Development Of Transition Metal Catalyzed Site Selective Carbohydrate Functionalization Reactions And Tissue Selective Protein Degraders

Carbohydrates are synthetically challenging molecules with vital biological roles in all living systems. To better understand the biological functions of this fundamentally important class of molecules, novel methodologies are urgently needed in two different directions: building block synthesis and selective glycosylation. During my Ph.D. study, I developed two different methodologies for building block synthesis, which could simplify the assembly of oligosaccharides.Differentiation of hydroxy groups on the carbohydrate is usually considered challenging as a result of the almost identical chemical environment. 1,2-trans diols are even more difficult to deal with compared to 1,2-cis diols. In my first project, I developed a method for regio- and stereo-selective OH carbene insertion together with my collaborator. Under very mild conditions, a series of 1,2-trans diols can be selectively functionalized. The regioselectivity originated from interactions between substrates and transition-metal catalysts, while the stereochemistry came from intramolecular proton delivery. The newly introduced moiety can work as a protection group, function group for the glycoconjugate mimic synthesis, or participate in the following glycosylation reactions and impact the anomeric selectivity. Inspired by the regio-selectivity of first projects, I developed another transition metal-catalyzed reaction, which could successfully epimerize one hydroxyl group in 1,2-trans diols, thus many rare sugars can be accessed easily starting from readily available common sugars. Compared to the traditional route, the method I developed can simplify the synthesis significantly and is more environmentally friendly. Synthesis of aminosugars through direct amination of 1,2-trans diols is also investigated. Bromodomain (BRD) is an evolutionarily conserved protein-protein interaction module that can recognize and bind acetylated lysine residues in histones and many other proteins. BRD4 protein, which is considered a transcriptional factor and epigenetic regulator, can bind to acetylated histone and recruit protein complexes to stabilize the binding of RNA polymerase II to histone. The dysregulation of BRD4 can cause cancer and other diseases such as immune and inflammatory diseases. Because of this, the BRD4 protein has been long considered an important therapeutic target. In the third project, I worked on the development of tissue-selective BRD4 degraders, aiming to provide a novel therapy for prostate cancer. By attaching tissue-selective ligands to BRD4 degraders, we successfully achieved selectivity among different cell lines, which proved our initial hypothesis. The tri-functional degraders will be tested in vivo in the future.

This book focuses on the drug discovery and development applications of transition metal catalyzed processes, which can efficiently create preclinical and clinical drug candidates as well as marketed drugs. The authors pay particular attention to the challenges of transitioning academically-developed reactions into scalable industrial processes. Additionally, the book lays the groundwork for how continued development of transition metal catalyzed processes can deliver new drug candidates. This work provides a unique perspective on the applications of transition metal catalysis in drug discovery and development – it is a guide, a historical prospective, a practical compendium, and a source of future direction for the field.

This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact.

This book provides a comprehensive overview of Expressed Protein Ligation (EPL), detailing methods and protocols to generate site-specifically modified proteins. Chapters include an overview of the protein semi-synthesis field, as well as related areas that have contributed to the development of EPL such as protein splicing and peptide synthesis. Following the introductory chapters, the rest of the book guides readers through protocols to perform EPL reactions, methods to synthesize peptide thioesters and to perform peptide and protein ligations, label proteins inside living cells, protocols for the semi-synthesis of phorphorylated, glycosylated and ubiquitylated proteins, synthesis and assembly of assymetrically modified nucleosomes, use of ligation auxiliaries and synthesis of cyclic proteins, as well as novel desulfurization strategies and use of selective Cys side chain protection to obtain precisely modified proteins.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. Authoritative and cutting-edge, Expressed Protein Ligation: Methods and Protocols will ensure successful implementation of protein semi-synthesis methods to further study the structure and function of proteins.

The Application of Green Solvents in Separation Processes features a logical progression of a wide range of topics and methods, beginning with an overview of green solvents, covering everything from water and organic solvents, to ionic liquids, switchable solvents, eutectic mixtures, supercritical fluids, gas-expanded solvents, and more. In addition, the book outlines green extraction techniques, such as green membrane extraction, ultrasound-assisted extraction, and surfactant-mediated extraction techniques. Green sampling and sample preparation techniques are then explored, followed by green analytical separations, including green gas and liquid capillary chromatography, counter current chromatography, supercritical fluid chromatography, capillary electrophoresis, and other electrical separations. Applications of green chemistry techniques that are relevant for a broad range of scientific and technological areas are covered, including the benefits and challenges associated with their application. Provides insights into recent advances in greener extraction and separation processes Gives an understanding of alternatives to harmful solvents commonly used in extraction and separation processes, as well as advanced techniques for such processes Written by a multidisciplinary group of internationally recognized scientists

This indispensable two-volume handbook covers everything on this hot research field. The first part deals with the synthesis, modification, characterization and application of catalytic active zeolites, while the second focuses on such reaction types as cracking, hydrocracking, isomerization, reforming and other industrially important topics. Edited by a highly experienced and internationally renowned team with chapters written by the "Who's Who" of zeolite research.

Bioconjugate Techniques, 2nd Edition, is the essential guide to the modification and cross linking of biomolecules for use in research, diagnostics, and therapeutics. It provides highly detailed information on the chemistry, reagent systems, and practical applications for creating labeled or conjugate molecules. It also describes dozens of reactions with details on hundreds of commercially available reagents and the use of these reagents for modifying or cross linking peptides and proteins, sugars and polysaccharides, nucleic acids and oligonucleotides, lipids, and synthetic polymers. A one-stop source for proven methods and protocols for synthesizing bioconjugates in the lab Step-by-step presentation makes the book an ideal source for researchers who are less familiar with the synthesis of bioconjugates More than 600 figures that visually describe the complex reactions associated with the synthesis of bioconjugates Includes entirely new chapters on the latest areas in the field of bioconjugation as follows: Microparticles and nanoparticlesSilane coupling agentsDendrimers and dendronsChemoselective ligationQuantum dotsLanthanide chelatesCyanine dyesDiscrete PEG compoundsBuckyballs,fullerenes, and carbon nanotubesMass tags and isotope tagsBioconjugation in the study of protein interactions

Lays the foundation for new methods and applications of carbohydrate click chemistry Introduced by K. Barry Sharpless of The Scripps Research Institute in 2001, click chemistry mimics nature, giving researchers the tools needed to generate new substances quickly and reliably by joining small units together. With contributions from more than thirty pioneering researchers in the field, this text explores the many promising applications of click chemistry in glycoscience. Readers will learn both the basic concepts of carbohydrate click chemistry as well as its many biomedical applications, including synthetic antigens, analogs of cell-surface receptors, immobilized enzymes, targeted drug delivery systems, and multivalent cancer vaccines. Click Chemistry in Glycoscience examines a broad range of methodologies and strategies that have emerged from this rapidly evolving field. Each chapter describes new approaches, ideas, consequences, and applications resulting from the introduction of click processes. Divided into four sections, the book covers: Click chemistry strategies and decoupling Thio-click chemistry of carbohydrates Carbohydrate click chemistry for novel synthetic targets Carbohydrate click chemistry in biomedical sciences Thoroughly researched, the book reflects the most recent findings published in the literature. Diagrams and figures throughout the book enable readers to more easily grasp complex concepts and reaction processes. At the end of each chapter, references lead to the primary literature for further investigation of individual topics. The application of click chemistry to carbohydrates has tremendous implications for research. With this book as their guide, researchers have a solid foundation from which they can develop new methods and applications of carbohydrate click chemistry, including new carbohydrate-based therapeutics.

A valuable introduction to green oxidation for organic chemists interested in discovering new strategies and new reactions for oxidative synthesis Green Oxidation in Organic Synthesis provides a comprehensive introduction and overview of chemical preparation by green oxidative processes, an entry point to the growing journal literature on green oxidation in organic synthesis. It discusses both experimental and theoretical approaches for the study of new catalysts and methods for catalytic oxidation and selective oxidation. The book highlights the discovery of new reactions and catalysts in recent years, discussing mechanistic insights into the green oxidative processes, as well as applications in organic synthesis with significant potential to have a major impact in academia and industry. Chapters are organized according to the functional groups generated in the reactions, presenting interesting achievements for functional group formation by green oxidative processes with O2, H2O2, photocatalytic oxidation, electrochemical oxidation, and enzymatic oxidation. The mechanisms of these novel transformations clearly illustrated. Green Oxidation in Organic Synthesis will serve as an excellent reference for organic chemists interested in discovering new strategies for oxidative synthesis which address the priorities of green and sustainable chemistry.

Polymers are one of the most versatile and important materials used for capsule preparation despite various others available. Suitably formulated capsules can securely protect ingredients, deliver them to targeted sites, and release them expeditiously, improving functions and minimizing adverse effects. New polymers are constantly being explored to develop more efficient capsules as they are routinely used in pharmaceuticals, consumer healthcare products, nutrients, and food. This book focuses on the current state of the art of polymer-based capsules and delivery systems. It describes the formulation processes of capsules developed from redox-responsive polymers and polymer-functionalized carbon nanotubes, in addition to shedding light on coacervation of polymers for encapsulation. It reviews different active ingredients that can be used with polymer capsules in various products, encapsulation of essential oils using such capsules, and development of polymer capsules of cells and bacteriophages.