Design, Synthesis and Biological Evaluation of Anti-Cancer and Anti-Parasitic Histone Deacetylase Inhibitors PDF Download
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Author: Katharina Stenzel
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Category :
Languages : en
Pages :
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Author: Katharina Stenzel
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Category :
Languages : en
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Author: Ayad Abed Ali Chiad Al-Hamashi
Publisher:
ISBN:
Category :
Languages : en
Pages : 305
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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.
Author: Joseph Knoff
Publisher:
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Category : Chemistry, Organic
Languages : en
Pages : 0
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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.
Author: Qiao-Hong Chen
Publisher: MDPI
ISBN: 3036501401
Category : Business & Economics
Languages : en
Pages : 606
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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.
Author: Ahmed Negmeldin
Publisher:
ISBN:
Category : Biochemistry
Languages : en
Pages : 352
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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.
Author: Abdulateef Alqahtani
Publisher:
ISBN:
Category :
Languages : en
Pages : 95
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Cancer is the second leading cause of death in the United States of America and the entire world and the disease burden is exacerbated due to resistance to drugs that are currently in clinical use. Histone deacetylase (HDAC) enzymes are highly expressed in cancer cells and HDACs are considered viable targets for drug intervention. HDACs cleave the acetyl groups from acetylated lysine side chains of proteins and modulate crucial cellular processes including gene expression. Four HDAC inhibitors (HDACi) have been approved by the US FDA as anticancer drugs for clinical use, but these drugs have numerous side effects due to low selectivity. This study presents an attempt to develop selective HDAC inhibitors using 1-(1H-imidazol-2-yl) ethan-1-one moiety as a novel metal-binding group as possible alternative to current cancer drug treatment options. In this study, molecular modeling studies were carried out using crystal models of two different HDAC isoforms and HDLP to formulate novel HDAC inhibitors that have high selectivity. The designed analogs, 14a-g were synthesized and evaluated for biological activity. The compounds were tested for anti-proliferative activity in the NCI 60 cell lines assay. Compound 14a showed significant cell growth inhibition at 10 μM concentration with 87% mean cell growth inhibition. This compound was further tested in the dose response assay. It showed anti-proliferative activity in micro molar range against most of the cell lines while four leukemia cell lines were sensitive at sub-micro molar concentration of compound. Data from dose response assay showed that the activity improved significantly when a trifluoromethyl group is installed at the paraposition of the phenyl ring cap group and with N-methylation of the imidazole ring According to docking studies of all seven compounds 14a-g on HDLP, compounds with N-methyl imidazole rings 14a-d showed flipping of the molecule in the HDAC active site, the acetamide oxygen binding to zinc ion with a high glide score instead of the ketoimidazole moiety. This is an important observation as the methylation at this position may be used to alter and modulate the pharmacokinetic and selectivity properties of the compounds for further development as anticancer agents. Compound 14c showed anticancer activity against Hela cells at 10 μM concentration, and anti-inflammatory activity on microglial cells at sub-micro molar concentration. Although the results of the preliminary studies for anti-inflammatory activity were promising, additional biological studies are needed to validate and confirm these results.
Author: José A. Restituyo
Publisher:
ISBN:
Category : Genetic regulation
Languages : en
Pages : 214
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Author: Yufei Wang
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Category :
Languages : en
Pages :
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"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"--
Author: 余兆武
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Category :
Languages : en
Pages :
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