Publications by authors named "Johanna Senger"

15 Publications

  • Page 1 of 1

Harnessing the Role of HDAC6 in Idiopathic Pulmonary Fibrosis: Design, Synthesis, Structural Analysis, and Biological Evaluation of Potent Inhibitors.

J Med Chem 2021 07 12;64(14):9960-9988. Epub 2021 Jul 12.

Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100 Siena, Italy.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by a progressive-fibrosing phenotype. IPF has been associated with aberrant HDAC activities confirmed by our immunohistochemistry studies on HDAC6 overexpression in IPF lung tissues. We herein developed a series of novel HDAC6 inhibitors, having low inhibitory potency over HDAC1 and HDAC8, as potential pharmacological tools for IPF treatment. Their inhibitory potency was combined with low and toxicity. Structural analysis of and structure-activity relationship studies contributed to the optimization of the binding mode of the new molecules. The best-performing analogues were tested for their efficacy in inhibiting fibrotic sphere formation and cell viability, proving their capability in reverting the IPF phenotype. The efficacy of analogue was also determined in a validated human lung model of TGF-β1-dependent fibrogenesis. The results highlighted in this manuscript may pave the way for the identification of first-in-class molecules for the treatment of IPF.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300879PMC
July 2021

Screening and Phenotypical Characterization of Histone Deacetylase 8 (HDAC8) Inhibitors as Multistage Antischistosomal Agents.

ACS Infect Dis 2020 01 12;6(1):100-113. Epub 2019 Nov 12.

Institute of Biochemistry and Cell Biology (IBBC) , National Research Council (CNR) , Campus A. Buzzati-Traverso, via E. Ramarini 32 , 00015 Monterotondo ( Rome ), Italy.

Schistosomiasis (also known as bilharzia) is a neglected tropical disease caused by platyhelminths of the genus . The disease is endemic in tropical and subtropical areas of the world where water is infested by the intermediate parasite host, the snail. More than 800 million people live in endemic areas and more than 200 million are infected and require treatment. Praziquantel (PZQ) is the drug of choice for schistosomiasis treatment and transmission control being safe and very effective against adult worms of all the clinically relevant species. Unfortunately, it is ineffective on immature, juvenile worms; therefore, it does not prevent reinfection. Moreover, the risk of development and spread of drug resistance because of the widespread use of a single drug in such a large population represents a serious threat. Therefore, research aimed at identifying novel drugs to be used alone or in combination with PZQ are needed. histone deacetylase 8 (HDAC8) is a class I zinc-dependent HDAC, which is abundantly expressed in all stages of its life cycle, thus representing an interesting target for drug discovery. Through virtual screening and phenotypical characterization of selected hits, we discovered two main chemical classes of compounds characterized by the presence of a hydroxamate-based metal binding group coupled to a spiroindoline or a tricyclic thieno[3,2-]indole core as capping groups. Some of the compounds of both classes were deeply investigated and showed to impair viability of larval, juvenile, and adult schistosomes, to impact egg production and/or to induce morphological alterations of the adult schistosome reproductive systems. Noteworthy, all of them inhibit the recombinant form of HDAC8 enzyme . Overall, we identified very interesting scaffolds, paving the way to the development of effective antischistosomal agents.
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http://dx.doi.org/10.1021/acsinfecdis.9b00224DOI Listing
January 2020

Novel Sustainable-by-Design HDAC Inhibitors for the Treatment of Alzheimer's Disease.

ACS Med Chem Lett 2019 Apr 29;10(4):671-676. Epub 2019 Mar 29.

Department of Pharmacy and Biotechnology, Alma Mater Studiorum - University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy.

Alzheimer's disease (AD) represents a global problem, with an estimation of the majority of dementia patients in low- and middle-income countries by 2050. Thus, the development of sustainable drugs has attracted much attention in recent years. In light of this, taking inspiration from the HDAC inhibitor vorinostat (), we develop the first HDAC inhibitors derived from cashew nut shell liquid (CNSL), an inexpensive agro-food waste material. CNSL derivatives and display a HDAC inhibitory profile similar to , together with a more promising safety for compared to . Moreover, both compounds and particularly were able to effectively modulate glial cell-induced inflammation and to revert the pro-inflammatory phenotype. All these results demonstrate that the use of inexpensive food waste materials could be successfully applied for the development of accessible and sustainable drug candidates for the treatment of AD.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466821PMC
April 2019

Synthesis and Biological Investigation of Phenothiazine-Based Benzhydroxamic Acids as Selective Histone Deacetylase 6 Inhibitors.

J Med Chem 2019 02 1;62(3):1138-1166. Epub 2019 Feb 1.

Department of Pharmacy-Center for Drug Research , Ludwig-Maximilians University Munich , Butenandtstr. 5-13 , 81377 Munich , Germany.

The phenothiazine system was identified as a favorable cap group for potent and selective histone deacetylase 6 (HDAC6) inhibitors. Here, we report the preparation and systematic variation of phenothiazines and their analogues containing a benzhydroxamic acid moiety as the zinc-binding group. We evaluated their ability to selectively inhibit HDAC6 by a recombinant HDAC enzyme assay, by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines. Structure-activity relationship studies revealed that incorporation of a nitrogen atom into the phenothiazine framework results in increased potency and selectivity for HDAC6 (more than 500-fold selectivity relative to the inhibition of HDAC1, HDAC4, and HDAC8), as rationalized by molecular modeling and docking studies. The binding mode was confirmed by co-crystallization of the potent azaphenothiazine inhibitor with catalytic domain 2 from Danio rerio HDAC6.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519732PMC
February 2019

Novel spiroindoline HDAC inhibitors: Synthesis, molecular modelling and biological studies.

Eur J Med Chem 2018 Sep 31;157:127-138. Epub 2018 Jul 31.

European Research Centre for Drug Discovery and Development (NatSynDrugs) and Department of Biotechnology, Chemistry, and Pharmacy, Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100, Siena, Italy.

This paper describes the rational development of a series of novel spiroindoline derivatives endowed with selective inhibitory activity on the HDAC6 isoform. A convenient multicomponent one-pot protocol was applied for the assembly of the desired N1-substituted spiroindoline core which allowed a straightforward analoging. Computational studies and in vitro determination of inhibitory potency for the developed compounds against HDAC6 and HDAC1 isoforms were flanked by cell-based studies on histone H3 and α-tubulin acetylation. The effects on cancer cell cycle and apoptosis of the best performing derivatives were assessed on cancer cell lines highlighting a promising antitumor potential. In view of cell-based data and calculated drug-like properties, the selective HDAC6 inhibitor 5b, with a spiroindoline-based hydroxamate bearing a tert-butyl carbamate functionality, was selected to be further investigated for its potential in inhibiting tumor cells migration. It was able to potently inhibit cell migration in SH-SY5Y neuroblastoma cells and did not display toxicity in NIH3T3 mouse fibroblasts. Taken together, these data foster further investigation and optimization for this class of compounds as novel anticancer agents.
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http://dx.doi.org/10.1016/j.ejmech.2018.07.069DOI Listing
September 2018

Isoform-selective HDAC1/6/8 inhibitors with an imidazo-ketopiperazine cap containing stereochemical diversity.

Philos Trans R Soc Lond B Biol Sci 2018 06;373(1748)

School of Pharmacy, University of East Anglia, Norwich NR4 7TJ, UK

A series of hydroxamic acids linked by different lengths to a chiral imidazo-ketopiperazine scaffold were synthesized. The compounds with linker lengths of 6 and 7 carbon atoms were the most potent in histone deacetylase (HDAC) inhibition, and were specific submicromolar inhibitors of the HDAC1, HDAC6 and HDAC8 isoforms. A docking model for the binding mode predicts binding of the hydroxamic acid to the active site zinc cation and additional interactions between the imidazo-ketopiperazine and the enzyme rim. The compounds were micromolar inhibitors of the MV4-11, THP-1 and U937 cancer cell lines. Increased levels of histone H3 and tubulin acetylation support a cellular mechanism of action through HDAC inhibition.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.
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http://dx.doi.org/10.1098/rstb.2017.0364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915728PMC
June 2018

Structure-Activity Relationship of Propargylamine-Based HDAC Inhibitors.

ChemMedChem 2017 12 30;12(24):2044-2053. Epub 2017 Nov 30.

Organic and Bioorganic Chemistry, Bielefeld University, Universitätsstrasse 25, 33615, Bielefeld, Germany.

As histone deacetylases (HDACs) play an important role in the treatment of cancer, their selective inhibition has been the subject of various studies. These continuous investigations have given rise to a large collection of pan- and selective HDAC inhibitors, containing diverse US Food and Drug Administration (FDA)-approved representatives. In previous studies, a class of alkyne-based HDAC inhibitors was presented. We modified this scaffold in two previously neglected regions and compared their cytotoxicity and affinity toward HDAC1, HDAC6, and HDAC8. We were able to show that R-configured propargylamines contribute to increased selectivity for HDAC6. Docking studies on available HDAC crystal structures were carried out to rationalize the observed selectivity of the compounds. Substitution of the aromatic portion by a thiophene derivative results in high affinity and low cytotoxicity, indicating an improved drug tolerance.
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http://dx.doi.org/10.1002/cmdc.201700550DOI Listing
December 2017

Alkoxyurea-Based Histone Deacetylase Inhibitors Increase Cisplatin Potency in Chemoresistant Cancer Cell Lines.

J Med Chem 2017 07 19;60(13):5334-5348. Epub 2017 Jun 19.

Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf , Universitätsstraße 1, 40225 Düsseldorf, Germany.

The synthesis and biological evaluation of potent hydroxamate-based dual HDAC1/6 inhibitors with modest HDAC6 preference and a novel alkoxyurea connecting unit linker region are described. The biological studies included the evaluation of antiproliferative effects and HDAC inhibitory activity in the human ovarian cancer cell line A2780, the human squamous carcinoma cell line Cal27, and their cisplatin resistant sublines A2780CisR and Cal27CisR. The three most potent compounds 1g-i showed IC values in the low μM and sub-μM range. 1g-i revealed low nM IC values for HDAC6 with up to 15-fold preference over HDAC1, >3500-fold selectivity over HDAC4, and >100-fold selectivity over HDAC8. Furthermore, their ability to enhance cisplatin sensitivity was analyzed in Cal27 and Cal27CisR cells. Notably, a 48 h preincubation of 1g-i significantly enhanced the antiproliferative effects of cisplatin in Cal27 and Cal27CisR. 1g-i interacted synergistically with cisplatin. These effects were more pronounced for the cisplatin resistant subline Cal27CisR.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01538DOI Listing
July 2017

Design, Multicomponent Synthesis, and Anticancer Activity of a Focused Histone Deacetylase (HDAC) Inhibitor Library with Peptoid-Based Cap Groups.

J Med Chem 2017 07 16;60(13):5493-5506. Epub 2017 Jun 16.

Institut für Pharmazeutische und Medizinische Chemie, Heinrich-Heine-Universität Düsseldorf , Universitätsstraße 1, 40225 Düsseldorf, Germany.

In this work, we report the multicomponent synthesis of a focused histone deacetylase (HDAC) inhibitor library with peptoid-based cap groups and different zinc-binding groups. All synthesized compounds were tested in a cellular HDAC inhibition assay and an MTT assay for cytotoxicity. On the basis of their noteworthy activity in the cellular HDAC assays, four compounds were further screened for their inhibitory activity against recombinant HDAC1-3, HDAC6, and HDAC8. All four compounds showed potent inhibition of HDAC1-3 as well as significant inhibition of HDAC6 with IC values in the submicromolar concentration range. Compound 4j, the most potent HDAC inhibitor in the cellular HDAC assay, revealed remarkable chemosensitizing properties and enhanced the cisplatin sensitivity of the cisplatin-resistant head-neck cancer cell line Cal27CisR by almost 7-fold. Furthermore, 4j almost completely reversed the cisplatin resistance in Cal27CisR. This effect is related to a synergistic induction of apoptosis as seen in the combination of 4j with cisplatin.
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http://dx.doi.org/10.1021/acs.jmedchem.7b00197DOI Listing
July 2017

Targeting histone deacetylase 8 as a therapeutic approach to cancer and neurodegenerative diseases.

Future Med Chem 2016 09 30;8(13):1609-34. Epub 2016 Aug 30.

Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.

Histone deacetylase 8 (HDAC8), a unique class I zinc-dependent HDAC, is an emerging target in cancer and other diseases. Its substrate repertoire extends beyond histones to many nonhistone proteins. Besides being a deacetylase, HDAC8 also mediates signaling via scaffolding functions. Aberrant expression or deregulated interactions with transcription factors are critical in HDAC8-dependent cancers. Many potent HDAC8-selective inhibitors with cellular activity and anticancer effects have been reported. We present HDAC8 as a druggable target and discuss inhibitors of different chemical scaffolds with cellular effects. Furthermore, we review HDAC8 activators that revert activity of mutant enzymes. Isotype-selective HDAC8 targeting in patients with HDAC8-relevant cancers is challenging, however, is promising to avoid adverse side effects as observed with pan-HDAC inhibitors.
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http://dx.doi.org/10.4155/fmc-2016-0117DOI Listing
September 2016

Phenylpyrrole-based HDAC inhibitors: synthesis, molecular modeling and biological studies.

Future Med Chem 2016 09 24;8(13):1573-87. Epub 2016 Aug 24.

European Research Centre for Drug Discovery & Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy.

Aim: Histone deacetylases (HDACs) regulate the expression and activity of numerous proteins involved in the initiation and progression of cancer. Currently, three hydroxamate-containing HDAC pan-inhibitors have been approved as antitumor agents.

Results: We herein present the development of a series of novel phenylpyrrole-based derivatives stemmed from combined computational and medicinal chemistry efforts to rationally modulate HDAC1/6 isoform selectivity. In vitro activity on HDAC1 and HDAC6 isoforms and the effects of selected analogs on histone H3 and α-tubulin acetylation levels were determined. Cell-based data evidenced, for selected compounds, a promising antitumor potential and low toxicity on normal cells.

Conclusion: The newly developed compounds represent a valuable starting point for the development of novel anticancer agents.
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http://dx.doi.org/10.4155/fmc-2016-0068DOI Listing
September 2016

4-Biphenylalanine- and 3-Phenyltyrosine-Derived Hydroxamic Acids as Inhibitors of the JumonjiC-Domain-Containing Histone Demethylase KDM4A.

ChemMedChem 2016 09 9;11(18):2063-83. Epub 2016 Aug 9.

Institute of Pharmaceutical Sciences, Albert Ludwigs University Freiburg, Albertstraße 25, 79104, Freiburg im Breisgau, Germany.

Overexpression of the histone lysine demethylase KDM4A, which regulates H3K9 and H3K36 methylation states, has been related to the pathology of several human cancers. We found that a previously reported hydroxamate-based histone deacetylase (HDAC) inhibitor (SW55) was also able to weakly inhibit this demethylase with an IC50 value of 25.4 μm. Herein we report the synthesis and biochemical evaluations, with two orthogonal in vitro assays, of a series of derivatives of this lead structure. With extensive chemical modifications on the lead structure, also by exploiting the versatility of the radical arylation with aryldiazonium salts, we were able to increase the potency of the derivatives against KDM4A to the low-micromolar range and, more importantly, to obtain demethylase selectivity with respect to HDACs. Cell-permeable derivatives clearly showed a demethylase-inhibition-dependent antiproliferative effect against HL-60 human promyelocytic leukemia cells.
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http://dx.doi.org/10.1002/cmdc.201600218DOI Listing
September 2016

Synthesis and Biological Investigation of Oxazole Hydroxamates as Highly Selective Histone Deacetylase 6 (HDAC6) Inhibitors.

J Med Chem 2016 Feb 22;59(4):1545-55. Epub 2015 Dec 22.

Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg , Albertstraße 25, 79104 Freiburg, Germany.

Histone deacetylase 6 (HDAC6) catalyzes the removal of an acetyl group from lysine residues of several non-histone proteins. Here we report the preparation of thiazole-, oxazole-, and oxadiazole-containing biarylhydroxamic acids by a short synthetic procedure. We identified them as selective HDAC6 inhibitors by investigating the inhibition of recombinant HDAC enzymes and the protein acetylation in cells by Western blotting (tubulin vs histone acetylation). The most active compounds exhibited nanomolar potency and high selectivity for HDAC6. For example, an oxazole hydroxamate inhibits HDAC6 with an IC50 of 59 nM and has a selectivity index of >200 against HDAC1 and HDAC8. This is the first report showing that the nature of a heterocycle directly connected to a zinc binding group (ZBG) can be used to modulate subtype selectivity and potency for HDAC6 inhibitors to such an extent. We rationalize the high potency and selectivity of the oxazoles by molecular modeling and docking.
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http://dx.doi.org/10.1021/acs.jmedchem.5b01493DOI Listing
February 2016

Hydroxamates of para-aminobenzoic acid as selective inhibitors of HDAC8.

Bioorg Chem 2014 Dec 3;57:116-120. Epub 2014 Sep 3.

Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835 215, Jharkhand, India; Valens Pharma Services, Regus Citi Centre, Level 6, Chennai Citi Centre, 10/11, Dr. Radhakrishnan Salai, Chennai 600 004, Tamil Nadu, India. Electronic address:

A series of hydroxamates (4a-4l) were prepared from p-aminobenzoic acid to inhibit HDAC8. The idea is to substitute rigid aromatic ring in place of less rigid piperazine ring of hydroxamates reported earlier by our group. It is expected to increase potency retaining the selectivity. Result obtained suggested that the modifications carried out retained the selectivity towards HDAC8 isoform and increasing the potency in very few cases. Increase in potency is also associated with variation in cap aryl region. Two compounds (4f &4l) were found to inhibit HDAC8 at concentrations (IC50) less than 20μM.
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http://dx.doi.org/10.1016/j.bioorg.2014.08.005DOI Listing
December 2014

Total synthesis of (18S)- and (18R)-homolargazole by rhodium-catalyzed hydrocarboxylation.

Chemistry 2014 Feb 29;20(8):2164-8. Epub 2014 Jan 29.

Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstrasse 21, 79104 Freiburg i. Bg. (Germany), Fax: (+49) 761-203-8715.

Homolargazole derivatives, in which the macrocycle of natural largazole is extended by one methylene group, were prepared by the recently developed rhodium-catalyzed hydrocarboxylation reaction onto allenes. This strategy gives access to both the (18S)- and (18R)-stereoisomers in high stereoselectivity under ligand control.
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http://dx.doi.org/10.1002/chem.201303300DOI Listing
February 2014
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