Gold compounds for catalysis and metal-mediated transformations in biological systems

One of the challenges of modern inorganic chemistry is translating the potential of metal catalysts to living systems to achieve controlled non-natural transformations. This field poses numerous issues associated with the metal compounds biocompatibility, stability, and reactivity in complex aqueous environment. Moreover, it should be noted that although referring to ‘metal catalysis’, turnover has not yet been fully demonstrated in most of the examples within living systems. Nevertheless, transition metal catalysts offer an opportunity of modulating bioprocesses through reactions that are complementary to enzymes. In this context, gold complexes, both coordination and organometallic, have emerged as promising tools for bio-orthogonal transformations, endowed with excellent reactivity and selectivity, compatibility within aqueous reaction medium, fast kinetics of ligand exchange reactions, and mild reaction conditions. Thus, a number of examples of gold-templated reactions in a biologically relevant context will be presented and discussed here in relation to their potential applications in biological and medicinal chemistry.     

Recent Updates in Curcumin Pyrazole and Isoxazole Derivatives: Synthesis and Biological Application

Curcumin is an admired, plant‐derived compound that has been extensively investigated for diverse range of biological activities, but the use of this polyphenol is limited due to its instability. Chemical modifications in curcumin are reported to seize this limitation; such efforts are intensively performed to discover molecules with similar but improved stability and better properties. Focal points of these reviews are synthesis of stable pyrazole and isoxazole analogs of curcumin and application in various biological systems. This review aims to emphasize the latest evidence of curcumin pyrazole analogs as a privileged scaffold in medicinal chemistry. Manifold features of curcumin pyrazole analogs will be summarized herein, including the synthesis of novel curcumin pyrazole analogs and the evaluation of their biological properties. This review is expected to be a complete, trustworthy and critical review of the curcumin pyrazole analogs template to the medicinal chemistry community.     

氨基酸Schiff碱金属配合物的研究进展

本文概述了近年来国内外在氨基酸Ｓｃｈｉｆ碱金属配合物领域的研究进展。简介了它们的合成方法和在金属离子分析、药物化学、生物模拟、氨基酸的合成及拆分上的应用。     

Medicinal attributes of 1,2,3-triazoles: Current developments

1,2,3-Triazoles are important five-membered heterocyclic scaffold due to their extensive biological activities. This framework can be readily obtained in good to excellent yields on the multigram scale through click chemistry via reaction of aryl/alkyl halides, alkynes and NaN₃ under ambient conditions. It has been an emerging area of interest for many researchers throughout the globe owing to its immense pharmacological scope. The present work aims to summarize the current approaches adopted for the synthesis of the 1,2,3-triazole and medicinal significance of these architectures as a lead structure for the discovery of drug molecules such as COX-1/COX-2 inhibitors (celecoxib, pyrazofurin), HIV protease inhibitors, CB1 cannabinoid receptor antagonist and much more which are in the pipeline of clinical trials. The emphasis has been given on the major advancements in the medicinal prospectus of this pharmacophore for the period during 2008–2016.     

Biological activities of polypyridyl-type ligands: implications for bioinorganic chemistry and light-activated metal complexes

Polypyridyl coordinating ligands are common in metal complexes used in medicinal inorganic chemistry. These ligands possess intrinsic cytotoxicity, but detailed data on this phenomenon are sparse, and cytotoxicity values vary widely and are often irreproducible. To provide new insights into the biological effects of bipyridyl-type ligands and structurally related metal-binding systems, reports of free ligand cytotoxicity were reviewed. The cytotoxicity of 25 derivatives of 2,2′-bipyridine and 1,10-phenanthroline demonstrates that there is no correlation between IC₅₀ values and ligand properties such as pKa, log D, polarizability volume, and electron density, as indicated by NMR shifts. As a result of these observations, as well as the various reported mechanisms of action of polypyridyl ligands, we offer the hypothesis that biological effects are governed by the availability of and affinity for specific metal ions within the experimental model.     

Metal binding and structure-activity relationship of the metalloantibiotic peptide bacitracin

Bacitracin is a widely used metallopeptide antibiotic produced by Bacillus subtilis and Bacillus licheniformis with a potent bactericidal activity directed primarily against Gram-positive organisms. This antibiotic requires a divalent metal ion such as Zn(2+) for its biological activity, and has been reported to bind several other transition metal ions, including Mn(2+), Co(2+), Ni(2+), and Cu(2+). Despite the widespread use of bacitracin since its discovery in the early 1940s, the structure-activity relationship of this drug has not been established and the coordination chemistry of its metal complexes was not fully determined until recently. This antibiotic has been suggested to influence cell functioning through more than one route. Since bacterial resistance against bacitracin is still rare despite several decades of widespread use, this antibiotic can serve as an ideal lead for the design of potent peptidyl antibiotics lacking bacterial resistance. In this review, the results of physical (including NMR, EPR, and EXAFS) and molecular biological studies regarding the synthesis and structure of bacitracin, the coordination chemistry of its metal derivatives, the mechanism of its antibiotic actions, its influence on membrane function, and its structure and function relationship are discussed.     

The potential of organometallic complexes in medicinal chemistry

Organometallic complexes have unique physico-chemical properties, which have been widely used in homogenous catalysis, for example, for the synthesis of lead compounds and drug candidates. Over the past two decades, a few scientists from all over the world have extended the use of the specific characteristics of these compounds (e.g. structural diversity, possibility of ligand exchange, redox and catalytic properties) for medicinal purposes. The results are stunning. A few organometallic compounds have already entered clinical trials and it can be anticipated that several more will follow in coming years. In this short review, we present the specific advantages that organometallic metal complexes have over purely organic and also coordination compounds. Furthermore, using specific examples, we illustrate how these particular properties can be put to good use in medicinal chemistry. The examples we present have an emphasis on, but are not restricted to, anti-cancer activity.     

New copper(II), nickel(II) and zinc(II) complexes with 1,2,4-triazolo[1,5-a]pyrimidines and the chelating ligand 1,3-propanediamine: An unexpected coordination behavior for the 7-amine-derivative

Five new metal complexes with the metal ions Cu(II), Ni(II) and Zn(II) and containing 1,2,4-triazolo[1,5-a]pyrimidine derivatives and 1,3-propanediamine (tn) are described. The structural morphology of these coordination compounds depends on the triazolopyrimidine derivative used, being mononuclear for 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp) and 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one (HmtpO), and 1D-polymeric for 7-amine-1,2,4-triazolo[1,5-a]pyrimidine (7atp). In the 7atp case, this ligand does not coordinate through N3 atom, as expected, but through N1, N4 and N71 in a bridging fashion. This unexpected coordination mode seems to be induced by the stability of the polynuclear metal complex in presence of tn ligand. All isolated metal complexes have been characterized by single-crystal X-ray diffraction, IR and UV-Vis spectroscopies, and EPR measurements. Moreover, luminescence measurements have been carried out for 7atp ligand and its polynuclear complex with Zn(II).     

Synthesis and characterization of mononuclear oxovanadium(IV) complexes and their enzyme inhibition studies with a carbohydrate metabolic enzyme phosphodiesterase I

The increasing interest in vanadium coordination chemistry is based on its well-established chemical and biological functions. A beta-diketonato complex of oxovanadium(IV) is known to be having numerous catalytic applications and also exhibits promising insulin mimetic properties. In continuation of our structure activity relationship studies of metal complexes, we report herein the synthesis and characterization of the vanadium complexes of beta-diketonato ligand system with systematic variations of electronic and steric factors. Two complexes, VO(tmh)(2) (tmh = 2,2,6,6,-tetramethyl-3,5-heptanedione), and VO(hd)(2) (hd = 3,5-heptanedione) were synthesized and characterized by using different spectroscopic techniques. Elemental and mass spectral analysis supports the presence of two beta-diketonato ligands per VO(2+) unit. UV-Vis spectra in different solvents indicate coordination of coordinating solvent molecules at sixth position resulting in red shift of the band I transition. NMR and IR spectra reveal binding of coordinating solvent molecule at vacant sixth position trans to oxo group without releasing beta-diketonato ligands. Enzyme inhibition studies of these and other related oxovanadium(IV) complexes with beta-diketonato ligand system are conducted with snake venom phosphodiesterase I (SPVDE). All of these complexes showed significant inhibitory potential and were found to be non-competitive inhibitors against this enzyme.     

Copper(II) cation and bathophenanthroline coordination enhance therapeutic effects of naringenin against lung tumor cells

BioMetals - The development of new anticancer compounds is one of the challenges of bioinorganic and medicinal chemistry. Naringenin and its metal complexes have been recognized as promising...     

Influence of ligand denticity on the properties of novel ⁹⁹mTc(I)-carbonyl complexes. Application to the development of radiopharmaceuticals for imaging hypoxic tissue

An important issue in the development of metal-based radiopharmaceuticals is the selection of the labelling strategy in order to couple the metal to the pharmacophore without losing the biological activity. With the aim to evaluate the correlation between ligand denticity and biological behaviour of the corresponding (99m)Tc complexes, we designed a tridentate and a bidentate 5-nitroimidazole derivatives suitable for (99m)Tc(I) tricarbonyl complexation and with potential use as radiopharmaceuticals towards hypoxic tissue diagnosis. Ligands were synthesized using metronidazol, a pharmaceutical containing the bioreductive pharmacophore as starting material. The chelating units were connected to the pharmacophore using the click reaction of Huisgen. Both (99m)Tc complexes were obtained in high yield and were hydrophilic and stable in labelling milieu. The complex obtained from the tridentate ligand exhibited high stability in human plasma, low protein binding and a favourable biodistribution characterized by low blood and liver uptake, fast elimination and negligible uptake in other organs or tissues. Selective uptake and retention in tumour together with favourable tumour/muscle ratio makes this (99m)Tc-complex a promising candidate for further evaluation as potential hypoxia imaging agent in tumours. The bidentate ligand, on the other hand, yielded a less stable (99m)Tc-complex that experimented hydrolysis in vitro and decomposition in human plasma and showed high protein binding, high blood and liver uptake and moderate excretion. Although selective uptake and retention in tumour was also observed physicochemical and biological behaviour are inadequate for in vivo use, demonstrating that denticity of the ligand is particularly important and that tridentate ligands are preferable in order to prepare (99m)Tc-tricarbonyl complexes for Nuclear Medicine imaging.     

2,3-diarylpyran-4-ones: a new series of selective cyclooxygenase-2 inhibitors

A new series of cyclooxygenase-2 (COX-2) inhibitors with gamma-pyrone as central scaffold unit has been synthesized and their biological activities were evaluated against cyclooxygenase inhibitory activity. The changes of physical properties of the molecules were performed according to the medicinal chemistry principles and moderate oral anti-inflammatory activity was obtained with this series of inhibitors.     

Recent synthesis of aminophosphonic acids as potential biological importance

Aminophosphonic acids are an important group of medicinal compounds, and their synthesis has been a focus of considerable attention in synthetic organic chemistry as well as medicinal chemistry. Although the phosphonic and carboxylic acid groups differ considerably with respect to shape, size, and acidity, α-aminophosphonic acids are considered to be structural analogues of the corresponding amino acids and the transition state mimics peptide hydrolysis. This review summarizes recent developments in the synthesis, characterization and biological activity of α-aminophosphonic acid and N-analogues. An account of both uses will be presented, emphasizing one of the potential future developments, and some implications in medicinal chemistry are also disclosed. In addition, a brief account on the characterization of N-(phosphonomethyl) glycine derivatives will be presented.     

Synthesis,spectroscopic, and structural characterization of the first aqueous cobalt(II)-citrate complex: toward a potentially bioavailable form of cobalt in biologically relevant fluids

Citric acid represents a class of carboxylic acids present in biological fluids and playing key roles in biochemical processes in bacteria and humans. Its ability to promote diverse coordination chemistries in aqueous media, in the presence of metal ions known to act as trace elements in human metabolism, earmarks its involvement in a number of physiological functions. Cobalt is known to be a central element of metabolically important biomolecules, such as B12, and therefore its biospeciation in biological fluids constitutes a theme worthy of chemical and biological perusal. In an effort to unravel the aqueous chemistry of cobalt in the presence of a physiologically relevant ligand, citrate, the first aqueous, soluble, mononuclear complex has been synthesized and isolated from reaction mixtures containing Co(II) and citrate in a 1:2 molar ratio at pH approximately 8. The crystalline compound (NH4)4[Co(C6H5O7)2] (1) has been characterized spectroscopically (UV/vis, EPR) and crystallographically. Its X-ray structure consists of a distorted octahedral anion with two citrate ligands fulfilling the coordination requirements of the Co(II) ion. The magnetic susceptibility measurements of 1 in the range from 6 to 295 K are consistent with a high-spin complex containing Co(II) with a ground state S=3/2. Corroborating this result is the EPR spectrum of 1, which shows a signal consistent with the presence of a Co(II) system. The spectroscopic and structural properties of the complex signify its potential biological relevance and participation in speciation patterns arising under conditions consistent with those employed for its synthesis and isolation.     

The role of redox-active metals in the mechanism of action of bleomycin.

Belomycin is a glycopeptide antibiotic routinely used to treat human cancer. It is commonly thought to exert its biological effects as a metallodrug, which oxidatively damages DNA. This review systematically examines the properties of bleomycin which contribute to its reaction with DNA in vitro and may be important in the breakage of DNA in cells. Because strand cleavage results from the reductive activation of dioxygen by metallobleomycins, the mechanism of this process is given primary attention. Current understanding of the structures of the coordination sites of various metallobleomycins, their thermodynamic stabilities, their propensity to form adduct species, and their properties in ligand substitution reactions provide a foundation for consideration of the chemistry of dioxygen activation as well as a basis for thinking about the metal-speciation of bleomycin in biological systems. Oxidation-reduction pathways of iron-bleomycin, copper-bleomycin, and other metal-bleomycin species with O2 are then examined, including information on photochemical activation. With this background, structural and thermodynamic features of the binding interactions of DNA with bleomycin, its metal complexes, and adducts of metallobleomycins are reviewed. Then, the DNA cleavage reaction involving iron-bleomycin is scrutinized on the basis of the preceding discussion. Particular emphasis is placed on the constraints which the presence of DNA places on the mechanism of dioxygen activation. Similarly, the reactions of other metalloforms of bleomycin with DNA are reviewed. The last topic is an analysis of current understanding of the relationship of bleomycin-induced cellular DNA damage to the model developed above, which has evolved on the basis of chemical experimentation. Consideration is given to the question of the importance of DNA strand breakage caused by bleomycin for the mechanism of cytotoxic activity of the drug.     

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.     

Trace metal complexation by the triscatecholate siderophore protochelin: structure and stability

Although siderophores are generally viewed as biological iron uptake agents, recent evidence has shown that they may play significant roles in the biogeochemical cycling and biological uptake of other metals. One such siderophore that is produced by A. vinelandii is the triscatecholate protochelin. In this study, we probe the solution chemistry of protochelin and its complexes with environmentally relevant trace metals to better understand its effect on metal uptake and cycling. Protochelin exhibits low solubility below pH 7.5 and degrades gradually in solution. Electrochemical measurements of protochelin and metal–protochelin complexes reveal a ligand half-wave potential of 200 mV. The Fe(III)Proto³⁻ complex exhibits a salicylate shift in coordination mode at circumneutral to acidic pH. Coordination of Mn(II) by protochelin above pH 8.0 promotes gradual air oxidation of the metal center to Mn(III), which accelerates at higher pH values. The Mn(III)Proto³⁻ complex was found to have a stability constant of log β₁₁₀ = 41.6. Structural parameters derived from spectroscopic measurements and quantum mechanical calculations provide insights into the stability of the Fe(III)Proto³⁻, Fe(III)H₃Proto, and Mn(III)Proto³⁻ complexes. Complexation of Co(II) by protochelin results in redox cycling of Co, accompanied by accelerated degradation of the ligand at all solution pH values. These results are discussed in terms of the role of catecholate siderophores in environmental trace metal cycling and intracellular metal release.     

Modification of radiation response by metal complexes: a review with emphasis of nonplatinum studies

There is a need to develop compounds which alter the effects of radiation, particularly in the hypoxic radioresistant cell, following the limited success to date of the electron-affinic nitroimidazoles. The chemistry of transition metals is briefly outlined to point out certain aspects which might be exploited in the design of radiosensitizers. The best known clinical example of a metal complex which enhances the effect of radiation in hypoxic cells is the successful antineoplastic cisplatin. Past studies on enhancement of radiation damage by complexes of metals other than platinum, mainly in bacterial spores and bacterial and mammalian cells, have been summarized according to the metal used. The many mechanisms by which metal complexes could interact with radiation are outlined, and examples are given where possible. This survey emphasizes the need for a systematic study of the effect of metal/ligand variation on radiosensitization with regard to mechanisms of action to assess the potential of these compounds as radiosensitizers. Metal complexes offer many advantages, both for the study of mechanisms by which radiation kills cells and for drug development.     

A benzoboroxole‐based affinity ligand for glycoprotein purification at physiological pH

Developing ligands capable of carbohydrate recognition has become increasingly important as the essential roles of glycoproteins and glycolipids in a diverse array of cellular signaling, pathophysiology, and immune response mechanisms are elucidated. Effective ligands for the glycan portion of glycoproteins and glycolipids are needed for pre‐enrichment proteomics strategies, as well as for the purification of individual glycoproteins from complex biological milieu encountered both in biochemistry research and bio‐pharmaceutical development. In this work, we developed a carbohydrate specific affinity ligand for glycoprotein purification using a one‐pot, multi‐component synthesis reaction (Ugi synthesis) and an amine‐functionalized benzoboroxole moiety immobilized on agarose beads. Benzoboroxoles are unique boronic acid derivatives that have recently been found to bind specifically to the cis‐diol groups of carbohydrates at physiological pH, with superior affinity to any other Wulff‐type boronic acid. The solid‐phase affinity ligand developed herein specifically binds the carbohydrate moiety of the glycoprotein glucose oxidase, as well as a fluorescein isothiocyanate‐dextran, as shown through deglycosylation binding studies. Additionally, the ligand is able to purify glucose oxidase from crude Escherichia coli lysate, at physiological pH, equitably to commercially available boronic acid‐functionalized agarose beads that required alkaline pH conditions. Thus, this affinity ligand is a marked improvement on current, commercially available boronic acid‐based glycoprotein enrichment matrices and has the potential to exhibit high individual glycoprotein specificity because of the additional functional groups available for variation on the Ugi scaffold. Copyright © 2015 John Wiley & Sons, Ltd.