The Design, Synthesis, and Biological Evaluation of Selective Histone Deacetylase (HDAC) Inhibitors PDF Download
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Author: Joseph Knoff
Publisher:
ISBN:
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: Joseph Knoff
Publisher:
ISBN:
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: 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: 余兆武
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ISBN:
Category :
Languages : en
Pages :
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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: Paolo Di Fruscia
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ISBN:
Category :
Languages : en
Pages :
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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.
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Category :
Languages : en
Pages :
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Author: Katharina Stenzel
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Category :
Languages : en
Pages :
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Author: Anthony Palermo
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Category :
Languages : en
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"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." --
Author: José A. Restituyo
Publisher:
ISBN:
Category : Genetic regulation
Languages : en
Pages : 214
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