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The Design And Synthesis Of Highly Potent Epothilone B Analogues And Progress Toward The Total Synthesis Of Sinularia Natural Products
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Book Synopsis The Design and Synthesis of Highly Potent Epothilone B Analogues and Progress Toward the Total Synthesis of Sinularia Natural Products by : Benjamin Anthony Pratt
Download or read book The Design and Synthesis of Highly Potent Epothilone B Analogues and Progress Toward the Total Synthesis of Sinularia Natural Products written by Benjamin Anthony Pratt and published by ProQuest. This book was released on 2008 with total page 384 pages. Available in PDF, EPUB and Kindle. Book excerpt: As the first epothilone analogue has recently been approved for clinical use by the FDA, the epothilones stand on the verge of becoming the standard for chemotherapeutic care. A new batch of designed Epothilone B analogues has been synthesized that possess broad structural diversity on the heterocyclic sidechain and unrivaled biological activity against drug-susceptible and drug-resistant cell lines. The most potent epothilone analogues from this study are currently under development toward becoming clinical candidates. Progress has been made toward the total synthesis of the complex and biologically active norcembranoid class of Sinularia natural products. Development of a convergent synthesis to a common, key intermediate has allowed for the near completion of Norcembranolide and Sinuleptolide. Within this synthetic strategy is the development of a novel rhodium-catalyzed macrocyclic ring closing reaction and a palladium-mediated acetylenic ketone rearrangement to 2,5-furans. This synthetic strategy provides access to the key intermediate of 8 complex natural products in the norcembrane, yonarane and dimeric-norcembrane families.
Book Synopsis Synthesis of Natural and Designed Antitumor Agents by : Derek Rhoades
Download or read book Synthesis of Natural and Designed Antitumor Agents written by Derek Rhoades and published by . This book was released on 2016 with total page 422 pages. Available in PDF, EPUB and Kindle. Book excerpt: The epothilones are an intriguing class of natural products and a classic in total synthesis. Their remarkable biological properties have been under investigation for the last two decades and endeavors into their synthesis reached levels of global intensity. Clinical trials of natural and designed epothilones are currently ongoing, and one derivative is approved by the U.S. Food and Drug Administration (FDA). In spite of the massive attention that the epothilones, in particular epothilone B, have enjoyed over the years, the excitement has waned since its initial burst in the mid 1990's. This was mostly due to their generally narrow therapeutic window. However, the continuing maturation of various selective drug delivery systems, such as antibody drug conjugates (ADCs), has provoked a renaissance for designed analogues of the epothilones and other natural products that were originally pursued but ultimately abandoned because of undesired side effects stemming from their potency and their specific formulation. Thus, Chapter 1 of this dissertation describes the molecular design and synthesis of epothilone B analogues that possess attachment sites suitable for conjugation to ADCs or related systems. These analogues were synthesized utilizing a Stille coupling protocol with the historically successful macrocyclic vinyl iodide 1.33 and novel N-arylpyrazolyl stannanes as the coupling partners. As a further development, the use of an aziridine functional group as an isosteric replacement for the epoxide moiety of epothilone B was investigated. These efforts culminated in the discovery of a convenient, commercially viable route for accessing a plethora of novel aziridinyl epothilone B analogues in seven steps from natural epothilone B. Highlights of this synthesis include the recently developed Ess-Kürti-Falck aziridination, and an in-depth survey of the Horner-Wadsworth-Emmons reaction and its related Still-Gennari modification as it relates to [beta]-heteroaryl phosphonates, an understudied yet highly valuable class of compounds for the synthesis of complex heterocycles. Thailanstatin A is a recently isolated natural product with impressive therapeutic potential. Its unique mechanism of action as a potent inhibitor of the spliceosome, as well as its structural features which are naturally tailored to accommodate ADCs or related technologies, prompted its total synthesis. Chapter 2 of this dissertation describes the total synthesis of thailanstatin A, which was accomplished in a longest linear sequence of 9 steps from readily available starting materials. The tetrahydropyran components of this molecule conveniently derive from cheap chiral pool materials, L-threonine and D-glucal, and a final stage Suzuki coupling between advanced vinyl iodide and vinyl boronate pinacol ester intermediates was employed to deliver the target molecule in a reliable manner. A key methodological development realized en route to the target was the oxa-Michael/hydrogenation sequence of an [alpha],[beta],[gamma],[delta]-unsaturated aldehyde to enable diastereodivergent access to highly substituted tetrahydropyrans. The high utility of this approach is currently guiding the exploration of designed analogues of this natural product, the results of which will provide potential lead compounds for therapeutic candidates and add new insights into the SARs of this intriguing class of bioactive compounds.
Book Synopsis Synthesis of Epothilone Analogs: Toward the Development of Potent Anticancer Drugs by :
Download or read book Synthesis of Epothilone Analogs: Toward the Development of Potent Anticancer Drugs written by and published by . This book was released on 1999 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The epothilones are naturally occurring cytotoxic molecules that possess a remarkable ability to arrest cell division through the stabilization of microtuble assemblies. The in vitro and in vivo studies with desoxyepothilone B (dEpoB) have established that the desoxy compound is well tolerated and virtually curative against a variety of sensitive and resistant xenograft tumors in animal models. In light of these discoveries, a new analogue, 2l-hydroxy-12,13-desoxyepothilone B (dEpoF), has been designed and synthesized. The preliminary biological studies suggest that the new analogue is highly potent against various tumor cell lines and may have an advantage over dEpoB due to the presence of an extra hydroxy group. A chemical synthesis of dEPoF that would be able to support a serious and substantial discovery research program directed toward the clinical development is in active progress.
Book Synopsis Strategy Toward the Total Synthesis of Epothilones A and B by :
Download or read book Strategy Toward the Total Synthesis of Epothilones A and B written by and published by . This book was released on 2000 with total page 34 pages. Available in PDF, EPUB and Kindle. Book excerpt: Having accomplished total syntheses of epothilone A and B, we have been engaged in a new stage of investigation that involves development of efficient strategies for a large scale epothilone preparation and search for more potent analogues. Efficient and processable syntheses of key building blocks of l2,l3-desoxyepothilone B (dEpoB) by catalytic asymmetric induction has been achieved. dEpoB is a potent anticancer agent, showing a highly promising therapeutic potential in the currently undergoing phase I study. The syntheses of two epothilone analogues, 15(S)-aza-l2,13-desoxyepothilone B and the epimeric l5(R)-aza-12,l3- desoxyepothilone B have been accomplished. Tubulin binding and cytotoxicity profiles of these analogues have also been investigated. Another epothilone, l2,l3-desoxyepothilone F (dEpoF), was synthesized and evaluated for antitumor potential. The results from an in vitro assay reveal that this new analogue is highly active against various tumor cell lines with a potency comparable to that of dEpoB. In particular, the growth of resistant tumor cells is inhibited by dEpoF at concentrations where paclitaxel (Taxol) is basically ineffective. A preliminary assessment of its in vivo activity is also promising. The new analogue, containing an additional hydroxyl group at C21, provides advantages over other epothilones in terms of water solubility and can serve as a readily functionalizable handle to produce other useful compounds for pertinent biological studies.
Book Synopsis Efficient Access to Bryostatin and Functional Bryostatin Analogs by : Adam James Schrier
Download or read book Efficient Access to Bryostatin and Functional Bryostatin Analogs written by Adam James Schrier and published by . This book was released on 2011 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The bryostatins are a family of structurally complex natural products isolated from the marine bryozoan Bugula neritina. Bryostatin 1 is currently being investigated for cancer, Alzheimer's and HIV/AIDS indications. Despite these remarkable activities, research on the bryostatins is hampered by their low natural abundance. Efficient access by total chemical synthesis has been in large part precluded by the bryostatins' structural complexity. This dissertation describes the design, synthesis, and preliminary biological evaluation of functional bryostatin analogs that possess biological activities comparable or superior to the natural product. These fully synthetic analogs were convergently assembled in a uniquely step-economical manner using novel macrocyclization strategies, including macroacetalization and Prins-driven macrocyclization approaches. Bryostatin analogs were identified that possess unique affinities (subnanomolar) and selectivities for protein kinase C (PKC). Synthetic bryostatin analogs also exhibit subnanomolar antileukemic activity in in vitro assays. The convergent total synthesis of bryostatin 9, a highly potent congener of the natural product family, is also described.
Book Synopsis Progress Toward the Total Synthesis of the Epoxyquinoid Family of Natural Products by :
Download or read book Progress Toward the Total Synthesis of the Epoxyquinoid Family of Natural Products written by and published by . This book was released on 2007 with total page 228 pages. Available in PDF, EPUB and Kindle. Book excerpt: Enyne metathesis is a powerful C-C bond forming reaction that combines an alkene and an alkyne and forms a conjugated 1,3-diene. The scope of enyne metathesis was expanded by combining various alkynes with vinyl ethers. Typically vinyl ethers are poor metathesis substrates, but a method was developed for the synthesis of dienol ethers utilizing ruthenium carbenes. The products of these reactions were subjected to [4+2] cycloaddition conditions to give substituted cyclohexene rings. The epoxyquinoid family is a highly targeted series of natural products. A general method for the synthesis of the core structure of these natural products has been explored. An enyne cross metathesis/ring closing metathesis step was designed as the key reaction to this synthesis. A Darzen's condensation between a chiral [alpha]-alkoxy aldehyde and a chloroacyl oxazolidinone was successfully employed to join two fragments of the molecule as well as to install an epoxide. A highly diastereoselective cuprate addition set the stereochemistry of the first stereogenic center. The early intermediates were prepared via easily scalable organic syntheses procedures including utilizing a carbohydrate as the source of chirality. Ring closing enyne metathesis to form the epoxyquinoid core was evaluated in two epimeric series.
Book Synopsis Total Synthesis of Cyclopropyl-epothilone B Analogs and Studies Towards the Total Synthesis of Michaolide E by : Raphael Schiess
Download or read book Total Synthesis of Cyclopropyl-epothilone B Analogs and Studies Towards the Total Synthesis of Michaolide E written by Raphael Schiess and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Design, Synthesis, and Biological Evaluation of 12,13-cycloalkl Epothilones by : Kenji Namoto
Download or read book Design, Synthesis, and Biological Evaluation of 12,13-cycloalkl Epothilones written by Kenji Namoto and published by . This book was released on 2002 with total page 510 pages. Available in PDF, EPUB and Kindle. Book excerpt: An array of new epothilone analogues, namely 12,13-cycloalkyl epothilones, were prepared through chemical synthesis and subsequently evaluated with in vitro tubulin polymerization assays and cytotoxicity assays against a panel of cancer cell lines. Guided by the careful analysis of the existing SARs of epothilones, the synthetic targets were selected, the synthetic plans and strategies were formulated, and the actual syntheses were executed. Based on well-established stereochemical transformations combined with highly convergent approach, the synthetic effort culminated in a variety of stereochemically well-defined potent 12,13-cycloalkylepothilone analogues, the biological investigation of which clarified some important problems in the existing SARs such as the role of C12,13-epoxide and the potency enhancing effect of C12 methyl group. In addition, the most potent epothilone analogues identified in this study are being further evaluated towards clinical studies because of their potentially suitable pharmacological profiles.
Book Synopsis Progress Toward the Total Synthesis of Marineosins A & B ; Total Synthesis of Tambjamine K and Unnatural Analogs with Improved Anticancer Activity, and Discovery of Selective M1 Antagonists by : Leslie N. Aldrich
Download or read book Progress Toward the Total Synthesis of Marineosins A & B ; Total Synthesis of Tambjamine K and Unnatural Analogs with Improved Anticancer Activity, and Discovery of Selective M1 Antagonists written by Leslie N. Aldrich and published by . This book was released on 2012 with total page 323 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Formal Syntheses of Eribulin and Synthesis of Biologically-active Small Molecules by : Anissa Kaghad
Download or read book Formal Syntheses of Eribulin and Synthesis of Biologically-active Small Molecules written by Anissa Kaghad and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Natural products have been used as medicines since the dawn of recorded history and, today, continue to be an integral part of the drug discovery process. Yet, their impact has decreased significantly over the past two decades following the advent of high-throughput screening (HTS) and the post-genomic era. In this regard, total synthesis has served as a powerful tool to address some of the challenges associated with natural product drug discovery. A noticeable example is the discovery and development of the natural product analogue, eribulin mesylate, the most complex, fully synthetic drug on the market. Albeit impressive, the commercial process of eribulin involves a total of 67 steps from which, 45 are used to construct the C14-C35 fragment of the macrocyclic lactone. To improve upon this process, we exploited methodology developed in the Britton group for tetrahydrofuran synthesis. Most notably, we anticipated that the application of our expertise in the stereoselective synthesis of hydroxytetrahydrofurans would allow us to considerably reduce the overall length of the synthesis and consequently the cost of producing eribulin. Following this strategy, we have developed concise and stereoselective syntheses of two C14-C35 key fragments and also, a scalable synthesis of the C14-C26 building block. Nucleoside analogues have largely been used as anticancer drugs or for the treatment of infectious diseases. Among them, immucillin H was approved in Japan in 2017 to treat peripheral T-cell lymphoma and immucillin A was found active against a broad range of viruses. Driven by the concept of "step economy", we have developed a concise and stereoselective formal synthesis of these two nucleoside analogues. Moreover, a collaboration between the Britton group, the Structural Genomics Consortium, and Bayer has led to the design and synthesis of inhibitors selective against PRMT4, an enzyme overexpressed in several cancers.
Book Synopsis Progress Toward the Total Synthesis of Garsubellin A and Structurally Related Phloroglucin Natural Products by : Sarah Jane Spessard
Download or read book Progress Toward the Total Synthesis of Garsubellin A and Structurally Related Phloroglucin Natural Products written by Sarah Jane Spessard and published by . This book was released on 2003 with total page 64 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Studies Toward The Total Synthesis Of Subincanadine E by : Corinne Marie Sadlowski
Download or read book Studies Toward The Total Synthesis Of Subincanadine E written by Corinne Marie Sadlowski and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Progress towards a concise total synthesis of subincanadine E is reported. This natural product was first isolated from the Picralima nitida cell suspension culture line in 1982 under the name pericine and later in 2002 from Aspidosperma subincanum as subincanadine E. It is the most potent compound of its class with in vitro cytotoxicity against both murine lymphoma L1210 and human epidermoid carcinoma KB cells (LD50, 0.3 ug/mL and 4.4 ug/mL, respectively) and was found to be six times more potent than codeine as an opiate agonist in a 3H-naloxone binding study (IC50, 0.6 umol/L). The first-generation synthesis produced an undesired internal olefin that, upon attempted isomerization, catalyzed an unusual intermolecular Diels-Alder reaction. A revised second-generation synthesis employed (±)-harmicine and showcased an intramolecular Pd-catalyzed cross-coupling reaction that furnished an unanticipated 5-membered ring instead of the predicted 6-membered ring via methylene linker activation. Further studies utilizing an amide intermediate and organocuprate chemistry produced no desired carbon-carbon bond formation. A third-generation synthesis was carried out from enantiopure (S)-carvone. This route explored regioselective oxime formation and protecting group manipulations for a subsequent Beckmann rearrangement, which provided the first access to 5-amino derivatives of carvone. An intramolecular Pd-catalyzed cross-coupling reaction was performed to construct the aza-bicycle prior to indole installation. Contingent on its success, indole introduction and a double alkylation would provide an akuammicine-like scaffold that can ring-open upon hydride exposure to afford (15S)-subincanadine E in 16 overall steps. This work accomplished 10 steps toward the first total asymmetric synthesis of (15S)-subincanadine E.
Book Synopsis Stereoselective Syntheses of Certain Natural Products and Their Analogues from Chiral-pool and Enzymatically-derived Building Blocks by : Joshua Neil Victor Timshell Buckler
Download or read book Stereoselective Syntheses of Certain Natural Products and Their Analogues from Chiral-pool and Enzymatically-derived Building Blocks written by Joshua Neil Victor Timshell Buckler and published by . This book was released on 2018 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: This thesis is comprised of six scientific articles and is preceded by an overview that contextualises all of this published/submitted work. The first section of this thesis is comprised of Publications 1-3 and is concerned with the synthesis of novel, oxygenated analogues of the natural and non-natural enantiomeric forms of the Amaryllidaceae alkaloid galanthamine, a reversible and selective acetylcholine esterase (AChE) inhibitor that is used clinically in the treatment of Alzheimer's disease. Specifically, Publication 1 is an invited book chapter that details synthetic approaches to galanthamine and certain analogues pursued by the Banwell Group. It contextualises the strategy employed in preparing oxygenated analogues of galanthamine by the author in latter part of the first section of this thesis. Publication 2 is an invited review article that showcases the methodologies that have been developed within the Banwell Group for manipulating enzymatically-derived and homochiral cis-1,2-dihydrocatechols so as to generate a significant range of biologically active natural products. Publication 3 describes the synthesis of certain oxygenated derivatives of both (+)- and (-)-galanthamine and the evaluation of these as AChE inhibitors. The second section of this thesis is comprised of Publications 4 and 5. These detail the synthesis of certain polyfunctionalized, cyclohexene-based chirons from L-(+)- and D-(-)-tartaric acid, respectively, and their elaboration into various natural product scaffolds. Specifically, Publication 4 describes the preparation of the aforementioned chirons from L-(+)-tartaric acid and its elaboration to the enantiomer of a key intermediate described in Publication 3 that is used to produce oxygenated analogues of (-)-galanthamine. Publication 5 further demonstrates the utility of these new chirons in total synthesis by employing the enantiomer of this chiron (prepared from D-(+)-tartaric acid) as a key intermediate in the first total synthesis of the structurally unusual natural product aspergillusol B. The final section of this thesis is comprised of Publication 6. This details work on the total synthesis of the four diastereomeric forms of the pro-angiogenic guaiacylglycerol 8-O-4ʹ-coniferyl ethers (GGCE) in an effort to establish the role stereochemistry plays on their capacities to act as pro-angiogenic agents. The syntheses feature an Evans/Seebach syn-aldol reaction utilising auxiliaries derived from either L-(+)- or D-(-)-valine. In the case of syntheses of the anti-compounds this was followed by a Mitsunobu inversion of the benzylic alcohol. The four diastereomers were assessed for their pro-angiogenic properties in a human microvascular endothelial cell tubule assay. Whilst they were all active, the compounds containing the 8S-ether linkage were the most potent.
Book Synopsis Part I. A Scalable Synthesis of (−)-rasfonin Enabled by a Convergent Enantioselective [alpha]-hydroxymethylation Strategy by : Justin Michael Niziol
Download or read book Part I. A Scalable Synthesis of (−)-rasfonin Enabled by a Convergent Enantioselective [alpha]-hydroxymethylation Strategy written by Justin Michael Niziol and published by . This book was released on 2020 with total page 352 pages. Available in PDF, EPUB and Kindle. Book excerpt: "Part I. A scalable synthesis of (-)-rasfonin enabled by a convergent enantioselective [alpha]-hydroxymethylation strategy. A scalable total synthesis of (-)-rasfonin, a potent antitumor agent, has been achieved. The synthetic strategy features a highly convergent approach based on a single protocol construction of both molecular hemispheres via catalytic enantioselective a-hydroxymethylation of simple aliphatic aldehydes. The described route has been successful in near-gram quantities of the natural product and serves as the first synthetic strategy to provide sufficient material for broad biological testing. With a keen focus on efficiency, atom economy, cost, and overall yield, the synthetic route described herein is certainly the shortest and most effective way currently described to synthesize significant quantities of (-)-rasfonin. Part II. Studies towards the total synthesis of FK-506. The synthesis of advanced intermediates towards the total synthesis of FK-506 is described herein. FK-506 has been an interesting synthetic target for some time, as it is not only structurally complex, but also a highly potent immunosuppressant. The purpose of the synthesis is to provide FK-506 in its natural form, as well as provide the option for late-stage functionalization in order to manipulate its level of toxicity. Our synthesis towards FK-506 is highly convergent, relying on the synthesis and combination of 4 subunits. Using a modified Julia olefination reaction, the major subunits of FK-506 have been successfully coupled to provide highly advanced structures. The following work also shows the improvement in yield, scalability, and simplicity of numerous reactions in the multiple routes towards the target molecule."--Pages ix-x.
Book Synopsis Efforts Toward an Oxa-conjugate Addition Based Approach to (+)-Neopeltolide Synthesis by : Taylor P. A. Hari
Download or read book Efforts Toward an Oxa-conjugate Addition Based Approach to (+)-Neopeltolide Synthesis written by Taylor P. A. Hari and published by . This book was released on 2012 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: (+)-Neopeltolide is a highly potent marine polyketide natural product with activity against multiple cancer cell lines in vitro. The nanomolar range of antifungal and anticancer cytotoxicity in this tetrahydropyran (THP)-containing polyketide, combined with its limited natural supply, has led to several syntheses. In this study, the feasibility of an oxa-Michael conjugate addition route to cis-2,6-THP rings is examined through the efforts toward a total synthesis of the macrocyclic core of (+)-neopeltolide using a highly convergent route. This study is based on the successful preliminary results with a simple 14-member ring model system and the synthesis of the key aldehyde intermediate shown below. The highlighted transformation of this synthesis will be a transannular oxa-conjugate addition to generate the cis-2,6-tetrahydropyran ring system. This route also highlights a highly convergent Wittig coupling to generate the full carbon framework of (+)-neopeltolide. One of the key goals of this project is to compare this synthesis with a chemo-enzymatic total synthesis that relies on chemistry catalyzed by polyketide synthase enzymes in the late stage of the synthesis.
Book Synopsis Total Synthesis of Blennolide C and Related C4a Functionalized Tetrahydroxanthenones by : Emilie M. C. Gérard
Download or read book Total Synthesis of Blennolide C and Related C4a Functionalized Tetrahydroxanthenones written by Emilie M. C. Gérard and published by . This book was released on 2009 with total page 175 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Progress Towards the Total Synthesis of Steroidal Natural Products Clionastatins A and B by : Samuel Steucek Tartakoff
Download or read book Progress Towards the Total Synthesis of Steroidal Natural Products Clionastatins A and B written by Samuel Steucek Tartakoff and published by . This book was released on 2015 with total page 348 pages. Available in PDF, EPUB and Kindle. Book excerpt: A total synthesis of naturally occurring polychlorinated steroids, clionastatins A and B, was undertaken. Efforts were first directed at the synthesis of a truncated tricyclic steroid core and multiple synthetic routes were developed, many of which featured a Diels-Alder reaction. Ultimately, these efforts culminated in the successful synthesis of the clionastatin core. Efforts then focused on development of a bicyclic diene that would allow us to apply the successful Diels-Alder route to the synthesis of a tetracycle, which could be elaborated into clionastatin A. While a suitable diene was made and a tetracyclic cycloadduct was synthesized, the undesired stereochemistry of that cycloadduct suggests that an alternative route to the clionastatins may be necessary.
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