Download Free Histone Deacetylase Inhibitors For Selective Anti Cancer Therapeutics Book in PDF and EPUB Free Download. You can read online Histone Deacetylase Inhibitors For Selective Anti Cancer Therapeutics and write the review.

This book reviews the latest developments in the design, synthesis, and molecular mechanism of action of Histone Deacetylase (HDAC) inhibitors in the context of potential cancer therapy. HDAC inhibitors are emerging as promising anticancer drug molecules that promote growth arrest, differentiation and apoptosis of cancer cells with tumor selective toxicity. The book begins with an overview of various epigenetic modifying enzymes that are involved in cancer transition and progression; before exploring the potential of HDACs in cancer treatment. It provides a classification of HDAC inhibitors based on their structural attributes, and addresses HDAC-induced cytotoxicity.. Lastly, it discusses and assesses the rationale behind therapies that combine HDAC inhibitors with other anticancer agents to treat solid tumors. Given its scope, it offers a valuable resource for all researchers, clinicians, and students working in formulation, drug discovery, oncology, and personalized medicine.
Activating mutations of ras genes are frequently found in human cancers. Since Ras proteins and their functions play an important role in tumorigenesis, it is important to develop targeted anticancer therapeutics against Ras-related human cancers. We observed that in addition to tumorigenic ability, oncogenic H-Ras possesses a novel proapoptotic ability to facilitate the induction of apoptosis by histone deacetylase inhibitors (HDACIs), such as FR901228 and trichostatin A (TSA). HDACIs make up a new class of structurally diverse anticancer agents and have been shown to exhibit antimetastatic and antiangiogenic activities toward malignantly transformed cells. We detected that expression of oncogenic H-Ras potentiated intracellular reactive oxygen species (ROS) in human and mouse cells to enhance HDACI-induced ROS, thereby contributing to the induction of selective apoptosis and caspase activation. The first part (Part I) of this dissertation focuses on the understanding of Ras proteins, their role in normal and transformed cell physiology, and current treatment options against Ras-related human cancers, as well as the role of HDACIs and ROS in anticancer therapeutics. The next three parts (Part II-IV) focus on revealing the mechanisms for the novel pro-apoptotic ability of oncogenic H-Ras that allow HDACIs to induce selective apoptosis of the oncogenic H-Ras expressing cells. Results in Part II & III verify the pro-apoptotic activity of oncogenic H-Ras in the increased susceptibility of human cancer cells to HDACIs. The caspase pathways, the B-Raf and extracellular signal regulated kinase pathway, p21[superscript Cip]1 and p27[superscript Kip]1, and core histone contents are regulated differently by FR901228 in oncogenic H-Ras-expressed cells than their counterparts in parental cells, contributing to the increased susceptibility to the induction of selective apoptosis. Results in Part IV describe the role of reactive oxygen species in the pro-apoptotic ability of oncogenic H-Ras to enhance the cell susceptibility to HDACIs. Intracellular ROS was cooperatively up-regulated by oncogenc H-Ras and HDACI treatment to induce selective apoptosis of oncogenic H-Ras-expressing cells. The last section (Part V) summarizes the findings with their importance and discusses future directions.
Provides information on the exciting and fast-moving field of cancer research.
Despite major advances in cancer treatment strategies in recent years, significant limitations still remain. Selectively targeting cancer cells without affecting normal cells is a challenging task. Epigenetic modifications such as histone acetylation and methylation seem to play a crucial role in cancer pathophysiology. Histone acetylation is the most extensively studied epigenetic modification. Two groups of enzymes, histone deacetylases (HDACs) and histone acetyltransferases (HATs) control the acetylation status of histones. HDAC enzymes, which are overexpressed in many cancer tissues, provide a potential target for cancer chemotherapy. Therefore, HDAC inhibitors are currently being widely investigated as anticancer agents. Most of the current HDAC inhibitors are not selective and have toxic side effects. Selective inhibition of specific HDAC isoforms to preferentially suppress the proliferation of cancer cells is a goal yet to be achieved. Largazole is a macrocyclic, depsipeptide anticancer agent isolated from a marine cyanobacterium. It is a class I selective HDAC inhibitor. The depsipeptide cap group (CG) of largazole interacts with a less conserved area of the HDACs surface and can be targeted to develop isoform-selective HDAC inhibitors. We have used molecular modeling approaches to design several new largazole analogs with modified CGs to modulate the binding interaction with the enzyme surface. We used a novel protection/deprotection protocol to synthesize these analogs. The antiproliferative activity and HDAC isoform selectivity of the synthesized analogs were evaluated. The majority of the clinically used HDAC inhibitors are hydroxamates. Poor selectivity, poor pharmacokinetics, and severe toxic side effects are major limitations in their clinical use. There is a high need to develop new HDAC inhibitors with non-hydroxamate zinc binding groups (ZBG) with superior activity and selectivity profiles. We used molecular modeling studies to design a new class of HDAC inhibitors containing a 1-(1H-imidazol-2-yl)ethan-1-one (HIE) moiety as the ZBG. A structure-activity relationship (SAR) study was conducted by synthesizing a series of HIEs with different structural properties. Some of these compounds showed promising cell growth inhibition with GI50s in the upper nanomolar to lower micromolar range. A representative HIE compound inhibited purified HDAC enzymes with single digit micromolar IC50, with no selectivity preference among different HDAC isoforms. Replacing the ZBG with other groups such as 1-(thiazol-2-yl)ethan-1-one (TE), 1-(pyrimidin-2-yl)ethan-1-one (PE), and 1-(2-hydroxyphenyl)ethan-1-one (HPE) did not result in active compounds.
Natural HDAC Inhibitors for Epigenetic Combating of Cancer Progression deals only with HDAC inhibitors from natural origins including bacteria, fungi, marine organisms and, notably, from diverse plant sources. This book is unique in the sense that it is the only book that discusses wholly and solely HDAC inhibitors of natural origin in the context of cancer chemotherapy. Another peculiar feature of this book is that it debates futuristic nanotechnology approaches for escalating the aqueous solubility, cancer cell uptake, bioavailability and other favourable pharmacological parameters, including the cytotoxicity of natural HDAC inhibitors against cancer cells. The major features of this book encompass General compendium of HDAC inhibitors with deep emphasis on the toxicity issues of synthetic HDAC inhibitors Various groups of natural HDAC inhibitors, their representatives and premier sources Cyclic tetrapeptides of natural origin and their importance as cancer chemotherapeutic agents Hydroxamates and depsipeptides from natural sources and their promising role in cancer therapy Natural flavonoids, their HDAC inhibitory tendency and marvellous anticancer activity Non-flavonoid natural HDAC inhibitors and their pleasing cytotoxic effects towards cancer models Combined therapy involving natural flavonoids with other anticancer molecules for synergistic and additive benefits against cancer models Non-flavonoid HDAC inhibitors and conventional drugs in collaborative mode against aggressive malignancies Nanotechnology-based delivery of natural HDAC inhibitors for greater therapeutic efficacy over traditional combinatorial therapy This book is highly beneficial to university professors and research scholars working on epigenetic therapeutics in general, and natural HDAC inhibitors in particular. This book is equally important to medical oncologists, biochemistry as well as pharmacy candidates and students of master's and undergraduate level with a desire to do a doctorate on HDACs, natural HDAC inhibitors, HDAC inhibitor (natural)-based combinatorial chemotherapy and delivery of these inhibitors selectively to tumour sites through revolutionary nanotechnological tactics.
Advances in Anticancer Agents in Medicinal Chemistry is an exciting eBook series comprising a selection of updated articles previously published in the peer-reviewed journal Anti-Cancer Agents in Medicinal Chemistry. The first volume gathers reviews of many classes of drugs of contemporary interest for cancer therapy and is devoted to small molecules inhibitors of various proteins involved in cancer development such as Casein kinase 2 (CK2), Protein kinase B (PKB), mTOR, Hsp90, P-glycoprotein (P-gp), Kinesin spindle protein (KSP), Cyclooxygenase 2 (COX-2), Histone deacetylase enzymes (HDACs) and Topoisomerase I. Advances in Anticancer Agents in Medicinal Chemistry will be of particular interest to readers interested in anti cancer drug therapy as the series provides additional value to scientific research by entailing an approach of bringing relevant reviews up-to-date and thus more valuable for reference purposes.
There have been tremendous advances in our understanding of molecular and tumor biology during the past few years. In the field of cancer therapeutics, it is expected that cytotoxic drug approaches will be gradually replaced with treatments based on biological targeted approaches. Hopefully these new targeted therapies will significantly increase efficacy and lack the devastating and troublesome side effects elicited by cytotoxic chemotherapy. This volume is the first book to cover the general topic of targeted cancer therapy. It presents a range of targets such as tumor angiogenesis, cell cycle control and cell signalling, COX-2, apoptosis/cell survival, invasion and metastasis and approaches like kinase inhibitors, antisense, and antibody-based therapeutics. The emphasis is on preclinical development, including target validation, development of biomarkers, strategies for combination approaches, and development of resistance. The particular challenges involved in translating these data to clinical application are discussed. This volume should be of broad general interest to researchers and clinicians involved in cancer therapy as well as other scientists interested in current strategies for cancer treatment.
Histone deacetylase (HDAC) proteins have become an important target for the treatment of several diseases including cancers, neurodegenerative diseases and inflammatory diseases. Four such inhibitors are approved by the FDA as anti-cancer drugs, but unfortunately, they inhibit numerous HDAC isoforms which leads to side effects in clinical settings. In this work, we have developed multiple libraries of chemical biology tools that selectively inhibit a small number of HDAC proteins with the goal of decreasing the possible therapeutic side effects related to non-selective inhibition. With this, our strategy was to develop novel libraries of HDAC inhibitors based on two new types of metal binding groups that are not present in any of the FDA approved inhibitors. Several benzamide type HDAC inhibitors were synthesized across two projects, with the same goal of selectively inhibiting HDAC1. The synthesized compounds were tested in vitro and in cellular assays to determine isoform selectivity and toxicity to cancer cells. The compounds that displayed the highest selectivity in these two projects were the p-chloro N-(2-aminophenyl) benzamide, and the tryptophanyl aminobiphenyl amide, Bnz-3. These two compounds displayed 16.8- and 29-fold selectivity for HDAC1 over HDAC2, while being between 17- and 320-fold selective for HDAC1 over HDACs3-9. Furter validation of these findings was performed via docking analysis. A new series of compounds combining the unique findings of both libraries was proposed with extensive support from computational methods. In addition, another compound library bearing the trifluoromethyl ketone (TFMK) binding group was designed and synthesized, with preliminary findings of in vitro experiments detailed herin. The TFMK analogs of the FDA approved inhibitor SAHA made use of a modified metal binding group to promote selectivity for the lesser studied class IIa HDAC isoforms HDAC4, 5, 7, and 9. Docking studies of the TFMK SAHA analogs with modifications at the C2-, C3-, and C4- positions show promise towards promoting selective inhibition of class IIa HDAC isoforms. Both classes of inhibitors can be used lead compounds and as chemical tools to aid in the elucidation of the functions of specific HDAC isoforms as they relate to cancer biology.