Download or read book Design Synthesis and Biological Evaluation of Selective Estrogen Receptor Modulator histone Deacetylase Inhibitor Hybrid Drug Molecules written by Yufei Wang and published by . This book was released on 2020 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "The prognosis for those diagnosed with breast cancer has dramatically improved since the 1980’s, primarily due to improved diagnostic and treatment methods. One such treatment is a class of drugs called selective estrogen receptor modulators (SERMs). SERMs are a popular treatment option for breast cancer, commonly employed as adjuvant therapy. Prototypical examples of SERMs are tamoxifen and raloxifene. Despite their widespread success, breast cancers can often develop resistance to SERMs. As a result, other biological targets which may mitigate this resistance have been identified. Recent interest in the field has arisen around histone deacetylases (HDACs), which are a class of enzymes that have been implicated in promoting resistance in breast carcinoma. Studies have demonstrated the combination treatment of SERMs and HDAC inhibitors (HDACi’s) elicits a cooperative effect in enhancing cytotoxicity and resensitizing resistant breast cancers. In an effort to maximize the cooperative effects of SERMs and HDACi’s, the project detailed in this thesis describes the design, synthesis, and biological evaluation of a series of hybrid raloxifene/HDACi molecules that combine the pharmacophores of both drug classes. Previous work by the Gleason laboratory found tamoxifen/HDACi hybrids to exhibit potent biological activity, but further exploration of these would be laborious due to their inherent instability. As a result, a synthesis of raloxifene/HDACi hybrids was developed. Significant synthetic challenges resulted from the comparatively electron-deficient nature of key intermediates, making known methods used for raloxifene inapplicable towards these targets. After notable route scouting and reaction optimization, these challenges were resolved and a small library of seven hybrid drug molecules were successfully synthesized and purified prior to biological evaluation. Fluorogenic HDACi assays determined the IC50 values of the raloxifene/HDACi hybrids against HDAC1 and HDAC6. All hybrids demonstrated sub-micromolar IC50 values for HDAC1. For HDAC6, one hybrid showed low micromolar potency for HDAC6, while all others had sub-micromolar values. Generally, carbon-linked hybrids were more potent than oxygen-linked hybrids against HDAC1, while the reverse was true for HDAC6.Preliminary biological assays performed by the Mader lab at the Université de Montréal demonstrate all hybrids antagonize the ER at a low micromolar dose, both in the presence and in the absence of E2. A more conclusive result of the SERM/HDACi hybrids can be drawn once further biological testing has been completed by the Mader lab"--

Download or read book Design Synthesis and Biological Evaluation of Selective Estrogen Receptor Modulator histone Deacetylase Inhibitor Hybrid Molecules written by Anthony Palermo and published by . This book was released on 2018 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Therapeutic options for the treatment of breast cancer have long been limited to invasive surgical procedures, or chemo- and radiotherapies that are plagued with detrimental side-effects. Selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, are a large subclass of molecules that have been used in adjuvant therapies and have provided substantial clinical benefits as preventative and long-term treatment options. Despite their success, endocrine therapies face several challenges including the development of endocrine resistance and, in the case of tamoxifen, the increased risk of endometrial cancer. Recent studies have shown that dual administration of SERMS and histone deacetylase inhibitors (HDACis) in vitro have led to cooperative effects such as increased drug potency, the resensitization of endocrine resistant cell lines, and an overall decrease in the risk of endometrial cancer development. In an effort to combine the cooperative effects of SERMs and HDACis, this project focuses on the design, synthesis, and biological evaluation of a series of hybrid SERM/HDACi molecules that combine the pharmacophores of both drug classes.The design of the hybrids was based on previous research projects investigating hybrid antiestrogens within the Gleason group. This project expanded on a promising subsetof 4-OHT based hybrids and began with in silico screening of a virtual library using the FORECASTOR docking platform. Seven compounds were chosen for synthesis and a previously devised route was unsuccessfully attempted using a McMurry cross-coupling as the key step. An alternate route to the triphenylethylene scaffold is hinged on a highly convergent and modular three-component coupling reaction was designed and successfully carried out. Four hybrids were synthesized and purified by preparatory HPLC prior to biological evaluation.Fluorogenic HDACi assays to determine the hybrid affinities of HDACs 3 and 6 were carried out by the author within the Gleason lab. Three of the four hybrids showed lowmicromolar HDAC 3 potencies (IC50) and the fourth showed submicromolar potency, and suggested that increased chain-lengths led to a higher degree of HDAC inhibition. HDAC 6 inhibition results trended similar to those of HDAC 3 and three of the four hybrids showed submicromolar potencies. Cell-based bioluminescence resonance energy transfer (BRET) and luciferase transactivation assays were conducted by the Mader lab at Université de Montréal to evaluate the ER affinity and antagonism profile of the hybrids. Each hybrid exhibited full antagonism against the ER and three of the hybrids showed submicromolar IC50 values with regards to their ER affinity. MCF-7 breast cancer cell growth curves were carried out and a single hybrid outperformed 4-hydroxytamoxifen (4-OHT), tamoxifen, and endoxifen. The ER data alongside the HDACi results are suggestive of a hybrid SERM/HDACi that was capable of eliciting a cooperative antiproliferative effect against the breast cancer cell line.The final chapter of this thesis presents a brief project regarding the design of a 3-acyl-1,5-diene substrate for the organocatalytic Cope rearrangement. A novel diazepanecarboxylate organocatalyst capable of catalyzing the Cope rearrangement of hindered aldehydes via iminium catalysis was recently reported by the Gleason group. DFT calculations suggested that iminium ion formation of 3-acyl-1,5-dienes would accelerate the Cope rearrangement. The final 3-acyl-1,5-diene substrate was shown to be capable of undergoing the Cope rearrangement under simple thermal conditions and future work will investigate the potential for organocatalytic rate acceleration." --

Download or read book Design Synthesis and Evaluation of Selective Estrogen Receptor Modulator histone Deacetylase Inhibitor Merged Bifunctional Ligands written by Benjamin Williams and published by . This book was released on 2014 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Breast cancer remains one of the most persistent threats to women's health in the Western world. The selective estrogen receptor modulator (SERM) tamoxifen is a front-line treatment for the disease, but suffers from a high rate of acquired resistance and an increased risk of endometrial cancer. As such, improved small molecule inhibitors with the ability to overcome antiestrogen resistance while limiting adverse side effects are valuable pharmaceutical targets. Histone deacetylase inhibitors (HDACi) have recently emerged as versatile anticancer agents with antiproliferative activity in breast cancer cells. Combination therapy of SERMs and HDACi has demonstrated enhanced cytotoxicity and the ability to restore tamoxifen sensitivity to antiestrogen-resistant cancer cell lines. This research project describes a novel approach to overcoming antiestrogen resistance by combining the anticancer properties and cooperative activity of SERMs and HDACi into compact, merged bifunctional ligands. Previous research by the Gleason laboratory indicated that HDACi functionality, in the form of zinc-chelating hydroxamic acids, could be integrated into the polar side chain of SERMs while maintaining antiestrogenicity at micromolar concentrations. Building from these preliminary results, a series of novel hybrid molecules was designed with zinc-binding groups incorporated into the aliphatic side chain or the triphenylethylene core structure of the active tamoxifen metabolite 4-hydroxytamoxifen (4-OHT). The resulting structures were investigated in silico using the molecular docking program FITTED. Twelve hybrid compounds were then synthesized by geminal Suzuki coupling and McMurry coupling procedures. Despite the propensity of the compounds to isomerize around the central double bond, the majority of the syntheses proceeded diastereoselectively and HPLC purification furnished the final products as a single isomer or in good diastereomeric excess. The HDAC inhibition and ER antagonism of the bifunctional molecules were evaluated in collaboration with the Mader laboratory of the Université de Montréal. Side chain-substituted hybrid compounds demonstrated good affinity for the ER binding pocket and nanomolar ER inhibitory activity. In addition, long-chain chimeric ligands possessing amide linkers exhibited significant HDAC 6 inhibition, with one compound displaying inhibitory activity at sub-micromolar concentrations. However, these side-chain substituted hybrids also exhibited substantial ER agonism in the absence of estradiol, which limited their effectiveness as antiestrogens. Conversely, a compound containing a phenyl hydroxamic acid in the aromatic core of 4-OHT acted as a full antagonist at micromolar concentrations and displayed no estrogenic behaviour. The core-substituted hybrid also exhibited modest HDAC inhibition, though it lacked the strong activity of its side chain counterparts. The synthesized SERM/HDACi molecules therefore displayed encouraging results and provided important structural insight into the future creation of bifunctional ligands.A brief side project is also described as a contribution towards the total synthesis of (R)-puraquinonic acid. The enantioselective synthesis of this natural product was previously accomplished by the Gleason group using a novel lactam auxiliary alkylation sequence to set the molecule's sole stereocenter. However, the specific rotation of the final product was opposite that expected and contradicted previous stereochemical assignments of the alkylation sequence. To address this inconsistency, a convergent stereochemical proof was completed which allowed direct comparison of alkylation products to auxiliary-based Mannich addition products that could be characterized by X-ray diffraction. The absolute stereochemistry of the sequence was thereby unambiguously assigned and strongly supported the conclusion that our group had successfully synthesized (R)-puraquinonic acid." --

Download or read book Design Synthesis and Biological Evaluation of Novel Antiestrogens written by Rodrigo Mendoza Sánchez and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Breast cancer is the most common form of cancer in women in the Western world and the second most fatal after lung cancer. Estrogens play a crucial role in normal breast development, but also contribute to mammary tumorigenesis. Estrogen signaling is mediated by intracellular estrogen receptors (ER[alpha] and ER[beta]), with ER[alpha] being a common target in breast cancer therapeutics. Two classes of competitive estrogen inhibitors have been investigated and proved to be useful for breast cancer treatment: full antiestrogens (FAE's) and selective estrogen receptor modulators (SERM's). A novel platform, FORECASTER, was developed in the Moitessier laboratory with the aim of integrating computational, medicinal and combinatorial chemistry. The successful validation of FORECASTER as a computer-aided drug design platform is described. In our quest for potent SERMs, this platform was used to build virtual combinatorial libraries and to filter and extract a highly diverse library from the NCI database. The virtual screening of a diverse library seeded with known active compounds followed by a search for analogs yielded a high enrichment factor. Moreover, the virtual screening of a designed virtual combinatorial library that included known actives resulted in a highly discriminative process. The laboratory of Dr. Sylvie Mader at University of Montreal showed that only FAE's induce a strong and fast SUMOylation of ER[alpha] in a variety of cell lines, strongly suggesting that SUMOylation is a general property related to full antiestrogenicity. A collaboration between the Gleason and Mader laboratories resulted in an SAR study of ER[alpha] ligands with different side chain lengths that revealed a specific side chain length of 15 to 19 atoms was necessary to differentiate SERM's from FAE's through the induction of SUMOylation. Histone deacetylase inhibitors (HDACi's) have emerged as a new and growing class of anticancer agents. Recent findings have shown that co-treatment of SERM's or FAE's with HDACi's can significantly decrease the growth of breast cancer cells. Inspired by the success of the vitamin D/HDACi hybrids developed within our group, and taking advantage of structural features of both kinds of molecules, we developed a new family of antiestrogen/HDACi hybrids. A first generation set of hybrids were designed by replacing the tertiary amide of FAE ICI-164,384 with three different zinc binding groups: hydroxamic acid, o-aminoanilide and N-butylhydroxamate. Both the hydroxamic acid and the o-aminoanilide hybrids displayed both antiestrogenic and HDAC inhibitory activities whereas N-butylhydroxamate hybrid displayed antiestrogenic activity but a poor HDAC inhibition profile. All hybrids inhibited MCF-7 cell proliferation and validated the proof of concept regarding the formation of this class of hybrids. However, none of the hybrids showed an improved profile compared to known antiestrogens or HDACi's. A second generation set of hybrids exploiting the same zinc binding groups with SERM- and FAE-like side chains were developed in an effort to balance the activity of our hybrids. Hydroxamic acids showed a consistent inhibition of HDAC's while displaying poor antiestrogenic activity in most cases. Ortho-amino anilides showed modest HDAC inhibition activity and only aliphatic-based o-amino-anilides behaved as antiestrogens. N-Butyl-hydroxamates showed a reduced potency to inhibit HDAC's compared to their hydroxamic acid counterparts but retained antiestrogenic behaviour. Overall, our second-generation hybrids did not show equal or improved HDAC inhibition and antiestrogenic activities relative to known antiestrogens and HDACi's. " --

Download or read book Efforts Toward the Design and Synthesis of Small Molecule Inhibitors of the Estrogen Receptor written by Laurie Lim and published by . This book was released on 2011 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The investigation and development of small molecule inhibitors for the estrogen receptor is presented. Successful interpretation of its key protein-protein interactions with several coactivators is described using computational methods. Further examination using a known set of small molecule ligands failed to predict affinity for the receptor. It was determined that a computational assessment was unfeasible for the design of new ligands. The design and synthesis of SERM-HDACi (selective estrogen receptor modulator-histone deacetylase inhibitor) multiple ligands is described in detail. Multiple ligands are a single entity created to target more than one site in the body, therefore a SERM-HDACi multiple ligand will potentially target the estrogen receptor and histone deacetylases. Docking studies were used to determine three potential SERM-HDACi hybrid candidates to be synthesized in the lab. Several synthetic routes were explored to achieve a stereoselective ...

Download or read book Design Synthesis and Biological Evaluation of Histone Deacetylase HDAC Inhibitors written by Ahmed Negmeldin and published by . This book was released on 2017 with total page 352 pages. Available in PDF, EPUB and Kindle. Book excerpt: The dual HDAC6/8 selective inhibitors can be used as lead compounds and as a chemical tool to study HDAC related cancer biology. The observed enhancement of selectivity upon modifying the linker region of the non-selective inhibitor SAHA shows that modifying current drugs, like SAHA, could lead to substantial improvement in its pharmacodynamic properties.

Download or read book Design Synthesis and Biological Evaluation of Anti cancer and Anti parasitic Histone Deacetylase Inhibitors written by Katharina Stenzel and published by . This book was released on 2017 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Finding an Ideal SERM written by Sophie G. Bender and published by . This book was released on 2020 with total page 349 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Anticancer Agents written by Qiao-Hong Chen and published by MDPI. This book was released on 2021-03-02 with total page 606 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book is a printed edition of the Special Issue entitled “Anticancer Agents: Design, Synthesis and Evaluation” that was published in Molecules. Two review articles and thirty research papers are included in the Special Issue. Three second-generation androgen receptor antagonists that have been approved by the U.S. FDA for the treatment of prostate cancer have been reviewed. Identification of mimics of protein partners as protein-protein interaction inhibitors via virtual screening has been summarized and discussed. Anticancer agents targeting various protein targets, including IGF-1R, Src, protein kinase, aromatase, HDAC, PARP, Toll-Like receptor, c-Met, PI3Kdelta, topoisomerase II, p53, and indoleamine 2,3-dioxygenase, have been explored. The analogs of three well-known tubulin-interacting natural products, paclitaxel, zampanolide, and colchicine, have been designed, synthesized, and evaluated. Several anticancer agents representing diverse chemical scaffolds were assessed in different kinds of cancer cell models. The capability of some anticancer agents to overcome the resistance to currently available drugs was also studied. In addition to looking into the in vitro ability of the anticancer agents to inhibit cancer cell proliferation, apoptosis, and cell cycle, in vivo antitumor efficacy in animal models and DFT were also investigated in some papers.

Download or read book Vitamin D written by Martin Hewison and published by Academic Press. This book was released on 2017-12-14 with total page 1268 pages. Available in PDF, EPUB and Kindle. Book excerpt: Vitamin D: Volume 2: Health, Disease and Therapeutics, Fourth Edition, authoritatively covers the evidence for new roles for vitamin D, ranging from cardiovascular disease, to cancer, diabetes, inflammatory bowel disease, multiple sclerosis and renal disease. This collection represents a who’s who of vitamin D research and the coverage is appropriately broad, drawing in internal medicine, orthopedics, oncology and immunology. Clinical researchers will gain a strong understanding of the molecular basis for a particular area of focus. Offers a comprehensive reference, ranging from basic bone biology, to biochemistry, to the clinical diagnostic and management implications of vitamin D Saves researchers and clinicians time in quickly accessing the very latest details on the diverse scientific and clinical aspects of Vitamin D, as opposed to searching through thousands of journal articles Chapter authors include the most prominent and well-published names in the field Targets chemistry, metabolism and circulation, mechanisms of action, mineral and bone homeostasis and vitamin D deficiency Presents a clinical focus on disorders, analogs, cancer, immunity, inflammation, disease and therapeutic applications

Download or read book Design and Synthesis of Organic Molecules as Antineoplastic Agents written by Carla Boga and published by MDPI. This book was released on 2020-12-28 with total page 210 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book is a collection of Special Issue articles with a multidisciplinary character, linking biology, medicine, and synthetic organic chemistry. The synthesis and full characterization of about 180 novel organic species, both of natural and synthetic origin, often designed with the support of in-silico studies, are set out in the book. In several articles, molecular hybridization approaches have been used as a successful multi-target strategy for the design and development of novel antitumor agents. Rigorous and careful biochemical studies ranging from in-vitro experiments on a plethora of human-cancer derived cell lines to in-vivo and ex-vivo studies allowed the authors to identify the molecular targets and gain useful information on structure–activity relationships (SAR). For this reason, this collection should interest many readers from different scientific fields.

Download or read book Microwaves in Organic and Medicinal Chemistry written by C. Oliver Kappe and published by John Wiley & Sons. This book was released on 2006-05-12 with total page 422 pages. Available in PDF, EPUB and Kindle. Book excerpt: The authors of this guide are experts on the use of microwaves for drug synthesis as well as having much experience in teaching courses held under the auspices of the American Chemical Society and the IUPAC. In this handy source of information for any practicing synthetic chemist they focus on common reaction types in medicinal chemistry, including solid-phase and combinatorial methods. They consider the underlying theory, latest developments in microwave applications and include a variety of examples from recent literature, as well as less common applications that are equally relevant for organic and medicinal chemists. An indispensable reference for researchers with an affinity to modern methods.

Download or read book Estrogen Receptor and Breast Cancer written by Xiaoting Zhang and published by Humana Press. This book was released on 2019-11-08 with total page 432 pages. Available in PDF, EPUB and Kindle. Book excerpt: The discovery of ER by Dr. Elwood Jensen exactly 60 years ago has not only led to the birth of a whole new vital nuclear receptor research field but also made a rapid, direct and lasting impact on the treatment and prevention of breast cancer. Since that landmark discovery, tremendous progress has been made in our understanding of the molecular functions of ER and development of targeted therapies against ER pathways for breast cancer treatment. However, there is currently no book available addressing these discoveries and recent advancement in a historical and systematic fashion. This book is intended to provide comprehensive, most up-to-date information on the history and recent advancement of ER and breast cancer by world renowned leaders in the field. These chapters include the history of the discovery of ER; physiological and pathological roles of ER; recent discovery of ER cistrome, transcriptome and its regulation of noncoding RNAs such as microRNAs and enhancer RNAs in breast cancer; development and clinical practices of the first targeted therapy Tamoxifen and other antiestrogens for breast cancer treatment; structural basis of ER and antiestrogen actions; molecular insights into endocrine resistance; the role of ER mutants, ER-beta and environmental estrogens in breast cancer; and emerging state-of-the-art therapeutic approaches currently in development to overcome treatment resistance and future perspectives. The book will provide undergraduate and graduate students, basic scientists and clinical cancer researchers, residents, fellows, as well as clinicians, oncology educators and the general public a thorough and authoritative review of these exciting topics.

Download or read book Chemical Epigenetics written by Antonello Mai and published by Springer Nature. This book was released on 2020-03-31 with total page 569 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book presents an authoritative review of the most significant findings about all the epigenetic targets (writers, readers, and erasers) and their implication in physiology and pathology. The book also covers the design, synthesis and biological validation of epigenetic chemical modulators, which can be useful as novel chemotherapeutic agents. Particular attention is given to the chemical mechanisms of action of these molecules and to the drug discovery prose which allows their identification. This book will appeal to students who want to know the extensive progresses made by epigenetics (targets and modulators) in the last years from the beginning, and to specialized scientists who need an instrument to quickly search and check historical and/or updated notices about epigenetics.

Download or read book How Tobacco Smoke Causes Disease written by United States. Public Health Service. Office of the Surgeon General and published by . This book was released on 2010 with total page 728 pages. Available in PDF, EPUB and Kindle. Book excerpt: This report considers the biological and behavioral mechanisms that may underlie the pathogenicity of tobacco smoke. Many Surgeon General's reports have considered research findings on mechanisms in assessing the biological plausibility of associations observed in epidemiologic studies. Mechanisms of disease are important because they may provide plausibility, which is one of the guideline criteria for assessing evidence on causation. This report specifically reviews the evidence on the potential mechanisms by which smoking causes diseases and considers whether a mechanism is likely to be operative in the production of human disease by tobacco smoke. This evidence is relevant to understanding how smoking causes disease, to identifying those who may be particularly susceptible, and to assessing the potential risks of tobacco products.

Download or read book Molecular Epidemiology written by Paul A. Schulte and published by Academic Press. This book was released on 2012-12-02 with total page 609 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book will serve as a primer for both laboratory and field scientists who are shaping the emerging field of molecular epidemiology. Molecular epidemiology utilizes the same paradigm as traditional epidemiology but uses biological markers to identify exposure, disease or susceptibility. Schulte and Perera present the epidemiologic methods pertinent to biological markers. The book is also designed to enumerate the considerations necessary for valid field research and provide a resource on the salient and subtle features of biological indicators.

Download or read book 2 Oxoglutarate Dependent Oxygenases written by Christopher J Schofield and published by Royal Society of Chemistry. This book was released on 2015-05-06 with total page 508 pages. Available in PDF, EPUB and Kindle. Book excerpt: Since the discovery of the first examples of 2-oxoglutarate-dependent oxygenase-catalysed reactions in the 1960s, a remarkably broad diversity of alternate reactions and substrates has been revealed, and extensive advances have been achieved in our understanding of the structures and catalytic mechanisms. These enzymes are important agrochemical targets and are being pursued as therapeutic targets for a wide range of diseases including cancer and anemia. This book provides a central source of information that summarizes the key features of the essential group of 2-oxoglutarate-dependent dioxygenases and related enzymes. Given the numerous recent advances and biomedical interest in the field, this book aims to unite the latest research for those already working in the field as well as to provide an introduction for those newly approaching the topic, and for those interested in translating the basic science into medicinal and agricultural benefits. The book begins with four broad chapters that highlight critical aspects, including an overview of possible catalytic reactions, structures and mechanisms. The following seventeen chapters focus on carefully selected topics, each written by leading experts in the area. Readers will find explanations of rapidly evolving research, from the chemistry of isopenicillin N synthase to the oxidation mechanism of 5-methylcytosine in DNA by ten-eleven-translocase oxygenases.