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Synthetic Efforts Toward The Total Synthesis Of Bryostatin 1 Emphasis On The C17 C27 Fragment
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Book Synopsis Synthetic Efforts Toward the Total Synthesis of Bryostatin 1 Emphasis on the C17-C27 Fragment by : Victoria Lynn Wilde
Download or read book Synthetic Efforts Toward the Total Synthesis of Bryostatin 1 Emphasis on the C17-C27 Fragment written by Victoria Lynn Wilde and published by . This book was released on 2008 with total page 294 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Supply Impacting Synthesis of Bryostatin 1 and the Design, Synthesis, and Evaluation of Bryostatin 1 Analogs by : Akira Joseph Shimizu
Download or read book Supply Impacting Synthesis of Bryostatin 1 and the Design, Synthesis, and Evaluation of Bryostatin 1 Analogs written by Akira Joseph Shimizu and published by . This book was released on 2019 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The marine derived natural product bryostatin 1 has been investigated in preclinical studies for a wide range of indications (cancer, Alzheimer's disease, HIV/AIDS eradication, multiple sclerosis, fragile X syndrome, and others). Bryostatin 1 has been evaluated in more than 40 clinical trials for three of these highly impactful indications: cancer, Alzheimer's disease, and HIV eradication. The trials in Alzheimer's disease and the eradication of HIV are ongoing, and there is a planned trial in which bryostatin 1 will act as an adjuvant to enhance CAR T cell therapy used to treat cancer. Unfortunately, the isolation of bryostatin 1 from its source organism is not economically or environmentally sustainable, placing the supply of bryostatin 1 for clinical evaluation in jeopardy. Additionally, although bryostatin 1 has impressive biologic activity, it was not evolved for human use. Bryostatin 1 has been heavily studied, but significantly less preclinical evaluation has been performed on designed bryostatin 1 analogs. These analogs have the potential to be more efficacious and have fewer off target side effects relative to the parent natural product. Prior research indicates that the putative pathway for the activity of bryostatin 1 is exogenous regulation of protein kinase C (PKC) activity. The PKC family of enzymes plays a central and complex role in both normal and diseased states. Structurally different PKC modulators have exhibited drastically different biologic activities. Further understanding how the subtle structural elements of the bryostatin 1 scaffold affect its multiple PKC mediated activities, potentially through isoform specificity or differential protein ligand orientation, could aid in the development of analog compounds with improved functional activity. This thesis details of the collaborative team effort to solve the bryostatin 1 supply problem through a step-economical and scalable total synthesis (19 longest linear sequence, 29 total steps, 4.8% yield). To reduce the number of steps in the longest linear sequence, this total synthesis convergently constructs bryostatin 1 by bringing together two similarly complex fragments late in the synthesis. This thesis focuses on the synthetic route to one of those fragments, the C-ring fragment, and the final steps in the total synthesis of bryostatin 1. The scalable nature of the bryostatin 1 total synthesis provided access to unprecedented amounts of highly complex intermediates with many of the key structural features of bryostatin 1. This thesis also describes how those intermediates were leveraged to produce a library of "close-in" analogs to bryostatin 1. These analogs were used to test hypotheses about which molecular interactions between bryostatin 1, PKC, and cellular membranes contribute to the amazing phenotypic activity of bryostatin 1. A subset of these bryostatin 1 analogs have been advanced to more complex functional assays to determine if the analogs have superior efficacy or tolerability relative to bryostatin 1.
Book Synopsis Studies Toward the Total Synthesis of Bryostatin 1 by : David Curtis Whritenour
Download or read book Studies Toward the Total Synthesis of Bryostatin 1 written by David Curtis Whritenour and published by . This book was released on 1988 with total page 608 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Towards the Total Synthesis of Bryostatin 1 by : Seyed Hassan Seradj
Download or read book Towards the Total Synthesis of Bryostatin 1 written by Seyed Hassan Seradj and published by . This book was released on 2009 with total page 137 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Scalable Total Synthesis of Bryostatin 1 Enables the Design, Synthesis, and Biological Evaluation of Bryostatin Analogs by : Clayton Thomas Hardman
Download or read book Scalable Total Synthesis of Bryostatin 1 Enables the Design, Synthesis, and Biological Evaluation of Bryostatin Analogs written by Clayton Thomas Hardman and published by . This book was released on 2020 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Bryostatin 1 is a natural product that was originally isolated from the marine sponge Bugula neritina more than 50 years ago. Following its isolation, it has demonstrated unprecedented clinical potential across a number of indications, including HIV/AIDS eradication, the treatment of Alzheimer's disease and neurological disorders, and cancer immunotherapy. Despite this unique portfolio of indications, the natural supply of bryostatin 1 from its source organism is limited and variable and maintaining a consistent supply of the natural product has hindered its clinical advancement. To enable the continued clinical evaluation of bryostatin 1, we developed a scalable total synthesis of the natural product that can sustainably supply future clinical studies of this exciting clinical candidate. Despite its promising activity, bryostatin 1 is a marine natural product that is neither evolved nor optimized for the treatment of human disease. Historically, the scarcity of isolated material and the challenges associated with making modifications of the delicate and densely functionalized bryostatin skeleton have precluded efforts to optimize the biological activity of this natural product lead through derivatization and exploration of structure-activity relationships (SAR) around the macrocycle. Drawing on the synthetic platform we developed in our scalable synthesis of bryostatin 1, we accomplished the design, synthesis, and biological evaluation of the first close-in analogs of bryostatin 1. Using a function-oriented synthesis (FOS) strategy informed by a combination of computational and biological data surrounding bryostatin's interaction with its protein target, protein kinase C (PKC), we synthesized a series of bryostatin analogs designed to maintain PKC affinity while allowing for a systematic investigation of their biological function. By leveraging the modularity of our bryostatin 1 synthesis, we developed complementary late-stage diversification strategies that provide efficient synthetic access to parallel series of bryostatin analogs with modifications in the A- and B-rings. In agreement with our pharmacophore model, these new agents retain affinity for PKC but exhibit variable PKC translocation kinetics. We further demonstrate that select analogs potently induce increased cell surface expression of CD22, a promising target for the treatment of leukemias and lymphomas, in in vitro models of acute lymphoblastic leukemia (ALL) and AIDS-related lymphomas, highlighting the potential general use of bryostatin and bryostatin analogs for enhancing antigen-targeted cancer immunotherapies. Finally, bryostatin 1 has been shown to prevent progressive neurodegeneration in a mouse model of multiple sclerosis (MS). Working with Professors Paul Kim and Michael Kornberg at Johns Hopkins, we show that several bryostatin analogs replicate the anti-inflammatory effects of bryostatin 1 on innate immune cells in vitro and lead analog SUW133 attenuates neuroinflammation and prevents the development of MS-related neurological deficits in vivo. We further demonstrate that this activity is dependent on PKC. These findings identify bryostatin analogs as promising drug candidates for targeting innate immunity in neuroinflammation and create a platform for evaluation of synthetic PKC modulators for the treatment of MS and other neuroinflammatory diseases.
Book Synopsis The Design, Synthesis, and Evaluation of Novel Bryostatin Analogs by : Vishal Anil Verma
Download or read book The Design, Synthesis, and Evaluation of Novel Bryostatin Analogs written by Vishal Anil Verma and published by . This book was released on 2008 with total page 374 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Total Synthesis of Natural Products by : Jie Jack Li
Download or read book Total Synthesis of Natural Products written by Jie Jack Li and published by Springer Science & Business Media. This book was released on 2013-03-14 with total page 292 pages. Available in PDF, EPUB and Kindle. Book excerpt: 'Total Synthesis of Natural Products' is written and edited by some of today's leaders in organic chemistry. Eleven chapters cover a range of natural products, from steroids to alkaloids. Each chapter contains an introduction to the natural product in question, descriptions of its biological and pharmacological properties and outlines of total synthesis procedures already carried out. Particular emphasis is placed on novel methodologies developed by the respective authors and their research groups. This text is ideal for graduate and advanced undergraduate students, as well as organic chemists in academia and industry.
Book Synopsis The Design, Synthesis and Biological Evaluation of the First Totally Synthetic Bryostatin Analogues by : Blaise Lippa
Download or read book The Design, Synthesis and Biological Evaluation of the First Totally Synthetic Bryostatin Analogues written by Blaise Lippa and published by . This book was released on 2000 with total page 718 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Dissertation Abstracts International by :
Download or read book Dissertation Abstracts International written by and published by . This book was released on 2005 with total page 884 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Anticancer Drug Development by : Bruce C. Baguley
Download or read book Anticancer Drug Development written by Bruce C. Baguley and published by Elsevier. This book was released on 2001-11-17 with total page 411 pages. Available in PDF, EPUB and Kindle. Book excerpt: Here in a single source is a complete spectrum of ideas on the development of new anticancer drugs. Containing concise reviews of multidisciplinary fields of research, this book offers a wealth of ideas on current and future molecular targets for drug design, including signal transduction, the cell division cycle, and programmed cell death. Detailed descriptions of sources for new drugs and methods for testing and clinical trial design are also provided. - One work that can be consulted for all aspects of anticancer drug development - Concise reviews of research fields, combined with practical scientific detail, written by internationally respected experts - A wealth of ideas on current and future molecular targets for drug design, including signal transduction, the cell division cycle, and programmed cell death - Detailed descriptions of the sources of new anticancer drugs, including combinatorial chemistry, phage display, and natural products - Discussion of how new drugs can be tested in preclinical systems, including the latest technology of robotic assay systems, cell culture, and experimental animal techniques - Hundreds of references that allow the reader to access relevant scientific and medical literature - Clear illustrations, some in color, that provide both understanding of the field and material for teaching
Book Synopsis Synthetic and Mechanistic Investigations of Analogues of Bryostatin 1 by : Stacey Ellen Brenner
Download or read book Synthetic and Mechanistic Investigations of Analogues of Bryostatin 1 written by Stacey Ellen Brenner and published by . This book was released on 2005 with total page 498 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Ruthenium and Palladium Catalysis by : Hanbiao Yang
Download or read book Ruthenium and Palladium Catalysis written by Hanbiao Yang and published by . This book was released on 2006 with total page 560 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Natural Products in Medicinal Chemistry by : Stephen Hanessian
Download or read book Natural Products in Medicinal Chemistry written by Stephen Hanessian and published by John Wiley & Sons. This book was released on 2013-12-18 with total page 658 pages. Available in PDF, EPUB and Kindle. Book excerpt: The inspiration provided by biologically active natural products to conceive of hybrids, congeners, analogs and unnatural variants is discussed by experts in the field in 16 highly informative chapters. Using well-documented studies over the past decade, this timely monograph demonstrates the current importance and future potential of natural products as starting points for the development of new drugs with improved properties over their progenitors. The examples are chosen so as to represent a wide range of natural products with therapeutic relevance among others, as anticancer agents, antimicrobials, antifungals, antisense nucleosides, antidiabetics, and analgesics. From the content: * Part I: Natural Products as Sources of Potential Drugs and Systematic Compound Collections * Part II: From Marketed Drugs to Designed Analogs and Clinical Candidates * Part III: Natural Products as an Incentive for Enabling Technologies * Part IV: Natural Products as Pharmacological Tools * Part V: Nature: The Provider, the Enticer, and the Healer
Book Synopsis Bioactive Marine Natural Products by : Dewan S. Bhakuni
Download or read book Bioactive Marine Natural Products written by Dewan S. Bhakuni and published by Springer Science & Business Media. This book was released on 2006-06-30 with total page 397 pages. Available in PDF, EPUB and Kindle. Book excerpt: Bioactive Marine Natural Products is the first book available that covers all aspects of bioactive marine natural products. It fills the void in the literature for bioactive marine natural products. The book covers various aspects of marine natural products and it is hoped that all the major classes of bioactive compounds are included. Different classes of marine organisms and the separation and isolation techniques are discussed. The chemistry and biology of marine toxins, peptides, alkaloids, nucleosides and prostanoids are discussed in detail. Biological, toxicological and clinical evaluations are also dealt with to ensure that the book may be adopted at any stage by any practicing organic chemist or biologist, working in academia or in R and D divisions of pharmaceutical companies. Each chapter in the book includes an abstract to highlight the major points discussed in the text and concluding remarks are given. References to books, monographs, review articles and original papers are provided at the end of each chapter.
Book Synopsis Chirotechnology by : Roger A. Sheldon
Download or read book Chirotechnology written by Roger A. Sheldon and published by CRC Press. This book was released on 1993-05-27 with total page 456 pages. Available in PDF, EPUB and Kindle. Book excerpt: This reference provides an introduction to the phenomenon of chirality and its importance in conjunction with biological activity and offers an easy-to-read examination of practical, industrially relevant methods for the synthesis of optically active compounds.;Furnishing hands-on guidelines for the development of economically viable synthetic compounds, Chirotechnology: explains optical isomerism and stereochemistry; gives a general overview of various methods of synthesis; supplies detailed explications of specific techniques, including fermentation, crystallization, the chirality pool, enzymatic methods, and catalytic asymmetric synthesis; illustrates and compares approaches with examples taken directly from industry such as the synthesis of pharmaceuticals, agrochemicals, flavours, and fragrances; and clarifies the importance of determining which approach to use for the synthesis of particular molecules.;With over 1100 literature citations, tables and figures, Chirotechnology is a reference for chemical engineers; industrial, organic and medicinal chemists; and bioprocess technologists, as well as a text for upper-level undergraduate, graduate and continuing-education students in these disciplines.
Book Synopsis Organic Synthesis with Carbohydrates by : Geert-Jan Boons
Download or read book Organic Synthesis with Carbohydrates written by Geert-Jan Boons and published by John Wiley & Sons. This book was released on 2008-04-15 with total page 348 pages. Available in PDF, EPUB and Kindle. Book excerpt: Carbohydrates offer a ready source of enantiomerically pure starting materials. They have been used for the imaginative synthesis of a wide range of compounds, and have been found to be effective chiral auxiliaries which enable the introduction of a range of functionalities in a highly enantioselective manner. In a subject dominated by volumes at research and professional level, this book provides a broad understanding of the use of carbohydrates in organic synthesis, at postgraduate student level. Emphasis is placed on retrosynthetic analysis, with discussion of why a particular synthetic route has been chosen, and mechanistic explanations are provided for key and novel reactions. Wherever possible, the authors highlight points of general significance to organic synthesis. Selected experimental conditions and reaction details are incorporated to ensure that information can be utilised in research. The book is extensively referenced and so provides a convenient point of entry to the primary literature.
Book Synopsis Anion-Binding Catalysis by : Olga Garcia-Mancheno
Download or read book Anion-Binding Catalysis written by Olga Garcia-Mancheno and published by John Wiley & Sons. This book was released on 2022-03-21 with total page 418 pages. Available in PDF, EPUB and Kindle. Book excerpt: Explores the potential of new types of anion-binding catalysts to solve challenging synthetic problems Anion-Binding Catalysis introduces readers to the use of anion-binding processes in catalytic chemical activation, exploring how this approach can contribute to the future design of novel synthetic transformations. Featuring contributions by world-renowned scientists in the field, this authoritative volume describes the structure, properties, and catalytic applications of anions as well as synthetic applications and practical analytical methods. In-depth chapters are organized by type of catalyst rather than reaction type, providing readers with an accessible overview of the existing classes of effective catalysts. The authors discuss the use of halogens as counteranions, the combination of (thio)urea and squaramide-based anion-binding with other types of organocatalysis, anion-binding catalysis by pnictogen and tetrel bonding, nucleophilic co-catalysis, anion-binding catalysis by pnictogen and tetrel bonding, and more. Helping readers appreciate and evaluate the potential of anion-binding catalysis, this timely book: Illustrates the historical development, activation mode, and importance of anion-binding in chemical catalysis Explains the analytic methods used to determine the anion-binding affinity of the catalysts Describes catalytic and synthetic applications of common NH- and OH-based hydrogen-donor catalysts as well as C-H triazole/triazolium catalysts Covers amino-catalysis involving enamine, dienamine, or iminium activation approaches Discusses new trends in the field of anion-binding catalysis, such as the combination of anion-binding with other types of catalysis Presenting the current state of the field as well as the synthetic potential of anion-binding catalysis in future, Anion-Binding Catalysis is essential reading for researchers in both academia and industry involved in organic synthesis, homogeneous catalysis, and pharmaceutical chemistry.
