The Synthesis Of Cyclic Natural Products As Potential Peptide Mimetics And Proteinase Inhibitors
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Cyclic Peptides
Author | : Jesko Koehnke |
Publisher | : Royal Society of Chemistry |
Total Pages | : 392 |
Release | : 2017-12-14 |
Genre | : Science |
ISBN | : 1788013778 |
Cyclic peptides are increasingly employed as chemical tools in biology and drug discovery. They have gained a lot of interest as alternative sources of new drugs to traditional small molecules. This book introduces cyclic peptides and provides a thorough overview of biosynthetic and fully synthetic approaches to their preparation. Following an introduction to cyclic peptides, biosynthetic and traditional chemical routes to cyclic peptides are reviewed. Due to their size, their synthesis is not trivial. Recent advances in the incorporation of novel structural units are presented in addition to how synthesis and biological methods can be combined. The chemical analysis of this molecular class is also discussed. Furthermore, chapters detail the progression of cyclic peptides as tools in biology and as potential drugs, providing a future vision of their importance. In total, this book provides the reader with a comprehensive view of the state-of-the-art of cyclic peptides, from construction to possible clinical utility. This book will be an essential resource for students, researchers and scientists within industry in medicinal, bioorganic, natural product and analytical chemistry fields.
Synthesis of Cyclic Peptide Natural Products and Inhibitors of Histone Modifying Enzymes
Author | : Hanae Benelkebir |
Publisher | : |
Total Pages | : |
Release | : 2011 |
Genre | : |
ISBN | : |
Natural products have been the source of numerous leads for several drugs. As these natural products are often isolated in small quantities, it is necessary to produce them synthetically to allow testing for biological activity. Furthermore, synthesis allows the preparation of unnatural analogues for SAR studies. Cyclic peptides represent an important family of biologically active natural products. The hepta- and octacyclopeptides sanguinamide A and sanguinamide B were recently isolated in submicromolar amounts by the Molinski group. The lack of material prevented biological evaluation of the natural products. For this reason and to confirm the structural elucidation we have targeted the total synthesis of sanguinamides. In addition to two proline residues, sanguinamides A and B include heterocycles and natural L-amino acid residues. We have completed the total syntheses of sanguinamides A and B; however the synthetic rotamers differed in both cases from the natural rotamers. We have investigated the influence of macrocyclisation on cis/trans conformational preference of the proline residues for the synthesis of sanguinamide A. We attempted several isomerisations and calculated the relative energies of the different sanguinamide conformers. [D-Ile]-Sanguinamide A, Cys(tBu) analogue of sanguinamide A and the synthetic sanguinamide B displayed antibacterial activity while the synthetic trans, trans-sanguinamide A displayed mild tyrosine kinase inhibitory activity. While extracted stylissamide A showed inhibition of translation during the elongation step, even though being structurally identical to the natural product, the synthetic compound prepared by macrocyclisation from a linear precursor was found to be totally inactive. Histones undergo different types of covalent modifications on the N-terminal tails such as acetylation, phosphorylation and methylation. Histone modification is a major mechanism of regulation in gene expression, replication and repair. Deregulation of histone modifications leads to cancer progression and therefore, inhibitors of enzymes which are able to catalyse the addition and removal of these epigenetic marks have therapeutic potential for treating cancer. An enzyme of particular interest is the family of zinc-dependent histone deacetylases (HDACs) that remove acetyl groups from acetylated lysine residues. Depsipeptides were prepared as HDAC inhibitors. We will ii present our total synthesis of largazole along with a range of analogues and discuss the SAR obtained from HDAC and cell proliferation assays. We elucidated the stereochemistry of burkholdac B by total synthesis of three diastereomers. The diastereomers made along with the natural product were tested as HDAC inhibitors. We are interested in inhibitors of lysine-specific demethylase 1 (LSD1) which is a different kind of epigenetic enzyme involved in demethylation of histone proteins in chromatin. Tranylcypromine is known to be an LSD1 inhibitor. Analogues of PCPA have been synthesised in order to explore the structure-activity relationships of this inhibitor. Analogues were also prepared and tested as LSD1 inhibitors.
Inhibitors of Protein–Protein Interactions
Author | : Ali Tavassoli |
Publisher | : Royal Society of Chemistry |
Total Pages | : 357 |
Release | : 2020-12-07 |
Genre | : Science |
ISBN | : 178801569X |
Protein-protein interactions (PPI) are at the heart of the majority of cellular processes, and are frequently dysregulated or usurped in disease. Given this central role, the inhibition of PPIs has been of significant interest as a means of treating a wide variety of diseases. However, there are inherent challenges in developing molecules capable of disrupting the relatively featureless and large interfacial areas involved. Despite this, there have been a number of successes in this field in recent years using both traditional drug discovery approaches and innovative, interdisciplinary strategies using novel chemical scaffolds. This book comprehensively covers the various aspects of PPI inhibition, encompassing small molecules, peptidomimetics, cyclic peptides, stapled peptides and macrocycles. Illustrated throughout with successful case studies, this book provides a holistic, cutting-edge view of the subject area and is ideal for chemical biologists and medicinal chemists interested in developing PPI inhibitors.
Total Chemical Synthesis of Proteins
Author | : Ashraf Brik |
Publisher | : John Wiley & Sons |
Total Pages | : 626 |
Release | : 2021-06-08 |
Genre | : Science |
ISBN | : 3527346600 |
How to synthesize native and modified proteins in the test tube With contributions from a panel of experts representing a range of disciplines, Total Chemical Synthesis of Proteins presents a carefully curated collection of synthetic approaches and strategies for the total synthesis of native and modified proteins. Comprehensive in scope, this important reference explores the three main chemoselective ligation methods for assembling unprotected peptide segments, including native chemical ligation (NCL). It includes information on synthetic strategies for the complex polypeptides that constitute glycoproteins, sulfoproteins, and membrane proteins, as well as their characterization. In addition, important areas of application for total protein synthesis are detailed, such as protein crystallography, protein engineering, and biomedical research. The authors also discuss the synthetic challenges that remain to be addressed. This unmatched resource: Contains valuable insights from the pioneers in the field of chemical protein synthesis Presents proven synthetic approaches for a range of protein families Explores key applications of precisely controlled protein synthesis, including novel diagnostics and therapeutics Written for organic chemists, biochemists, biotechnologists, and molecular biologists, Total Chemical Synthesis of Proteins provides key knowledge for everyone venturing into the burgeoning field of protein design and synthetic biology.
Peptide Macrocycles
Author | : Matthew B. Coppock |
Publisher | : Humana |
Total Pages | : 469 |
Release | : 2021-11-02 |
Genre | : Technology & Engineering |
ISBN | : 9781071616888 |
This volume explores the latest techniques and strategies used to study the field of peptide macrocycles. The chapters in this book ae organized into four parts: macrocycles synthesis, combinational library synthesis and screening, macrocycle characterization, and unique applications. Part One looks at a variety of peptide cyclization methodologies, and Part Two describes methods for the creation of peptide macrocycles libraries and their subsequent screening against biological targets of interest. Part Three discusses the study and characterization of peptide macrocycle-target interactions, and Part Four introduces unique applications for peptide macrocycles, from higher-order structure formation to post-synthetic functional modifications. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Cutting-edge and comprehensive, Peptide Macrocycles: Methods and Protocols is a valuable resource for both novice and expert researchers looking to learn more about this developing field.
Drug Design
Author | : Gerhard Klebe |
Publisher | : Springer |
Total Pages | : 0 |
Release | : 2013-07-10 |
Genre | : Medical |
ISBN | : 9783642179068 |
Unique work on structure-based drug design, covering multiple aspects of drug discovery and development. Fully colored, many images, computer animations of 3D structures (these only in electronic form). Makes the spatial aspects of interacting molecules clear to the reader, covers multiple applications and methods in drug design. Structures by mode of action, no therapeutic areas. Of high relevance for academia and industrial research. Focus on gene technology in drug design, omics-technologies computational methods experimental techniques of structure determination multiple examples on mode of action of current drugs, ADME-tox properties in drug development, QSAR methods, combinatorial chemistry, biologicals, ribosome, targeting protein-protein interfaces.
Biodiversity, Ecosystem Functioning, and Human Wellbeing
Author | : Shahid Naeem |
Publisher | : Oxford University Press |
Total Pages | : 387 |
Release | : 2009-07-30 |
Genre | : Business & Economics |
ISBN | : 0199547955 |
The book starts by summarizing the development of the basic science and provides a meta-analysis that quantitatively tests several biodiversity and ecosystem functioning hypotheses.
Solid-Phase Peptide Synthesis
Author | : Gregg B. Fields |
Publisher | : Academic Press |
Total Pages | : 828 |
Release | : 1997-10-21 |
Genre | : Medical |
ISBN | : |
The critically acclaimed laboratory standard for more than forty years, Methods in Enzymology is one of the most highly respected publications in the field of biochemistry. Since 1955, each volumehas been eagerly awaited, frequently consulted, and praised by researchers and reviewers alike. More than 275 volumes have been published (all of them still in print) and much of the material is relevant even today-truly an essential publication for researchers in all fields of life sciences. Key Features * Solid-phase peptide synthesis * Applications of peptides for structural and biological studies * Characterization of synthetic peptides