Metals in membranes

In this critical review we discuss recent advances in understanding the modes of interaction of metal ions with membrane proteins, including channels, pumps, transporters, ATP-binding cassette proteins, G-protein coupled receptors, kinases and respiratory enzymes. Such knowledge provides a basis for elucidating the mechanism of action of some classes of metallodrugs, and a stimulus for the further exploration of the coordination chemistry of metal ions in membranes. Such research offers promise for the discovery of new drugs with unusual modes of action. The article will be of interest to bioinorganic chemists, chemical biologists, biochemists, pharmacologists and medicinal chemists. (247 references).     

Highly Chemoselective gem-Difluoropropargylation of Aliphatic Alcohols

Despite the potential of α-fluoroethers in medicinal chemistry, their synthetic methods, especially etherification of aliphatic alcohols, have been limited. Herein, we developed two- and three-step gem-difluoropropargylation of aliphatic alcohols including amino acid derivatives and naturally occurring bioactive molecules. Highly chemoselective etherification proceeded by using the gem-difluoropropargyl bromide dicobalt complex in the presence of silver triflate and triethylamine. Decomplexation of dicobalt complexes was achieved by using cerium ammonium nitrate or N,N,N′-trimethylethylenediamine. The thus obtained gem-difluoropropargyl ethers were converted to various α-difluoroethers which are expected to be useful for medicinal chemistry.     

The emerging utility of ketenes in polymer chemistry

The continued evolution of functional materials that contribute to pressing societal challenges requires the development of powerful synthetic methodologies in polymer systems. Since their discovery by Staudinger in the early 20th century, the unique chemistry of ketenes have fascinated synthetic chemists and been the driver of revolutionary applications in photolithography, medicinal chemistry, and commodity materials. The versatile chemistry of ketenes, specifically their ability to act as an electrophile and/or undergo cycloaddition reactions, has recently been shown to provide a powerful platform for the design of next‐generation materials. This Highlight focuses on the history of ketenes in materials science and their recent renaissance in polymer chemistry, with specific focus being given to methodologies that provide reliable access to this important functional group in polymer systems. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 3769–3782     

The Deuterated “Magic Methyl” Group: A Guide to Site-Selective Trideuteromethyl Incorporation and Labeling by Using CD3 Reagents

In the field of medicinal chemistry, the precise installation of a trideuteromethyl group is gaining ever-increasing attention. Site-selective incorporation of the deuterated “magic methyl” group can provide profound pharmacological benefits and can be considered an important tool for drug optimization and development. This review provides a structured overview, according to trideuteromethylation reagent, of currently established methods for site-selective trideuteromethylation of carbon atoms. In addition to CD₃, the selective introduction of CD₂H and CDH₂ groups is also considered. For all methods, the corresponding mechanism and scope are discussed whenever reported. As such, this review can be a starting point for synthetic chemists to further advance trideuteromethylation methodologies. At the same time, this review aims to be a guide for medicinal chemists, offering them the available C−CD₃ formation strategies for the preparation of new or modified drugs.     

Parthenin—A Sesquiterpene Lactone with Multifaceted Biological Activities: Insights and Prospects

Parthenin, a sesquiterpene lactone of pseudoguaianolide type, is the representative secondary metabolite of the tropical weed Parthenium hysterophorus (Asteraceae). It accounts for a multitude of biological activities, including toxicity, allergenicity, allelopathy, and pharmacological aspects of the plant. Thus far, parthenin and its derivatives have been tested for chemotherapeutic abilities, medicinal properties, and herbicidal/pesticidal activities. However, due to the lack of toxicity–bioactivity relationship studies, the versatile properties of parthenin are relatively less utilised. The possibility of exploiting parthenin in different scientific fields (e.g., chemistry, medicine, and agriculture) makes it a subject of analytical discussion. The present review highlights the multifaceted uses of parthenin, on-going research, constraints in the practical applicability, and the possible workarounds for its successful utilisation. The main aim of this comprehensive discussion is to bring parthenin to the attention of researchers, pharmacologists, natural product chemists, and chemical biologists and to open the door for its multidimensional applications.     

Computer-aided prediction for medicinal chemistry via the Internet1

Some computational tools for medicinal chemistry freely available on the Internet were compared to examine whether the results of prediction obtained with different methods coincided or not. It was shown that the correlation coefficients varied from 0.65 to 0.90 for log P (seven methods), from 0.01 to 0.73 for aqueous solubility (four methods), and from 0.19 to 0.73 for drug-likeness (three methods). While for log P estimates, reasonable average pairwise correlation was found, for aqueous solubility and drug-likeness it was rather poor. Therefore, using computational tools freely available via the Internet, medicinal chemists should evaluate their accuracy versus experimental data for particular series of compounds. In contrast to prediction of above mentioned properties, which can be done with several Internet tools, wide profiling of biological activity can be obtained only with PASS Inet (http://www.ibmc.msk.ru/PASS). PASS Inet was tested by a dozen medicinal chemists for compounds from different chemical series with various kinds of biological activity, and in the majority of cases the results of prediction coincided with the experiments. New anxiolytics, antiarrhythmics, antileishmanials, and other biologically active agents have been identified on this basis. The advantages and limitations of computer-aided predictions for medicinal chemistry via the Internet are discussed.     

TRPing the switch on pain: an introduction to the chemistry and biology of capsaicin and TRPV1

Capsaicin has elicited great interest for many centuries due to its noticeable culinary and medical properties. The discovery of its receptor, TRPV1, sparked an explosion of interest in TRPV1 and the development of TRPV1 agonists and antagonists. This tutorial review provides an introduction to the history of both capsaicin and TRPV1. Two TRPV1 antagonists that are undergoing clinical trials are highlighted, as are some light-activated molecular tools that are enabling the intracellular study of this protein. This article will be of interest to chemists and biologists with an interest in TRPV1, cell signalling, or medicinal and biological chemistry.     

Chemists around the World,Take Your Part in the Circular Economy!

Based on recent examples and initiatives reported in the literature, this concept article discusses how chemistry can contribute to the circular economy approach in order to improve our current and future economical, societal, and environmental system. Through five proposed levels of contribution, chemists can take a significant part in this global approach via the consideration of green chemistry principles, the simplification of syntheses, the limitation of complex products preparation, the efficient utilization of resources but also the novel ways of waste valorization. A more systematic and generalized environmental and economic assessment from the lab-scale is also recommended. At last, chemists have to work even more collaboratively and in a multidisciplinary way, within chemistry and beyond.     

Impact of Fluoroalkyl Substituents on the Physicochemical Properties of Saturated Heterocyclic Amines

The physicochemical properties (pK_a(H), log P, and aqueous solubility) of fluoroalkyl-substituted heterocyclic amines were profiled to facilitate the amines’ rational application in medicinal chemistry research. The features of fluorine-containing compounds were compared to those of the corresponding parent non-fluorinated heterocycles and the corresponding fluorinated n-alkylamines. Amine basicity was observed to change in a monotonic fashion depending on the fluorination pattern. Although the introduction of fluoroalkyl groups had complex effects on the lipophilicity and aqueous solubility of the compounds, possible contributions of the fluorination pattern, ring size, and conformation of the substituent in the ring were addressed for a series of derivatives. The summarized data provide a useful guideline for the application of fluorinated motifs for fine-tuning a compound's properties related to drug discovery.     

Analytical Chemistry in Israel

Abstract

Analytical chemistry in Israel is not in as good a shape as one may wish. Several attempts have been made to instill interest in this branch of the profession among faculty members, practicing chemists and students, but no great stride forward can be recorded, and on the contrary, some set-backs must be noted. Nevertheless, analytical chemistry is practiced vigorously in several laboratories, and original Israeli contributions in this field have been noted by the international community of analytical chemists. It is on this background that the present survey is being presented.     

Photochemical reactions as key steps in five-membered N-heterocycle synthesis

The chemists have been interested in light as an energy source to induce chemical reactions since the beginning of scientific chemistry. This review summarizes the chemistry of photochemical reactions with emphasis of their synthetic applications. The organic photochemical reactions avoid the polluting or toxic reagents and therefore offer perspectives for sustainable processes and green chemistry. In summary, this review article describes the synthesis of a number of five-membered N-heterocycles.     

New Developments in Nitrogen Fixation

The production of ammonia from atmospheric dinitrogen at room temperature and ambient pressure in analogy to nature is a long-term goal for coordination chemists. Novel reactions of N₂-containing transition metal complexes with H₂, the first side-on N₂-bridged structure of an actinide complex, and an interesting variation of synthetic N₂ fixation are the key points addressed in this contribution. The results are related to the known chemistry of N₂ complexes, and their significance is discussed with respect to enzymatic N₂ fixation.     

Synthetically Important Alkali‐Metal Utility Amides: Lithium,Sodium, and Potassium Hexamethyldisilazides,Diisopropylamides, and Tetramethylpiperidides

Most synthetic chemists will have at some point utilized a sterically demanding secondary amide (R₂N^?). The three most important examples, lithium 1,1,1,3,3,3‐hexamethyldisilazide (LiHMDS), lithium diisopropylamide (LiDA), and lithium 2,2,6,6‐tetramethylpiperidide (LiTMP)—the “utility amides”—have long been indispensible particularly for lithiation (Li‐H exchange) reactions. Like organolithium compounds, they exhibit aggregation phenomena and strong Lewis acidity, and thus appear in distinct forms depending on the solvents employed. The structural chemistry of these compounds as well as their sodium and potassium congeners are described in the absence or in the presence of the most synthetically significant donor solvents tetrahydrofuran (THF) and N,N,N’,N’‐tetramethylethylenediamine (TMEDA) or closely related solvents. Examples of hetero‐alkali‐metal amides, an increasingly important composition because of the recent escalation of interest in mixed‐metal synergic effects, are also included.     

Integrating social and environmental justice into the chemistry classroom: a chemist’s toolbox

ABSTRACT

Although the chemical enterprise has provided numerous contributions to humanity, unintended consequences contribute to a disproportionate exposure of hazardous chemicals to certain populations based on race and socioeconomic status. Integrating concepts of social and environmental justice within chemistry curriculum provides an educational framework to help mitigate these impacts by training the next generation of chemists with justice-centered and green chemistry principles to guide their future work. Green and sustainable chemistry technologies can contribute to social equity and environmental justice. However, equity and social justice have only recently become a significant part of the green chemistry conversation. This article summarizes how the authors have explored issues of equity and environmental justice with the green and sustainable chemistry community. It offers a toolbox for college and university instructors containing foundational language, research, and idea-generation that can be used to strengthen the transition of a traditional chemistry curriculum toward a justice-centered one.     

Tracking chemical kinetics in high-throughput systems

Combinatorial chemistry and high‐throughput experimentation (HTE) have revolutionized the pharmaceutical industry—but can chemists truly repeat this success in the fields of catalysis and materials science? We propose to bridge the traditional “discovery” and “optimization” stages in HTE by enabling parallel kinetic analysis of an array of chemical reactions. We present here the theoretical basis to extract concentration profiles from reaction arrays and derive the optimal criteria to follow (pseudo)first‐order reactions in time in parallel systems. We use the information vector f and introduce in this context the information gain ratio, χ_r, to quantify the amount of useful information that can be obtained by measuring the extent of a specified reaction r in the array at any given time. Our method is general and independent of the analysis technique, but it is more effective if the analysis is performed on‐line. The feasibility of this new approach is demonstrated in the fast kinetic analysis of the carbon–sulfur coupling between 3‐chlorophenylhydrazonopropane dinitrile and β‐mercaptoethanol. The theory agrees well with the results obtained from 31 repeated C? S coupling experiments.     

PowerMV: a software environment for molecular viewing, descriptor generation, data analysis and hit evaluation

Ideally, a team of biologists, medicinal chemists and information specialists will evaluate the hits from high throughput screening. In practice, it often falls to nonmedicinal chemists to make the initial evaluation of HTS hits. Chemical genetics and high content screening both rely on screening in cells or animals where the biological target may not be known. There is a need to place active compounds into a context to suggest potential biological mechanisms. Our idea is to build an operating environment to help the biologist make the initial evaluation of HTS data. To this end the operating environment provides viewing of compound structure files, computation of basic biologically relevant chemical properties and searching against biologically annotated chemical structure databases. The benefit is to help the nonmedicinal chemist, biologist and statistician put compounds into a potentially informative biological context. Although there are several similar public and private programs used in the pharmaceutical industry to help evaluate hits, these programs are often built for computational chemists. Our program is designed for use by biologists and statisticians.     

Synthetic Gene Fragments in Genetic Engineering—The Renaissance of Chemistry in Molecular Biology

Chemistry and biology paved the way for a new scientific discipline, molecular genetics. The breathtaking progress in deciphering the genetic machinery of a living being within the last 20 years may be attributed mainly to the experimental skill and ingenuity of molecular biologists. Chemists lost interest in the investigation of biological problems. The advances in genetic engineering exemplify the new demands chemists are confronted with in contemporary science. Following a short introduction on the genetics of bacteria, the articles deals with the molecular basis of gene cloning, which is subdivided into in vitro recombination of nucleic acids and in vivo transformation of cells. Next, the criteria for the selection of passenger DNA, vectors, and host cells are discussed. Recombination and transformation are easy-to-learn experimental techniques, whereas the search for the positive clone requires detailed knowledge of microbiology and the ability to handle of a battery of modern biochemical techniques. Finally, the automated chemical synthesis of gene fragments serves to demonstrate that chemistry is starting to make its comeback into molecular biology.     

ortho-Quinols in (Bio)Synthesis of Natural Products

6-Alkyl-6-hydroxycyclohexa-2,4-dienone derivatives, commonly referred to as ortho-quinols, and their simple ester and ether variants constitute a class of organic compounds that aroused much interest amongst chemists over the past 70 years for several reasons related to organic synthesis, natural product chemistry and biochemistry. It was very early on that organic chemists understood the potential of the unique yet versatile chemical reactivity of such compounds to synthesize more complex structures, and it soon emerged that ortho-quinols could constitute key intermediates in the biosynthesis of certain natural products of various origins. This minireview discusses the chemistry of ortho-quinols from the point of view of their role in the synthesis and biosynthesis of natural products. Examples of completed syntheses of natural products mostly taken in the literature of the last 20 years or so, together with some chosen pieces from older but pioneering and most remarkable works, are highlighted to illustrate this discussion.     

Using halogen bonds to address the protein backbone: a systematic evaluation

Halogen bonds are specific embodiments of the sigma hole bonding paradigm. They represent directional interactions between the halogens chlorine, bromine, or iodine and an electron donor as binding partner. Using quantum chemical calculations at the MP2 level, we systematically explore how they can be used in molecular design to address the omnipresent carbonyls of the protein backbone. We characterize energetics and directionality and elucidate their spatial variability in sub-optimal geometries that are expected to occur in protein-ligand complexes featuring a multitude of concomitant interactions. By deriving simple rules, we aid medicinal chemists and chemical biologists in easily exploiting them for scaffold decoration and design. Our work shows that carbonyl-halogen bonds may be used to expand the patentable medicinal chemistry space, redefining halogens as key features. Furthermore, this data will be useful for implementing halogen bonds into pharmacophore models or scoring functions making the QM information available for automatic molecular recognition in virtual high throughput screening.