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Special Issue "Modulators of Histone Acetylation: A Medicinal Chemistry Perspective"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (10 January 2018)

Special Issue Editors

Guest Editor
Dr. Dante Rotili

Department of Chemistry and Technology of Drugs, “Sapienza” University of Rome, Italy
Website | E-Mail
Interests: drug discovery; medicinal chemistry; chemical biology; radiopharmaceuticals; epigenetics
Guest Editor
Prof. Rino Ragno

Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P. le A. Moro 5, 00185 Roma, Italy
Website | E-Mail
Interests: design and synthesis of bioactive compounds; development of new 3-D QSAR procedures and their application in drug design; molecular docking in drug design; extraction of bioactive compounds from natural sources

Special Issue Information

Dear Colleagues,

Histone protein modifications are key epigenetic regulatory marks that play pivotal roles in many crucial cellular events. In addition to a precisely balanced action of acetyltransferases (‘writers’) and deacetylases (‘erasers’), distinct effector proteins (‘readers’) recognize acetylated histones in a way that depends on the neighbouring amino-acid sequence and acetylation state. Dysregulation of histone acetylation state has been implicated in several cancer and non-cancer diseases, including inflammatory, neurological and metabolic disorders. Therefore, histone (de)acetylation processes are now more and more being considered as potential therapeutic targets.

This Special Issue aims to highlight recent efforts on the medicinal chemistry development of histone acetylation modulators and wants to put a special focus on innovative medicinal chemistry and chemical biology approaches for identifying second generation, highly potent and selective modulators of histone acetylation writers, erasers and readers with particular emphasis on their therapeutic potential.

We welcome original articles and short communications as well as a limited number of review articles on novel modulators of protein targets involved in histone acetylation. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Prof. Dr. Rino  Ragno
Dr. Dante Rotili
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Histone protein (de)acetylation
  • Bromodomains
  • Medicinal Chemistry
  • Epigenetics

Published Papers (4 papers)

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Research

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Open AccessFeature PaperArticle A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing
Molecules 2018, 23(3), 566; https://doi.org/10.3390/molecules23030566
Received: 30 January 2018 / Revised: 23 February 2018 / Accepted: 28 February 2018 / Published: 2 March 2018
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Abstract
A promising means in the search of new small molecules for the treatment of schistosomiasis (amongst other parasitic ailments) is by targeting the parasitic epigenome. In the present study, a docking based virtual screening procedure using the crystal structure of histone deacetylase 8
[...] Read more.
A promising means in the search of new small molecules for the treatment of schistosomiasis (amongst other parasitic ailments) is by targeting the parasitic epigenome. In the present study, a docking based virtual screening procedure using the crystal structure of histone deacetylase 8 from Schistosoma mansoni (smHDAC8) was designed. From the developed screening protocol, we were able to identify eight novel N-(2,5-dioxopyrrolidin-3-yl)-n-alkylhydroxamate derivatives as smHDAC8 inhibitors with IC50 values ranging from 4.4–20.3 µM against smHDAC8. These newly identified inhibitors were further tested against human histone deacetylases (hsHDAC1, 6 and 8), and were found also to be exerting interesting activity against them. In silico prediction of the docking pose of the compounds was confirmed by the resolved crystal structure of one of the identified hits. This confirmed these compounds were able to chelate the catalytic zinc ion in a bidentate fashion, whilst showing an inverted binding mode of the hydroxamate group when compared to the reported smHDAC8/hydroxamates crystal structures. Therefore, they can be considered as new potential scaffold for the development of new smHDAC8 inhibitors by further investigation of their structure–activity relationship. Full article
(This article belongs to the Special Issue Modulators of Histone Acetylation: A Medicinal Chemistry Perspective)
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Open AccessArticle The Fungal Metabolite Eurochevalierine, a Sequiterpene Alkaloid, Displays Anti-Cancer Properties through Selective Sirtuin 1/2 Inhibition
Molecules 2018, 23(2), 333; https://doi.org/10.3390/molecules23020333
Received: 12 January 2018 / Revised: 29 January 2018 / Accepted: 31 January 2018 / Published: 5 February 2018
Cited by 1 | PDF Full-text (2603 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
NAD+-dependent histone deacetylases (sirtuins) are implicated in cellular processes such as proliferation, DNA repair, and apoptosis by regulating gene expression and the functions of numerous proteins. Due to their key role in cells, the discovery of small molecule sirtuin modulators has
[...] Read more.
NAD+-dependent histone deacetylases (sirtuins) are implicated in cellular processes such as proliferation, DNA repair, and apoptosis by regulating gene expression and the functions of numerous proteins. Due to their key role in cells, the discovery of small molecule sirtuin modulators has been of significant interest for diverse therapeutic applications. In particular, it has been shown that inhibition of sirtuin 1 and 2 activities is beneficial for cancer treatment. Here, we demonstrate that the fungal metabolite eurochevalierine from the fungus Neosartorya pseudofischeri inhibits sirtuin 1 and 2 activities (IC50 about 10 µM) without affecting sirtuin 3 activity. The binding modes of the eurochevalierine for sirtuin 1 and 2 have been identified through computational docking analyses. Accordingly, this sequiterpene alkaloid induces histone H4 and α-tubulin acetylation in various cancer cell models in which it induces strong cytostatic effects without affecting significantly the viability of healthy PBMCs. Importantly, eurochevalierine targets preferentially cancer cell proliferation (selectivity factor ≫ 7), as normal human primary CD34+ stem/progenitor cells were less affected by the treatment. Finally, eurochevalierine displays suitable drug-likeness parameters and therefore represent a promising scaffold for lead molecule optimization to study the mechanism and biological roles of sirtuins and potentially a basis for development into therapeutics. Full article
(This article belongs to the Special Issue Modulators of Histone Acetylation: A Medicinal Chemistry Perspective)
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Graphical abstract

Open AccessFeature PaperArticle Carbamates as Potential Prodrugs and a New Warhead for HDAC Inhibition
Molecules 2018, 23(2), 321; https://doi.org/10.3390/molecules23020321
Received: 10 January 2018 / Revised: 25 January 2018 / Accepted: 31 January 2018 / Published: 2 February 2018
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Abstract
We designed and synthesized carbamates of the clinically-approved HDAC (histone deacetylase) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) in order to validate our previously-proposed hypothesis that these carbamates might serve as prodrugs for hydroxamic acid containing HDAC inhibitors. Biochemical assays proved our new compounds
[...] Read more.
We designed and synthesized carbamates of the clinically-approved HDAC (histone deacetylase) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) in order to validate our previously-proposed hypothesis that these carbamates might serve as prodrugs for hydroxamic acid containing HDAC inhibitors. Biochemical assays proved our new compounds to be potent inhibitors of histone deacetylases in vitro, and they also showed antiproliferative effects in leukemic cells. These results, as well as stability analysis led to the suggestion that the intact carbamates are inhibitors of histone deacetylases themselves, representing a new zinc-binding warhead in HDAC inhibitor design. This suggestion was further supported by the synthesis and evaluation of a carbamate derivative of the HDAC6-selective inhibitor bufexamac. Full article
(This article belongs to the Special Issue Modulators of Histone Acetylation: A Medicinal Chemistry Perspective)
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Review

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Open AccessReview The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors
Molecules 2018, 23(3), 551; https://doi.org/10.3390/molecules23030551
Received: 29 January 2018 / Revised: 21 February 2018 / Accepted: 27 February 2018 / Published: 2 March 2018
Cited by 1 | PDF Full-text (2941 KB) | HTML Full-text | XML Full-text
Abstract
Histone deacetylases (HDACs) are epigenetic drug targets that have gained major scientific attention. Inhibition of these important regulatory enzymes is used to treat cancer, and has the potential to treat a host of other diseases. However, currently marketed HDAC inhibitors lack selectivity for
[...] Read more.
Histone deacetylases (HDACs) are epigenetic drug targets that have gained major scientific attention. Inhibition of these important regulatory enzymes is used to treat cancer, and has the potential to treat a host of other diseases. However, currently marketed HDAC inhibitors lack selectivity for the various HDAC isoenzymes. Several studies have shown that HDAC3, in particular, plays an important role in inflammation and degenerative neurological diseases, but the development of selective HDAC3 inhibitors has been challenging. This review provides an up-to-date overview of selective HDAC3 inhibitors, and aims to support the development of novel HDAC3 inhibitors in the future. Full article
(This article belongs to the Special Issue Modulators of Histone Acetylation: A Medicinal Chemistry Perspective)
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