of the working parameters: contact procedure, batch time, concentration of chelators, and pH, are presented. The polymer structures and their metal complexes were characterized by IR spectroscopy. IR spectra proved that the metal was coordinated by nitrogen from TETA. The thermal properties of modified polymers and polychelates were also examined. Based on these experimental results and literature data, we discuss a possible binding mechanism and suggest the polychelate structures. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011