Digitalis Research in Berlin–Buch—Retrospective and Perspective Views

“The following remarks consist partially of matter of fact, and partially of opinion. The former will be permanent; the latter must vary with the detection of error, or the improvement of knowledge. I hazard them with diffidence, and hope they will be examined with candour.” These declarations, which stem from the famous book “An Account of the Foxglove and some of its Medical Uses” by physician William Withering in 1785 in which he introduced preparations from digitalis leaves in the therapy of dropsy (cardiac failure), are cited here by the senior author because of his awareness of the difficulties in presenting a balanced report on his life-long research project on the further development of digitalis. His decision to devote himself to digitalis research originated at the bedside, when as a physician he experienced the grim final stages of cardiac failure in which no real help for the patients is possible. Unfortunately, his research project did not fit into the research program decreed by the Ministry of Science of the German Democratic Republic, so that he was ordered to stop the digitalis project in favor of biomembrane studies. Fortunately, he got round the ban simply by labeling the digitalis-like acting steroids as probes for the cell membrane-located Na⁺/K⁺-transporting ATPase which he had just recognized as the digitalis target (receptor) enzyme. These and other ventures by the authors are collated here for the first time. The aim of this review is to foster straightforward research for solving a major challenge: the development of steroidal drugs for the prevention and cure of cardiac failure.     

Stereocontrolled Synthesis of Oligo(nucleoside phosphorothioate)s

Encouraging results obtained for modulation of gene expression by antisense oligonucleotides and their analogues have kindled hopes for a new generation of therapeutics against viral infections, cancer, and many other diseases. Among such analogues, oligo(nucleoside phosphorothioate)s (Oligo-S) have generally shown the highest efficacy in inhibiting the biosynthesis of “unwanted” proteins. The first clinical trials of antisense agents are now in progress using Oligo-S against genital warts and acute myeloid leukemia, and tests of Oligo-S against AIDS should follow soon. Nevertheless, their mechanism of action, internalization, cellular trafficking, subcellular localization, and interaction with cellular proteins is still poorly understood. It is assumed a priori that application involves rapid and efficient molecular recognition of target RNA by Oligo-S; however, the effects of the chirality of Oligo-S have so far been unappreciated, because Oligo-S has not yet been synthesized with stereocontrol. Indeed, the diastereomeric composition of Oligo-S has never been determined, primarily because of the lack of appropriate analytical methods. Since each of the diastereomers is a stereochemically unique chemical entity, questions arise as to which diastereomer is responsible for an observed biological response, including positive (curative) or possibly negative (toxic) side effects. In this review we intend provide a perhaps somewhat speculative assessment of the problems associated with the stereo-controlled synthesis of Oligo-S and to discuss the state-of-the-art in this field including strategies that may lead to Oligo-S of predetermined chirality. This article is not intended to discourage researchers from further studies of dia-steromeric mixtures of Oligo-S as potential pharmaceuticals. Throughout the history of medicinal chemistry numerous useful medicines were discovered, developed, and employed without the detailed knowledge of their structure. Indeed, the composition of the vaccines discovered by Pasteur is a subject of vigorous study still today.     

Chemistry and Biology of Taxol

One can view plants as a reference library of compounds waiting to be searched by a chemist who is looking for a particular property. Taxol, a complex polyoxygenated diterpene isolated from the Pacific Yew, Taxus brevifolia, was discovered during extensive screening of plant materials for antineoplastic agents during the late 1960s. Over the last two decades, interest in and research related to taxol has slowly grown to the point that the popular press now seems poised to scoop each new development. What was once an obscure compound, of interest only to the most masochistic of synthetic chemists and an equally small number of cellular biologists, has become one of the few organic compounds, which, like benzene and aspirin, is recognizable by name to the average citizen. In parallel, the scientific study of taxol has blossomed. Physicians are currently studying its effects on nearly every known neoplasm. Biologists are using taxol to study the mechanisms of cell function by observing the effects of its interactions with the cellular skeletal systems. Synthetic chemists, absorbed by the molecule's unique and sensitive structure and functionality, are exploring seemingly every available pathway for its synthesis. Indeed, the demand for taxol has risen so in the last five years that alternative sources to the extraction of T. brevifolia are being vigorously pursued. Because of the rapidly expanding scope of research in the multifaceted study of taxol, those who are interested in the field may find acquisition of a reasonable base of knowledge an arduous task. For this reason, this account attempts to bring together, for the first time, in a cogent overview the chemistry and biology of this unique molecule.     

Pyrone derivatives and metals: From natural products to metal-based drugs

Pyrone scaffolds are often present in natural products and many derivatives therefore exhibit favorable biocompatibility and toxicity profiles. Hydroxypyrones are obtained from natural sources or can be synthesized by different well established approaches and may easily be converted into the analogous thiopyrones and hydroxypyridones. These features make them well suited to drug development and other biological applications. Herein, we summarize recent literature on the use of (thio)pyr(id)ones in bioinorganic chemistry with a focus on their metal ion chelating properties. Selected examples and different approaches using (thio)pyr(id)ones are presented and the influence of structural modifications on their chemical, physical and biological properties are discussed.     

Disulfide-Reductase Inhibitors as Chemotherapeutic Agents: The Design of Drugs for Trypanosomiasis and Malaria

Viewed globally, parasitic diseases such as malaria and Chagas' cardiopathy pose an increasing threat to human health and welfare. Recognition of this problem and the challenge of synthesizing a quinine-like antimalarial agent sparked off the development of the chemical industry about 100 years ago. Our contribution deals with aspects of drug design, a young branch of pharmaceutical chemistry. As drug targets the flavoenzyme, glutathione reductase, and the recently discovered parasite enzyme, trypanothione reductase, were chosen. Based on the knowledge of the structure of these molecules, the modeling of enzyme inhibitors as potential chemotherapeutic agents against parasites has become possible. In addition, biochemical and clinical observations are considered since chemical principles of biological evolution can serve as guidelines for the pharmaceutical chemists. The picture shows two erythrocytes destroyed by malaria parasites. In the center of the photograph a parasite is just leaving its host cell through the ruptured cell membrane. Its target could be a neighboring healthy erythrocyte.     

A theoretical model for the Gla-TSR-EGF-1 region of the anticoagulant cofactor protein S: From biostructural pathology to specie

Protein S (PS), which functions as a species-specific anticoagulant cofactor to activated protein C (APC), is a mosaic protein that interacts with the phospholipid membrane via its -carboxyglutamate-rich (Gla) module. This module is followed by the thrombin-sensitive region (TSR), sensitive to thrombin cleavage, four epidermal growth factor (EGF)-like modules and a last region referred to as the sex hormone binding globulin (SHBG) domain. Of these, the TSR and the first EGF-like regions have been shown to be important for the species-specific interaction with APC. Difficulties in crystallising PS have so far hindered its study at the atomic level. Here, we report theoretical models for the Gla and EGF-1 modules of human PS constructed using prothrombin and factor X experimental structures. The TSR was built interactively. Analysis of the model linked with the large body of biochemical literature on PS and related proteins leads to suggestions that (i) the TSR stabilises the calcium-loaded Gla module through hydrophobic and ionic interactions and its conformation depends on the presence of the Gla module; (ii) the TSR does not form a calcium binding site but is protected from thrombin cleavage in the calcium-loaded form owing to short secondary structure elements and close contact with the Gla module; (iii) the PS missense mutations in this region are consistent with the structural data, except in one case which needs further investigation; and (iv) the two PS faces involving regions of residues Arg⁴⁹–Gln⁵²–Lys⁹⁷ (TSR-EGF-1) and Thr¹⁰³–Pro¹⁰⁶ (EGF-1) may be involved in species-specific interactions with APC as they are richer in nonconservative substitution when comparing human and bovine protein S. This preliminary model helps to plan future experiments and the resulting data will be used to further validate and optimise the present structure.     

Polymer Nanoassembly as Delivery Systems and Anti‐Bacterial Toolbox: From PGMAs to MSN@PGMAs

Researches on cargo delivery systems have received burgeoning attention and advanced rapidly. For synthetic nanodevices, polymer nanoassemblies and their inorganic‐organic hybrid materials, especially smart mesoporous silica nanoparticle (MSN)‐polymer hybrids (e. g., MSN@PGMAs), have attracted increasing attention in recent years. Their superior characteristics and unique features such as dynamic transition of morphology endow them the ability to efficiently entrap cargo molecules and undergo smart cargo delivery and release in response to various external stimuli. In this Personal Account, we present our recent research progress in the construction of cargo delivery systems based on polymers, poly(glycidyl methacrylate) (PGMA) and its derivatives in particular, ranging from polymer nanoparticles, reverse micelles, to vesicles and reverse vesicles, and their performance in the delivery and controlled release of model molecules and therapeutic agents. Significantly, MSN‐PGMA hybrid nanoassemblies (MSN@PGMAs), constructed with the aid of atom transfer radical polymerization, host‐guest interactions, or layer‐by‐layer self‐assembly techniques, and their potential bio‐related applications and anti‐bacterial applications as new nanocarriers are reviewed. Finally, the prospects and challenges of such nanoplatforms are also discussed.     

“Scaffold-Hopping” by Topological Pharmacophore Search: A Contribution to Virtual Screening

A chemically advanced template search (CATS) based on topological pharmacophore models has been developed as a technique for virtual screening. This technique has successfully identified novel potent Ca²⁺ antagonists (such as 2 ) that have a similar activity to 1 (a known T-channel blocking agent) in a library of several hundred thousand compounds on the basis of a correlation vector representation.     

A Fast and Efficient Track to Allosteric Modulators of Muscarinic Receptors: Microwave-Assisted Syntheses

Summary. By using microwave irradiation bisammonium-and bispyridinium-type allosteric modulators of muscarinic receptors can be obtained fast and efficiently.     

Self-catalytic mechanism of prebiotic reactions: From formamide to purine bases

Complete reaction pathway of prebiotic reactions for formation of the purine nucleobases adenine, hypoxanthine, guanine, isoguanine, 2,6-diaminopurine, and xanthine from pure formamide are presented. All reactants (hydrogen cyanide, ammonia, water, formic acid, urea) and catalysts (formamide and formimidic acid) needed in the self-catalyzed reactions are available from a starting compound, formamide. The required raw materials are obtained by partial decomposition of formamide.     

限域化学：碳基功能材料从基础研究到应用

限域化学研究的是对象在纳米尺度限域空间内的化学行为。限域空间内的化学环境不同于常规本体溶液,因而会出现许多奇特的现象,如反应选择性增强、活性增加、稳定性提高。本文结合笔者课题组近年来的工作,对限域化学领域碳基功能材料的限域策略,包括限域界面诱导、限域化学组装印刷及三维多孔受限体系作简要介绍,并阐述了其在催化、储能方面的应用。最后提出了限域化学未来发展面临的主要挑战,期望能为此领域研究提供参考。     

Melanin-based nanoparticles in biomedical applications: From molecular imaging to treatment of diseases

The melanin-based nanoparticles preparation methods were summarized here. Biomedical applications of melanin-based nanoparticles were also reviewed, including molecular imaging (magnetic resonance, positron emission tomography, and photoacoustic imaging) and treatment of diseases (drug delivery, photothermal therapy, antioxidant therapy, and iron overload therapy).     

Synthesis of Biologically Relevant 1,2,3- and 1,3,4-Triazoles: From Classical Pathway to Green Chemistry

Green Chemistry has become in the last two decades an increasing part of research interest. Nonconventional «green» sources for chemical reactions include micro-wave, mechanical mixing, visible light and ultrasound. 1,2,3-triazoles have important applications in pharmaceutical chemistry while their 1,2,4 counterparts are developed to a lesser extent. In the review presented here we will focus on synthesis of 1,2,3 and 1,2,4-triazole systems by means of classical and « green chemistry » conditions involving ultrasound chemistry and mechanochemistry. The focus will be on compounds/scaffolds that possess biological/pharmacophoric properties. Finally, we will also present the formal cycloreversion of 1,2,3-triazole compounds under mechanical forces and its potential use in biological systems.     

Transition-Metal Thiolates: From Molecular Fragments of Sulfidic Solids to Models for Active Centers in Biomolecules

Thiolates are presently a subject of great interest in the chemistry of complexes involving transition-metal elements and soft ligands. The manifold electronic and steric capabilities offered by the monodentate ligands RS^? and the bidentate chelate ligands ^?SRS^? have been used to stabilize a broad spectrum of mononuclear, oligomeric, and polymeric complexes with new and remarkable structures and properties. Impetus has especially been provided by the synthesis of polynuclear cagelike homo- and heteroleptic metal–sulfur frameworks, which can often be regarded as “molecular fragments” of the structures of inorganic sulfides. Thiolates and mixed sulfide-thiolates of the late open- and closed-shell 3d metals (Fe, Co, Ni, Cu, Zn) and some of their homologues (Au, Cd, Hg), as well as of Mo, are of particular importance as model complexes for biologically important metal centers coordinated by sulfur. They have played an important role in increasing our understanding of the structure, bonding, and function of the reactive centers in ferredoxins, rubredoxins, nitrogenases, blue copper proteins, metallothioneins, and antiarthritic drugs.     

Milestones in the Biochemistry of Silicon: From Basic Research to Biotechnological Applications

6.7 Gigatonnes of silicon are processed each year by marine organisms. Since it was known that silicon is an essential element for many biological systems, significant advances in the biochemistry of this element have been achieved from the classical viewpoint of silicon being a purely inorganic element. This article describes the proteins, genes, and molecular mechanisms of silicon metabolism in diatoms and sponges. These studies may help to reveal the role of silicon for optimal development and growth in many plants and animals as well as initiate the development of new technological methods for the shape-controlled production of new patterned silicone-based materials.