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.     

Dynamic accumulation and redistribution of methylmercury in the lens of developing zebrafish embryos and larvae

Neurotoxic methylmercury compounds are widespread in the environment and human exposure worries many communities worldwide. Despite numerous studies addressing methylmercury toxicity, the detailed mechanisms underlying its transport and accumulation, especially during early developmental stages, remain unclear. Zebrafish larvae are increasingly used as a model system for studies of vertebrate development and toxicology. Previously, we have identified the lens epithelium as the primary site for cellular mercury accumulation in developing zebrafish larvae (Korbas et al. in Proc Natl Acad Sci USA 105:12108–12112, 2008). Here we present a study on the dynamics of methylmercury accumulation and redistribution in the lens following embryonic and larval exposure to methylmercury l-cysteineate using synchrotron X-ray fluorescence imaging. We observed highly specific accumulation of mercury in the lens that continues well after removal of fish from treatment solutions, thus significantly increasing the post-exposure loading of mercury in the lens. The results indicate that mercury is redistributed from the original target tissue to the eye lens, identifying the developing lens as a major sink for methylmercury in early embryonic and larval stages.     

New insights into the metabolism of organomercury compounds: mercury-containing cysteine S-conjugates are substrates of human glutamine transaminase K and potent inactivators of cystathionine γ-lyase

Anthropogenic practices and recycling in the environment through natural processes result in release of potentially harmful levels of mercury into the biosphere. Mercury, especially organic forms, accumulates in the food chain. Mercury reacts readily with sulfur-containing compounds and often exists as a thiol S-conjugate, such as the l-cysteine (Cys)-S-conjugate of methylmercury (CH(3)Hg-S-Cys) or inorganic mercury (Cys-S-Hg-S-Cys). These S-conjugates are structurally similar to l-methionine and l-cystine/l-cystathionine, respectively. Bovine and rat glutamine transaminase K (GTK) catalyze transamination of sulfur-containing amino acids. Recombinant human GTK (rhGTK) has a relatively open catalytic active site, and we report here that this enzyme, like the rat and bovine enzymes, can also utilize sulfur-containing l-amino acids, including l-methionine, l-cystine, and l-cystathionine as substrates. The current study extends this list to include mercuric S-conjugates, and shows that CH(3)Hg-S-Cys and Cys-S-Hg-S-Cys are substrates and reversible inhibitors of rhGTK. The homocysteine S-conjugates, Hcy-S-Hg-S-Hcy and CH(3)Hg-S-Hcy, are also inhibitors. Finally, we show that HgCl(2), CH(3)Hg-S-Cys and Cys-S-Hg-S-Cys are potent irreversible inhibitors of rat cystathionine γ-lyase. The present study broadens our knowledge of the biochemistry of mercury compounds by showing that Cys S-conjugates of mercury interact with enzymes that catalyze transformations of biologically important sulfur-containing amino acids.     

Heterochromatic Effects on the Behavior of Reversed Acrocentric Compound-X Chromosomes in DROSOPHILA MELANOGASTER

Previous studies of reversed acrocentric compound-X chromosomes suggested peculiar influences of heterochromatin on both the synthesis and meiotic behavior of such compunds. It seemed, with respect to synthesis, that the long arm of the Y chromosome on an X.Y(L) chromosome was necessary in order for the heterochromatic exchange giving rise to reversed acrocentrics to occur, even though Y(L) itself did not participate in the compound-generating event. With respect to behavior, the resulting compounds appeared, presumably as a consequence of their singular generation, to contain an interstitial heterochromatic region that caused the distribution of exchanges between the elements of the compound to be abnormal (many zero and two-exchange tetrads with few, if any, single-exchange tetrads). Removing the intersititial heterochromatin (or, curiously, appending Y(L) as a second arm of the compound) eliminated the recombinational anomalies and resulted in typical tetrad distributions.--We provide evidence that these peculiarities, while presumably real, were likely the consequence of a special X.Y(L) chromosome that was used to synthesize the reversed acrocentrics examined in the early studies and are not general properties of either reversed acrocentric compounds or of interstitial heterochromatin. However, we show that specific heterochromatic regions do, in fact, profoundly influence the behavior of (apparently all) reversed acrocentric compound-X chromosomes. In particular, we demonstrate that specific portions of the Y chromosome and of the basal X-chromosome heterochromatin, when present as homologs for reversed acrocentric compounds, markedly and coordinately increase both the frequency of exchange between the elements of the compound and the fertility (egg production) of compound-bearing females. It is, we suppose, some aspect of this heterochromatic effect, produced by the special X.Y(L) chromosome, that caused the earlier-analyzed compounds to exhibit the observed anomalies.     

Medicinal applications of heavy-metal compounds

A brief summary of the key role for certain heavy-metal compounds in medicine is discussed, with a special focus on very recent findings in the following four topics: platinum anti-tumor compounds (novel mononuclear compounds, dinuclear compounds and trinuclear compounds with promising activity); ruthenium anti-tumor compounds (the first clinical trial for a Ru compound has begun); gadolinium NMR-imaging compounds (association with biomacromolecules is now possible); technetium compounds (the use of organometallic precursors opens a plethora of new species and enables the labeling of, for example, neurotransmitter molecules).     

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.     

Whi2 enhances methylmercury toxicity in yeast via inhibition of Akr1 palmitoyltransferase activity

BackgroundWe have previously reported that Whi2 enhances the toxicity of methylmercury in yeast. In the present study we examined the proteins known to interact with Whi2 to find those that influence the toxicity of methylmercury.MethodsGene disruption and site-directed mutagenesis were employed to examine the relationship of mercury toxicity and palmitoylation. Protein palmitoylation was examined using the acyl-biotinyl exchange method. Protein–protein interactions were detected by immunoprecipitation and immunoblotting.ResultsWe found that deletion of Akr1, a palmitoyltransferase, rendered yeast cells highly sensitive to methylmercury, and Akr1 is necessary for the methylmercury resistance of Whi2-deleted yeast. Palmitoyltransferase activity of Akr1 has an important role in the alleviation of methylmercury toxicity. Whi2 deletion or methylmercury treatment enhanced the palmitoyltransferase activity of Akr1, and methylmercury treatment reduced the binding between Akr1 and Whi2.ConclusionsWhi2 bonds to Akr1 (a protein that is able to alleviate methylmercury toxicity) and thus inhibits Akr1's palmitoyltransferase activity, which leads to enhanced methylmercury toxicity. In contrast, methylmercury might break the bond between Whi2 and Akr1, which enhances the palmitoyltransferase activity of Akr1 to alleviate methylmercury toxicity.General significanceThis study's findings propose that the Whi2/Akr1 system can be regarded as a defense mechanism that detects methylmercury incorporation of yeast cells and alleviates its toxicity.     

Bioremediation of Organometallic Compounds by Bacterial Degradation

The use of organometallic compounds in the environment is constantly increasing with increased technology and progress in scientific research. But since these compounds are fairly stable, as metallic bonds are stable, they are difficult to degrade or decompose naturally. The aim of this work was to isolate and characterize heterotrophic bacteria that can degrade organometallic compounds (in this case ‘ferrocene’ and its derivatives). A Gram-negative coccobacillus was isolated from a rusting iron pipe draining into a freshwater lake, which could utilize ferrocene as a sole source of carbon. Phylogenetic analysis based on 16S rDNA sequence suggested that the isolated organism resembled an environmental isolate of Bordetella. Ferrocene degradation was confirmed by plotting the growth curve of the bacterium in a medium with ferrocene as the sole source of carbon. Further confirmation of degradation of ferrocene and its derivatives was done using Gas Chromatography Mass Spectroscopy. Since the bacterium degraded organometallic compounds and released the metal in liquid medium, it could be suggested that this organism can also be used for extracting metal ions from organo-metal containing wastes.     

Interrelationships of selenium with other trace elements.

Biological interactions between selenium and a number of other elements occur that render selenium much less toxic than when it is present alone. These elements are arsenic, mercury, cadmium, and copper. Furthermore, the presence of selenium reduces the toxicity of mercury and cadmium. These are general biological interactions and have been found to occur in a number of animal species under a variety of conditions. It has been shown that the reaction products of selenium with mercury and cadmium are less toxic than an equal amount of selenium fed alone to chicks. The presence of arsenic shifts the excretion of selenium to the bile. There is no conclusive evidence that the presence of other elements reduces the absorption or retention of selenium. It is possible that some of the interactions are caused by the formation of a compound by selenium and other elements which has less affinity for active groups on biologically active compounds.--Hill, C.H. Interrelationships of selenium with other trace elements.     

BEAM: a beam search algorithm for the identification of cis-regulatory elements in groups of genes.

The identification of potential protein binding sites (cis-regulatory elements) in the upstream regions of genes is key to understanding the mechanisms that regulate gene expression. To this end, we present a simple, efficient algorithm, BEAM (beam-search enumerative algorithm for motif finding), aimed at the discovery of cis-regulatory elements in the DNA sequences upstream of a related group of genes. This algorithm dramatically limits the search space of expanded sequences, converting the problem from one that is exponential in the length of motifs sought to one that is linear. Unlike sampling algorithms, our algorithm converges and is capable of finding statistically overrepresented motifs with a low failure rate. Further, our algorithm is not dependent on the objective function or the organism used. Limiting the space of candidate motifs enables the algorithm to focus only on those motifs that are most likely to be biologically relevant and enables the algorithm to use direct evaluations of background frequencies instead of resorting to probabilistic estimates. In addition, limiting the space of candidate motifs makes it possible to use computationally expensive objective functions that are able to correctly identify biologically relevant motifs.     

cneViewer: a database of conserved non-coding elements for studies of tissue-specific gene regulation

There are thousands of strongly conserved non-coding elements (CNEs) in vertebrate genomes, and their functions remain largely unknown. However, without biologically relevant criteria for prioritizing them, selecting a particular CNE sequences to study can be haphazard. To address this problem, we present cneViewer-a database and webtool that systematizes information on conserved non-coding DNA elements in zebrafish. A key feature here is the ability to search for CNEs that may be relevant to tissue-specific gene regulation, based on known developmental expression patterns of nearby genes. cneViewer provides this and other organizing features that significantly facilitate experimental design and CNE analysis.     

Compressibility of protein transitions

We review the results of compressibility studies on proteins and low molecular weight compounds that model the hydration properties of these biopolymers. In particular, we present an analysis of compressibility changes accompanying conformational transitions of globular proteins. This analysis, in conjunction with experimental compressibility data on protein transitions, were used to define the changes in the hydration properties and intrinsic packing associated with native-to-molten globule, native-to-partially unfolded, and native-to-fully unfolded transitions of globular proteins. In addition, we discuss the molecular origins of predominantly positive changes in compressibility observed for pressure-induced denaturation transitions of globular proteins. Throughout this review, we emphasize the importance of compressibility data for characterizing protein transitions, while also describing how such data can be interpreted to gain insight into role that hydration and intrinsic packing play in modulating the stability of and recognition between proteins and other biologically important compounds.     

Effects of mercury compounds on the spontaneous and potassium-evoked release of [3H]dopamine from mouse striatal slices

The effects of mercury compounds on the spontaneous and potassium-evoked release of [3H]dopamine from mouse striatal slices have been examined. All mercury compounds examined produced concentration-dependent increases in the spontaneous release of [3H]dopamine, with an order of potency of methylmercury greater than mercuric (Hg2+) mercury greater than p-choloromercuribenzene sulfonic acid. Methylmercury had no effect on the 25 mM potassium evoked release of [3H]dopamine in the presence of 1.3 mM calcium. However, in calcium-free conditions, methylmercury significantly increased the potassium-evoked release of [3H]dopamine. Mercuric mercury significantly reduced the 25 mM potassium evoked release of [3H]dopamine in the presence of 1.3 mM calcium, and this response was not reversible with brief washing of the tissue. In calcium-free conditions, mercuric mercury significantly elevated the evoked release of [3H]dopamine, similar to the result obtained with methylmercury. It is suggested that mercury compounds alter dopaminergic synaptic function, possibly by disrupting calcium homeostasis or calcium-dependent processes, and that methylmercury and mercuric mercury can have differential effects to alter dopaminergic neurotransmission.     

Change in permeability of liposomes caused by methylmercury and inorganic mercury

The effects of two mercurial compounds, methylmercury and inorganic mercury, on lipids were examined by measuring permeability change of lipid bilayer, liposome. Both decrease in the cholesterol content and increase in the content of unsaturated fatty acid moieties in the lipid bilayers, augmented to susceptibility of the liposomes to the mercurial compounds. Inorganic mercury and methylmercury disrupted the lipid membrane to essentially the same extent. The influence on the permeability seems to be specific for mercury compounds. The significant increase in the permeability of some liposomal preparation noted even at the mercurial concentration of 10(-7) M strongly suggests that lipid in biomembrane could be one of the primary targets of these toxic substances.     

An application of machine learning methods to structural interaction fingerprints—a case study of kinase inhibitors

In this Letter, we present a novel methodology of searching for biologically active compounds, which is based on the combination of docking experiments and analysis of the results by machine learning methods. The study was performed for 5 different protein kinases, and several sets of compounds (active, inactive and assumed inactives) were docked into their targets. The resulting ligand–protein complexes were represented by the means of structural interaction fingerprints profiles (SIFts profiles) that constituted an input for ML methods. The developed protocol was found to be superior to the combination of classification algorithms with the standard fingerprint MACCSFP.     

Auspicious role of the steroidal heterocyclic derivatives as a platform for anti-cancer drugs

Steroids are polycyclic compounds that have a wide range of biological activities. They are bio-synthesized from cholesterol through a series of enzyme-mediated transformations, so they are highly lipophilic and readily enter most cells to interact with intracellular receptors, making them ideal vehicles for targeting a broad array of pathologies. New curative agents for cancers have been developed from several steroidal derivatives. Some biologically important properties of modified steroids are dependent on structural features of the steroid moiety and their side chains. Therefore, chemical derivatization of steroids provides a way to modify their function, and many structure–activity relationships have been confirmed by such synthetic modifications. Several studies demonstrate that steroidal heterocyclic derivatives can be effective in the prevention and treatment of many types of hormone-dependent cancers. The present review is a concise report on steroidal heterocyclic derivatives, with special emphasis on steroid heterocyclic derivatives with 5 membered rings or six-membered rings having interesting therapeutic potential as enzyme inhibitors and cytotoxic drugs to be used as candidates for anti-cancer drug development.     

Therapeutic potential of coumarin bearing metal complexes: Where are we headed?

The successfully application of some metallodrugs such as salvarsan, silver sulfadiazine and cisplatin in modern medicine launched the biological investigation of organometallic and metal-organic complexes. The availability and tunability of various ligands including N-heterocycles, phosphines, N-heterocyclic carbenes present an extended research area to chemists. In recent years, the preparation of the metal complexes of bioactive organic compounds is a new strategy. Coumarin derivatives are one of the classes of compounds used for this purpose, and many complexes of coumarin derivatives were prepared for enhanced biological activity, especially anticancer and antimicrobial. In this paper, we discuss the current situation of this topic.     

Toxicity,bioavailability and metal speciation

1. Environmental toxicology emphasizes the difference from traditional toxicology in which pure compounds of interest are added to purified diets, or injected into the test animals. When the objective is to study the fate and effects of trace elements in the environment, knowledge of the speciation of the elements and their physico-chemical forms is important.2. Cadmium salts such as the sulfides, carbonates or oxides, are practically insoluble in water. However, these can be converted to water-soluble salts in nature under the influence of oxygen and acids. Chronic exposure to Cd is associated with renal toxicity in humans once a critical body burden is reached.3. The solubility of As(III) oxide in water is fairly low, but high in either acid or alkali. In water, arsenic is usually in the form of the arsenate or arsenite. As(III) is systemically more poisonous than the As(V), and As(V) is reduced to the As(III) form before exerting any toxic effects. Organic arsenicals also exert their toxic effects in vivo in animals by first metabolizing to the trivalent arsenoxide form. Some methyl arsenic compounds, such as di- and trimethylarsines, occur naturally as a consequence of biological activity. The toxic effect of arsenite can be potentiated by dithiols, while As has a protective effect against the toxicity of a variety of forms of Se in several species.4. Selenium occurs in several oxidation states and many selenium analogues of organic sulfur compounds exist in nature. Selenium in selenate form occurs in alkaline soils, where it is soluble and easily available to plants. Selenite binds tightly to iron and aluminum oxides and thus is quite insoluble in soils. Hydrogen selenide is a very toxic gas at room temperature. The methylated forms of Se are much less toxic for the organism than selenite. However, the methylated Se derivatives have strong synergistic toxicity with other minerals such as arsenic.5. Aquatic organisms absorb and retain Hg in the tissues, as methylmercury, although most of the environmental Hg to which they are exposed is inorganic. The methylmercury in fish arises from the bacterial methylation of inorganic Hg. Methylmercury in the human diet is almost completely absorbed into the bloodstream. The nervous system is the principal target tissue affected by methylmercury in adult human beings, while kidney is the critical organ following the ingestion of Hg(II) salts.     

Nucleic acids as a basis for creating biosensors

Here we present a brief conception of biosensors. Structural peculiarities and properties of single- and double-stranded nucleic acids that are to be taken into account when creating biosensors on the basis of these biomolecules are considered. On the example of two biologically active compounds a possibility is shown for constructing biosensors on the basis of liquid-crystalline dispersions of low molecular mass DNA and on the basis of liquid-crystalline DNA dispersions immobilized due to their inclusion into the synthetic polymeric matrix.     

Inhibition of rainbow trout (Oncorhynchus mykiss) P450 aromatase activities in brain and ovarian microsomes by various environmental substances

Aromatase, a key steroidogenic enzyme that catalyses the conversion of androgens to estrogens, represent a target for endocrine disrupting chemicals. However, little is known about the effect of pollutants on aromatase enzymes in fish. In this study, we first optimized a rainbow trout (Oncorhynchus mykiss) microsomal aromatase assay to measure the effects of 43 substances belonging to diverse chemical classes (steroidal and non steroidal aromatase inhibitors, pesticides, heavy metals, organotin compounds, dioxins, polycyclic aromatic hydrocarbons) on brain and ovarian aromatase activities in vitro. Our results showed that 12 compounds were able to inhibit brain and ovarian aromatase activities in a dose-dependent manner with IC50 values ranging from the low nM to the high microM range depending on the substance: steroidal and non steroidal inhibitors of aromatase (4-hydroxyandrostenedione, androstatrienedione, aminogluthethimide), imidazole fungicides (clotrimazole, imazalil, prochloraz), triazole fungicides (difenoconazole, fenbuconazole, propiconazole, triadimenol), the pyrimidine fungicide fenarimol and methylmercury. Overall, this study demonstrates that rainbow trout brain and ovarian microsomal aromatase assay is suitable for evaluating potential aromatase inhibitors in vitro notably with respect to environmental screening. The results highlight that methylmercury and some pesticides that are currently used throughout the world, have the potential to interfere with the biosynthesis of endogenous estrogens in fish.