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Modulators of Histone Acetylation: A Medicinal Chemistry Perspective

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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) | Viewed by 23811

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Special Issue Editors

Prof. Dr. Dante Rotili

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Guest Editor

Department of Chemistry and Technology of Drugs, “Sapienza” University of Rome, 00185 Roma, Italy
Interests: drug discovery; epigenetics; medicinal chemistry; chemical biology; radiopharmaceuticals
Special Issues, Collections and Topics in MDPI journals

Dr. Rino Ragno

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Guest Editor

Rome Center for Molecular Design, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P. le A. Moro 5, 00185 Roma, Italy
Interests: medicinal chemistry; computational chemistry; 3D-QSAR; machine learning; drug design
Special Issues, Collections and Topics in MDPI journals

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 submissions that pass pre-check are 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 semimonthly 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 2700 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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14 pages, 4448 KiB

Open AccessFeature PaperArticle

A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing

by Conrad V. Simoben, Dina Robaa, Alokta Chakrabarti, Karin Schmidtkunz, Martin Marek, Julien Lancelot, Srinivasaraghavan Kannan, Jelena Melesina, Tajith B. Shaik, Raymond J. Pierce, Christophe Romier, Manfred Jung and Wolfgang Sippl

Molecules 2018, 23(3), 566; https://doi.org/10.3390/molecules23030566 - 02 Mar 2018

Cited by 32 | Viewed by 6226

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 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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14 pages, 2603 KiB

Open AccessArticle

The Fungal Metabolite Eurochevalierine, a Sequiterpene Alkaloid, Displays Anti-Cancer Properties through Selective Sirtuin 1/2 Inhibition

by Michael Schnekenburger, Véronique Mathieu, Florence Lefranc, Jun Young Jang, Marco Masi, Anake Kijjoa, Antonio Evidente, Hyun-Jung Kim, Robert Kiss, Mario Dicato, Byung Woo Han and Marc Diederich

Molecules 2018, 23(2), 333; https://doi.org/10.3390/molecules23020333 - 05 Feb 2018

Cited by 12 | Viewed by 4213

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 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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14 pages, 2886 KiB

Open AccessFeature PaperArticle

Carbamates as Potential Prodrugs and a New Warhead for HDAC Inhibition

by Kristina King, Alexander-Thomas Hauser, Jelena Melesina, Wolfgang Sippl and Manfred Jung

Molecules 2018, 23(2), 321; https://doi.org/10.3390/molecules23020321 - 02 Feb 2018

Cited by 7 | Viewed by 6339

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 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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13 pages, 2941 KiB

Open AccessReview

The Process and Strategy for Developing Selective Histone Deacetylase 3 Inhibitors

by Fangyuan Cao, Martijn R. H. Zwinderman and Frank J. Dekker

Molecules 2018, 23(3), 551; https://doi.org/10.3390/molecules23030551 - 02 Mar 2018

Cited by 42 | Viewed by 6381

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 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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