Templating ��-amylase peptide inhibitors with organotin compounds

Metal centers have been widely used to nucleate secondary structures in linear peptides. However, very few examples have been reported for peptide/organometal complexes. Here, we illustrate the use of organotin compounds as nucleation centers for secondary structures of linear peptide inhibitors of ??-amylase. Specifically, we utilized methyl-substituted tin compounds to template short type I ??-turns similar to the binding loop of tendamistat, the natural inhibitor of the enzyme, which are able to bind and inhibit ??-amylase. We show that enzyme activity is inhibited by neither the unstructured peptide nor the organotin compounds, but rather the peptide/organotin complex, which inhibits the enzyme with K _i?~?0.5???M. The results delineate a strategy to use organometallic compounds to drive the active conformation in small linear peptides.     

A molecular mechanics investigation of the structures and energetics of two classes of Ru(II) complexes with applications in homogeneous catalysis

We have used the extensible systematic forcefield (ESFF) to model two classes of chiral organometallic complexes with Ru(II) centres, both complexes having been shown to have excellent catalytic performance with respect to asymmetric ketone hydrogenation. Our results compare favourably with all available experimental data for these complexes, illustrating that the ESFF can be applied successfully to these systems. The results we obtain are useful and relevant in connection with the study of these complexes as catalysts and in turn the results support the further use of the ESFF for modelling other organometallic complexes.     

Mechanisms for the biomethylation of metals and metalloids.

The case of methylmercury pollution has demonstrated the profound importance of understanding biologically mediated transformation reactions that yield organometallic compounds with a high potential for bioaccumulation and toxicity. Toxic elements that form organometallic compounds, especially the metal-alkyls (e.g., methylmercury), deserve special concern. Most metal-alkyls are poisonous to the central nervous systems of higher organisms, and these compounds do accumulate in cells. Metal-alkyls that are stable in water, and that have been reported to be synthesized biologically, can be formed from the following toxic elements: Hg, Sn, As, Se, Te, Pd, Au, Tl and Pb. In this report we present details of the mechanisms for biological methylation of certain metals and metalloids with special emphasis on those elements that are widely dispersed in the biosphere. In addition we present preliminary results on the use of flourescence quenching techniques to determine cellular diffusion rates and partition coefficients for methylmercuric chloride.     

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.     

Approaching tumour therapy beyond platinum drugs: status of the art and perspectives of ruthenium drug candidates

The study of metal complexes for the treatment of cancer diseases has resulted in the identification of some unique properties of ruthenium-based compounds. Among these inorganic-based agents, two of them, namely the ruthenium(III) drugs NAMI-A and KP1019 have undertaken with some success the clinical evaluations of phase I and preliminary phase II trials in patients. Here we highlight the strategies that have led to the discovery of metal-based (NAMI-A and KP1019) and of organometallic (RM175, RAPTA-T, RDC11 and DW1/2) ruthenium-based complexes, and we report their main biological/pharmacological characteristics and expectations for further development.     

Antithrombotic and anticancer effects of garlic-derived sulfur compounds: a review

Garlic (Allium sativum L.) has a long history as being a food having a unique taste and odor along with some medicinal qualities. Modern scientific research has revealed that the wide variety of dietary and medicinal functions of garlic can be attributed to the sulfur compounds present in or generated from garlic. Although garlic produces more than 20 kinds of sulfide compounds from a few sulfur-containing amino acids, their functions are different from one another; e.g., allicin, methyl allyl trisulfide, and diallyl trisulfide have antibacterial, antithrombotic, and anticancer activities, respectively. The present paper reviews the physiological functions of garlic in the limited study fields of its antithrombotic and anticancer effects. Before describing these effects, however, we will discuss briefly some characteristics of garlic as a plant and some modes of absorption of orally-administered sulfur compounds from garlic.     

Computer graphics applications of electron deformation densities and electrostatic potentials in coordination chemistry

Computer programs have been developed in order to display on a raster scan device electron deformation densities and electrostatic potentials, both as 2D colour-filled contour maps and as 3D solid models. Furthermore, as this quantum chemical model has proved to be adequate for transition metal complexes, the combined use of the Xα formalism and computer graphics is expected to be of value in rationalizing the reactivity of coordination and organometallic compounds. The examples of [Cr(O₂)₄]³⁻, [Mo(O₂)₄]²⁻ and [Nb(O₂)₄]³⁻ are discussed in an attempt to understand the differences in catalytic properties exhibited by parent metal dioxygen complexes.     

Translational genetic approaches to substance use disorders: bridging the gap between mice and humans

While substance abuse disorders only occur in humans, mice and other model organisms can make valuable contributions to genetic studies of these disorders. In this review, we consider a few specific examples of how model organisms have been used in conjunction with studies in humans to study the role of genetic factors in substance use disorders. In some examples genes that were first discovered in mice were subsequently studied in humans. In other examples genes or specific polymorphisms in genes were first studied in humans and then modeled in mice. Using anatomically and temporally specific genetic, pharmacological and other environmental manipulations in conjunction with histological analyses, mechanistic insights that would be difficult to obtain in humans have been obtained in mice. We hope these examples illustrate how novel biological insights about the effect of genes on substance use disorders can be obtained when mouse and human genetic studies are successfully integrated.     

Blue Native electrophoresis to study mitochondrial and other protein complexes

The biogenesis and maintenance of mitochondria relies on a sizable number of proteins. Many of these proteins are organized into complexes, which are located in the mitochondrial inner membrane. Blue Native polyacrylamide gel electrophoresis (BN-PAGE) is a method for the isolation of intact protein complexes. Although it was initially used to study mitochondrial respiratory chain enzymes, it can also be applied to other protein complexes. The use of BN-PAGE has increased exponentially over the past few years and new applications have been developed. Here we review how to set up the basic system and outline modifications that can be applied to address specific research questions. Increasing the upper mass limit of complexes that can be separated by BN-PAGE can be achieved by using agarose instead of acrylamide. BN-PAGE can also be used to study assembly of mitochondrial protein complexes. Other applications include in-gel measurements of enzyme activity by histochemical staining and preparative native electrophoresis to isolate a protein complex. Finally, new ways of identifying protein spots in Blue Native gels using mass spectrometry are briefly discussed.     

Endophytic fungi from medicinal plants: a treasure hunt for bioactive metabolites

Endophytic fungi are ubiquitous organisms found in the plants, residing intercellular or intracellular, at least for a portion of their lives without causing apparent symptoms of infection. Almost all plants are known to harbor endophytes. The choice of the plant to be used for exploring endophytes for bioactives is important. Therefore, medicinal plants which are known to be used since centuries as an alternative source of medicine, are a valuable source for bioprospecting endophytes. Nevertheless, due to many reasons there is a dire need for novel resources for novel drugs which can be an answer to many deadly diseases. It is in this context that the present review was envisaged. The review reveals the importance of endophytic fungi from medicinal plants as a source of bioactive and chemically novel compounds. The bioactive metabolites produced by endophytic fungi originate from different biosynthetic pathways and belong to diverse structural groups such as terpenoids, steroids, quinones, phenols, coumarins etc. Endophytes therefore, represent a chemical reservoir for new compounds such as, anticancer, immunomodulatory, antioxidant, antiparasitic, antiviral, antitubercular, insecticidal etc. for use in the pharmaceutical and agrochemical industries. Although, efforts have been made to accommodate as many examples as possible but the depth of the subject is so vast that it cannot be covered in one single review. This in itself speaks of the fact that endophytic fungi from medicinal plants is indeed a treasure worth searching. In the present review only some selected examples have been covered.     

Aryl cyclopentadienyl tricarbonyl rhenium complexes: novel ligands for the estrogen receptor with potential use as estrogen radiopharmaceuticals

The need for imaging agents for estrogen receptor positive (ER+) tumors that are both cost effective and widely available, as well as the need for novel radiotherapeutic agents for the treatment of breast cancer, has prompted us to investigate cyclopentadienyl tricarbonyl metal [CpMet(CO)(3), Met=Re, Tc-99m] complexes that bind well to the ER. Thus, we have prepared a series of p-hydroxyphenyl-substituted CpRe(CO)(3) complexes and evaluated them (and, in some cases, their cyclopentadiene precursors) for binding to ER. These compounds constitute a new class of structurally integrated organometallic ligands for ER in which the CpMet(CO)(3 )organometallic unit forms the very structural core of these molecules and thus is necessarily intimately involved in their interaction with the receptor. The CpRe(CO)(3) compounds were prepared by reaction of the lithium salt of the arene-substituted cyclopentadiene with a suitable Re(CO)(3)(+) precursor, followed by deprotection of the methyl ether. The X-ray crystal structure of one of these analogues shows that it has the classical 'piano stool'-like geometry, with the alkyl groups directed upward, away from the tripodyl metal carbonyl base. The aryl-substituted CpRe(CO)(3) complexes that we have prepared all bind to the ER, some with affinity as great as 20% that of the native ligand, estradiol. In general, at least two p-hydroxyphenyl substituents and one to two alkyl groups attached to the organometallic cyclopentadienyl core are needed for high ER affinity. Where we have been able to make comparisons, the metal complexes bind to ER with an affinity greater than their cyclopentadiene precursors. The high affinity of some of these complexes indicates that the bulky Re(CO)(3) unit is able to exploit the considerable volume in the center of the ER ligand binding pocket that is not occupied by most ligands, a consideration that is supported by molecular modeling. The preparation of the best of these agents in technetium-99m labeled form is currently being investigated.     

Metal complexes as optical probes for DNA sensing and imaging

Transition and lanthanide metal complexes have rich photophysical properties that can be used for cellular imaging, biosensing and phototherapy. One of the applications of such luminescent compounds is the detection and visualisation of nucleic acids. In this brief review, we survey the recent literature on the use of luminescent metal complexes (including Re^I, Ru^II, Os^II, Ir^III, Pt^II, Eu^III and Tb^III) as DNA optical probes, including examples of compounds that bind selectively to non-duplex DNA topologies such as quadruplex, i-motif and DNA mismatches. We discuss the applications of metal-based luminescent complexes in cellular imaging, including time-resolved microscopy and super-resolution techniques. Their applications in biosensing and phototherapy are briefly mentioned in the relevant sections.     

Current findings,future trends,and unsolved problems in studies of medicinal mushrooms

The target of the present review is to draw attention to many critically important unsolved problems in the future development of medicinal mushroom science in the twenty-first century. Special attention is paid to mushroom polysaccharides. Many, if not all, higher Basidiomycetes mushrooms contain biologically active polysaccharides in fruit bodies, cultured mycelium, and cultured broth. The data on mushroom polysaccharides are summarized for approximately 700 species of higher Hetero- and Homobasidiomycetes. The chemical structure of polysaccharides and its connection to antitumor activity, including possible ways of chemical modification, experimental testing and clinical use of antitumor or immunostimulating polysaccharides, and possible mechanisms of their biological action, are discussed. Numerous bioactive polysaccharides or polysaccharide–protein complexes from medicinal mushrooms are described that appear to enhance innate and cell-mediated immune responses and exhibit antitumor activities in animals and humans. Stimulation of host immune defense systems by bioactive polymers from medicinal mushrooms has significant effects on the maturation, differentiation, and proliferation of many kinds of immune cells in the host. Many of these mushroom polymers were reported previously to have immunotherapeutic properties by facilitating growth inhibition and destruction of tumor cells. While the mechanism of their antitumor actions is still not completely understood, stimulation and modulation of key host immune responses by these mushroom polymers appears central. Particularly and most importantly for modern medicine are polysaccharides with antitumor and immunostimulating properties. Several of the mushroom polysaccharide compounds have proceeded through phases I, II, and III clinical trials and are used extensively and successfully in Asia to treat various cancers and other diseases. A total of 126 medicinal functions are thought to be produced by medicinal mushrooms and fungi including antitumor, immunomodulating, antioxidant, radical scavenging, cardiovascular, antihypercholesterolemia, antiviral, antibacterial, antiparasitic, antifungal, detoxification, hepatoprotective, and antidiabetic effects.     

Biochemistry of organometallic compounds

Recent studies have demonstrated that organometallics can be substrates of enzymes and may undergo biotransformations in the presence of microorganisms. Latest achievements in organometallic biosynthesis, applications of organometallics in biosensor systems and the properties and models of novel enzymes which attack the core of organometallic compounds, i.e., the metal-carbon bond, are discussed.     

Lanthanide Circularly Polarized Luminescence: Bases and Applications

Lanthanide (III) luminescence is very characteristic: it is characterized by narrow emission bands, large Stokes shift, and a long excited state lifetime. Moreover, chiral lanthanide complexes can emit strongly circularly polarized light in a way that is almost precluded to purely organic molecules. Thanks to the sensitivity and specificity of the Ln circularly polarized luminescence (CPL) signal, CPL‐active complexes are therefore employed as bioanalytical tools and other uses can be envisaged in many other fields. Here we present a brief overview of the most recently developed CPL‐active lanthanide complexes and a selected few examples of their applications. We briefly discuss the main mechanisms that can rationalize the observed outstanding CPL properties of these systems, and some practical suggestions on how to measure and report data. Chirality 27:1–13, 2015. © 2014 Wiley Periodicals, Inc.     

Analogs of Eu3+ DOTAM-Gly-Phe-OH and Tm3+ DOTAM-Gly-Lys-OH: synthesis and magnetic properties of potential PARACEST MRI contrast agents

Chelated lanthanide ions, especially gadolinium, have found wide use as contrast agents in magnetic resonance imaging. A new paradigm for generating contrast, termed PARACEST, was recently described that requires the slow exchange of water or other exchangeable protons present in the ligand framework. In previous work, we have described a synthetic method for the preparation of dipeptide conjugates of DOTAM for use as PARACEST agents. Two compounds possessed interesting magnetic properties: the Eu(3+) complex of DOTAM-Gly-Phe-OH and the Tm(3+) complex of DOTAM-Gly-Lys-OH. To understand the relationship between the structure of these complexes and their magnetic properties, we have expanded our synthetic methodology and prepared several new complexes. Ligands have been prepared in which the terminal phenylalanine moieties have been replaced with tryptophan or tyrosine, the distance to the amino acid residue possessing an alpha-substituent has been changed, or phenylalanine and lysine have been combined in the peptide sequence. The preparation of lanthanide(III) complexes of these ligands has been achieved and their PARACEST properties have been determined.     

Metal Complexes in Cancer Treatment: Journey So Far

Metal complexes in cancer therapy have attracted much interest mainly because metals exhibit unique characteristics, such as redox activity, metal-ligand interaction, structure and bonding, Lewis acid properties etc. In 1965, Barnett Rosenberg serendipitously discovered the metal-based compound cisplatin, an outstanding breakthrough in the history of metal-based anticancer complexes and led to a new area of anticancer drug discovery. Many metal-based compounds have been studied for their potential anticancer properties. Some of these compounds have FDA approval for clinical use, while others are now undergoing clinical trials for cancer therapy and detection. In the present study, we have highlighted the primary mode of action of metallic complexes and all FDA-approved/under clinical trial drugs with reference to cancer treatment. This review also focuses on recent progress on metal-based complexes such as platinum, ruthenium, iron, etc. with potential anticancer activities.     

Synthesis and in vitro characterization of organometallic rhenium and technetium glucose complexes against Glut 1 and hexokinase

A series of nine organometallic technetium-99m and rhenium complexes of glucose are presented and characterized in vitro regarding their potential as surrogates of [18F]-2-fluoro-desoxy glucose ([18F]-FDG). The glucose derivatives are functionalized at positions C-1, C-2, C-3, and C-6. Different spacer lengths and chelating systems have been introduced at these sites. For the (radio)labeling, the organometallic precursors [99mTc(H2O)3(CO)3]+ and [ReBr3(CO)3](2-) respectively have been used. The resulting complexes have been characterized chemically and radiochemically. The formation of uniform products has been observed on the macroscopic (Re) and no-carrier-added level (99mTc). The Tc-99m complexes revealed good inertness against ligand exchange (Cys and His) and excellent stability in physiological buffered saline as well as in human plasma over a period of 24 h at 37 degrees C. The rhenium complexes have been tested for competitive inhibition of the (yeast) hexokinase. Only for C-2 derivatized glucose complexes with extended spacer functionalities Ki values in the millimolar and sub-millimolar range have been observed. In silico molecular docking experiments supported these experimental findings. However, the competitive inhibitors are not recognized as a pseudosubstrate of hexokinase. The cellular uptake of all 99mTc-complexes into HT-29 colon carcinoma cells via Glut1 was generally low and unspecific independent of the position at the hexose ring, the chelating systems, or the overall charge of the corresponding metal complexes. The current results seem to preclude the use of these compounds as [18F]-FDG surrogates primarily due to the low cellular uptake via Glut1.     

Lectin activities of cytokines: functions and putative carbohydrate-recognition domains

The discovery that some cytokines have carbohydrate-binding (lectin) properties opens new concepts in the understanding of their mechanism of action. The carbohydrate-recognition domain (CRD), which is localized at the opposite of the receptor-binding domain, makes these molecules bi-functional. The expression of the biological activity of the cytokine relies on its carbohydrate-binding activity, which allows the association of the cytokine receptor with molecular complexes comprising the specific kinase/phosphatase involved in receptor phosphorylation/dephosphorylation and in specific signal transduction. As a correlate, a cytokine can act only on cells possessing both the receptor and the ligand. Two cytokines using the same receptor can have different target cells and functions because of their different lectin activities. Based on a few examples, the CRD can be predicted based on the 3-D structures of the molecules.     

7. Bioactivity in plants: the link between phytochemistry and medicine

The development of medicinal plant research over the last 30 years is reviewed with reference to the search for new active principles. Difficulties inherent to activity guided isolation and the specific requirements of bioassays are discussed. An overview is given on currently used systems for various bioactivities, with emphasis on simple bioassays for phytochemical laboratories. The progress in medicinal plant research is illustrated by selected examples of plant derived compounds of importance as drugs or pharmacological tools.