Targeting of the Mitochondrial TET1 Protein by Pyrrolo[3,2-b]pyrrole Chelators

Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies, including oncological disorders. Recent studies demonstrated that promising therapeutic strategies could potentially be based on the inh...

Full description

Saved in:
Bibliographic Details
Published in:International journal of molecular sciences 2022-09, Vol.23 (18), p.10850
Main Authors: Antonyová, Veronika, Tatar, Ameneh, Brogyányi, Tereza, Kejík, Zdeněk, Kaplánek, Robert, Vellieux, Fréderic, Abramenko, Nikita, Sinica, Alla, Hajduch, Jan, Novotný, Petr, Masters, Bettie Sue, Martásek, Pavel, Jakubek, Milan
Format: Article
Language:English
Subjects:
Acids
Antitumor activity
Cancer
Cell growth
Chelating agents
Correlation coefficients
Dioxygenase
DNA methylation
Enzymes
Epigenetics
Gene expression
Hydrazones
Iron
Leukemia
Ligands
Localization
Medical prognosis
Mitochondria
Mitochondrial DNA
Molecular docking
Protein transport
Proteins
Pyrroles
Thermophoresis
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c392t-bfffb257812029d5ac6e8f5cc8b010785c3ea2fb953e82e36056b071a6a2727d3
cites cdi_FETCH-LOGICAL-c392t-bfffb257812029d5ac6e8f5cc8b010785c3ea2fb953e82e36056b071a6a2727d3
container_end_page
container_issue 18
container_start_page 10850
container_title International journal of molecular sciences
container_volume 23
creator Antonyová, Veronika
Tatar, Ameneh
Brogyányi, Tereza
Kejík, Zdeněk
Kaplánek, Robert
Vellieux, Fréderic
Abramenko, Nikita
Sinica, Alla
Hajduch, Jan
Novotný, Petr
Masters, Bettie Sue
Martásek, Pavel
Jakubek, Milan
description Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies, including oncological disorders. Recent studies demonstrated that promising therapeutic strategies could potentially be based on the inhibition of the TET1 protein (ten-eleven translocation methylcytosine dioxygenase 1) by specific iron chelators. Therefore, in the present work, we prepared a series of pyrrolopyrrole derivatives with hydrazide (1) or hydrazone (2–6) iron-binding groups. As a result, we determined that the basic pyrrolo[3,2-b]pyrrole derivative 1 was a strong inhibitor of the TET1 protein (IC50 = 1.33 μM), supported by microscale thermophoresis and molecular docking. Pyrrolo[3,2-b]pyrroles 2–6, bearing substituted 2-hydroxybenzylidene moieties, displayed no significant inhibitory activity. In addition, in vitro studies demonstrated that derivative 1 exhibits potent anticancer activity and an exclusive mitochondrial localization, confirmed by Pearson’s correlation coefficient of 0.92.
doi_str_mv 10.3390/ijms231810850
format article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9505425</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2717684691</sourcerecordid><originalsourceid>FETCH-LOGICAL-c392t-bfffb257812029d5ac6e8f5cc8b010785c3ea2fb953e82e36056b071a6a2727d3</originalsourceid><addsrcrecordid>eNpdkd1LwzAUxYMobk4ffS_44oPVfCxJ-yLImB8wdQ_1SSSkabpmtM1MUmH_vZ0b4ny693J-HO7hAHCO4DUhKbwxy8ZjghIEEwoPwBCNMY4hZPzwzz4AJ94vIcQE0_QYDAjrJc7IELxk0i10MO0ismUUKh09m2BVZdvCGVlH2TRD0dzZoE0b5etovnbO1vadXOE4_1j9XDqaVLqWwTp_Co5KWXt9tpsj8HY_zSaP8ez14WlyN4sVSXGI87Isc0x5gjDEaUGlYjopqVJJDhHkCVVES1zmKSU6wZowSFkOOZJMYo55QUbgduu76vJGF0q3wclarJxppFsLK43YV1pTiYX9EimFdIxpb3C5M3D2s9M-iMZ4petattp2XmCOOEvGLEU9evEPXdrOtX28DcUoZSwlPRVvKeWs906Xv88gKDZNib2myDcZaYUD</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2716556693</pqid></control><display><type>article</type><title>Targeting of the Mitochondrial TET1 Protein by Pyrrolo[3,2-b]pyrrole Chelators</title><source>Publicly Available Content Database</source><source>PubMed Central</source><creator>Antonyová, Veronika ; Tatar, Ameneh ; Brogyányi, Tereza ; Kejík, Zdeněk ; Kaplánek, Robert ; Vellieux, Fréderic ; Abramenko, Nikita ; Sinica, Alla ; Hajduch, Jan ; Novotný, Petr ; Masters, Bettie Sue ; Martásek, Pavel ; Jakubek, Milan</creator><creatorcontrib>Antonyová, Veronika ; Tatar, Ameneh ; Brogyányi, Tereza ; Kejík, Zdeněk ; Kaplánek, Robert ; Vellieux, Fréderic ; Abramenko, Nikita ; Sinica, Alla ; Hajduch, Jan ; Novotný, Petr ; Masters, Bettie Sue ; Martásek, Pavel ; Jakubek, Milan</creatorcontrib><description>Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies, including oncological disorders. Recent studies demonstrated that promising therapeutic strategies could potentially be based on the inhibition of the TET1 protein (ten-eleven translocation methylcytosine dioxygenase 1) by specific iron chelators. Therefore, in the present work, we prepared a series of pyrrolopyrrole derivatives with hydrazide (1) or hydrazone (2–6) iron-binding groups. As a result, we determined that the basic pyrrolo[3,2-b]pyrrole derivative 1 was a strong inhibitor of the TET1 protein (IC50 = 1.33 μM), supported by microscale thermophoresis and molecular docking. Pyrrolo[3,2-b]pyrroles 2–6, bearing substituted 2-hydroxybenzylidene moieties, displayed no significant inhibitory activity. In addition, in vitro studies demonstrated that derivative 1 exhibits potent anticancer activity and an exclusive mitochondrial localization, confirmed by Pearson’s correlation coefficient of 0.92.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms231810850</identifier><identifier>PMID: 36142763</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Acids ; Antitumor activity ; Cancer ; Cell growth ; Chelating agents ; Correlation coefficients ; Dioxygenase ; DNA methylation ; Enzymes ; Epigenetics ; Gene expression ; Hydrazones ; Iron ; Leukemia ; Ligands ; Localization ; Medical prognosis ; Mitochondria ; Mitochondrial DNA ; Molecular docking ; Protein transport ; Proteins ; Pyrroles ; Thermophoresis</subject><ispartof>International journal of molecular sciences, 2022-09, Vol.23 (18), p.10850</ispartof><rights>2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2022 by the authors. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c392t-bfffb257812029d5ac6e8f5cc8b010785c3ea2fb953e82e36056b071a6a2727d3</citedby><cites>FETCH-LOGICAL-c392t-bfffb257812029d5ac6e8f5cc8b010785c3ea2fb953e82e36056b071a6a2727d3</cites><orcidid>0000-0001-6184-2947 ; 0000-0001-7323-3903 ; 0000-0003-3715-6626 ; 0000-0002-1922-5707</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2716556693/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2716556693?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,25731,27901,27902,36989,36990,44566,53766,53768,74869</link.rule.ids></links><search><creatorcontrib>Antonyová, Veronika</creatorcontrib><creatorcontrib>Tatar, Ameneh</creatorcontrib><creatorcontrib>Brogyányi, Tereza</creatorcontrib><creatorcontrib>Kejík, Zdeněk</creatorcontrib><creatorcontrib>Kaplánek, Robert</creatorcontrib><creatorcontrib>Vellieux, Fréderic</creatorcontrib><creatorcontrib>Abramenko, Nikita</creatorcontrib><creatorcontrib>Sinica, Alla</creatorcontrib><creatorcontrib>Hajduch, Jan</creatorcontrib><creatorcontrib>Novotný, Petr</creatorcontrib><creatorcontrib>Masters, Bettie Sue</creatorcontrib><creatorcontrib>Martásek, Pavel</creatorcontrib><creatorcontrib>Jakubek, Milan</creatorcontrib><title>Targeting of the Mitochondrial TET1 Protein by Pyrrolo[3,2-b]pyrrole Chelators</title><title>International journal of molecular sciences</title><description>Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies, including oncological disorders. Recent studies demonstrated that promising therapeutic strategies could potentially be based on the inhibition of the TET1 protein (ten-eleven translocation methylcytosine dioxygenase 1) by specific iron chelators. Therefore, in the present work, we prepared a series of pyrrolopyrrole derivatives with hydrazide (1) or hydrazone (2–6) iron-binding groups. As a result, we determined that the basic pyrrolo[3,2-b]pyrrole derivative 1 was a strong inhibitor of the TET1 protein (IC50 = 1.33 μM), supported by microscale thermophoresis and molecular docking. Pyrrolo[3,2-b]pyrroles 2–6, bearing substituted 2-hydroxybenzylidene moieties, displayed no significant inhibitory activity. In addition, in vitro studies demonstrated that derivative 1 exhibits potent anticancer activity and an exclusive mitochondrial localization, confirmed by Pearson’s correlation coefficient of 0.92.</description><subject>Acids</subject><subject>Antitumor activity</subject><subject>Cancer</subject><subject>Cell growth</subject><subject>Chelating agents</subject><subject>Correlation coefficients</subject><subject>Dioxygenase</subject><subject>DNA methylation</subject><subject>Enzymes</subject><subject>Epigenetics</subject><subject>Gene expression</subject><subject>Hydrazones</subject><subject>Iron</subject><subject>Leukemia</subject><subject>Ligands</subject><subject>Localization</subject><subject>Medical prognosis</subject><subject>Mitochondria</subject><subject>Mitochondrial DNA</subject><subject>Molecular docking</subject><subject>Protein transport</subject><subject>Proteins</subject><subject>Pyrroles</subject><subject>Thermophoresis</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><recordid>eNpdkd1LwzAUxYMobk4ffS_44oPVfCxJ-yLImB8wdQ_1SSSkabpmtM1MUmH_vZ0b4ny693J-HO7hAHCO4DUhKbwxy8ZjghIEEwoPwBCNMY4hZPzwzz4AJ94vIcQE0_QYDAjrJc7IELxk0i10MO0ismUUKh09m2BVZdvCGVlH2TRD0dzZoE0b5etovnbO1vadXOE4_1j9XDqaVLqWwTp_Co5KWXt9tpsj8HY_zSaP8ez14WlyN4sVSXGI87Isc0x5gjDEaUGlYjopqVJJDhHkCVVES1zmKSU6wZowSFkOOZJMYo55QUbgduu76vJGF0q3wclarJxppFsLK43YV1pTiYX9EimFdIxpb3C5M3D2s9M-iMZ4petattp2XmCOOEvGLEU9evEPXdrOtX28DcUoZSwlPRVvKeWs906Xv88gKDZNib2myDcZaYUD</recordid><startdate>20220916</startdate><enddate>20220916</enddate><creator>Antonyová, Veronika</creator><creator>Tatar, Ameneh</creator><creator>Brogyányi, Tereza</creator><creator>Kejík, Zdeněk</creator><creator>Kaplánek, Robert</creator><creator>Vellieux, Fréderic</creator><creator>Abramenko, Nikita</creator><creator>Sinica, Alla</creator><creator>Hajduch, Jan</creator><creator>Novotný, Petr</creator><creator>Masters, Bettie Sue</creator><creator>Martásek, Pavel</creator><creator>Jakubek, Milan</creator><general>MDPI AG</general><general>MDPI</general><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6184-2947</orcidid><orcidid>https://orcid.org/0000-0001-7323-3903</orcidid><orcidid>https://orcid.org/0000-0003-3715-6626</orcidid><orcidid>https://orcid.org/0000-0002-1922-5707</orcidid></search><sort><creationdate>20220916</creationdate><title>Targeting of the Mitochondrial TET1 Protein by Pyrrolo[3,2-b]pyrrole Chelators</title><author>Antonyová, Veronika ; Tatar, Ameneh ; Brogyányi, Tereza ; Kejík, Zdeněk ; Kaplánek, Robert ; Vellieux, Fréderic ; Abramenko, Nikita ; Sinica, Alla ; Hajduch, Jan ; Novotný, Petr ; Masters, Bettie Sue ; Martásek, Pavel ; Jakubek, Milan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c392t-bfffb257812029d5ac6e8f5cc8b010785c3ea2fb953e82e36056b071a6a2727d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Acids</topic><topic>Antitumor activity</topic><topic>Cancer</topic><topic>Cell growth</topic><topic>Chelating agents</topic><topic>Correlation coefficients</topic><topic>Dioxygenase</topic><topic>DNA methylation</topic><topic>Enzymes</topic><topic>Epigenetics</topic><topic>Gene expression</topic><topic>Hydrazones</topic><topic>Iron</topic><topic>Leukemia</topic><topic>Ligands</topic><topic>Localization</topic><topic>Medical prognosis</topic><topic>Mitochondria</topic><topic>Mitochondrial DNA</topic><topic>Molecular docking</topic><topic>Protein transport</topic><topic>Proteins</topic><topic>Pyrroles</topic><topic>Thermophoresis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Antonyová, Veronika</creatorcontrib><creatorcontrib>Tatar, Ameneh</creatorcontrib><creatorcontrib>Brogyányi, Tereza</creatorcontrib><creatorcontrib>Kejík, Zdeněk</creatorcontrib><creatorcontrib>Kaplánek, Robert</creatorcontrib><creatorcontrib>Vellieux, Fréderic</creatorcontrib><creatorcontrib>Abramenko, Nikita</creatorcontrib><creatorcontrib>Sinica, Alla</creatorcontrib><creatorcontrib>Hajduch, Jan</creatorcontrib><creatorcontrib>Novotný, Petr</creatorcontrib><creatorcontrib>Masters, Bettie Sue</creatorcontrib><creatorcontrib>Martásek, Pavel</creatorcontrib><creatorcontrib>Jakubek, Milan</creatorcontrib><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Research Library</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Antonyová, Veronika</au><au>Tatar, Ameneh</au><au>Brogyányi, Tereza</au><au>Kejík, Zdeněk</au><au>Kaplánek, Robert</au><au>Vellieux, Fréderic</au><au>Abramenko, Nikita</au><au>Sinica, Alla</au><au>Hajduch, Jan</au><au>Novotný, Petr</au><au>Masters, Bettie Sue</au><au>Martásek, Pavel</au><au>Jakubek, Milan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting of the Mitochondrial TET1 Protein by Pyrrolo[3,2-b]pyrrole Chelators</atitle><jtitle>International journal of molecular sciences</jtitle><date>2022-09-16</date><risdate>2022</risdate><volume>23</volume><issue>18</issue><spage>10850</spage><pages>10850-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies, including oncological disorders. Recent studies demonstrated that promising therapeutic strategies could potentially be based on the inhibition of the TET1 protein (ten-eleven translocation methylcytosine dioxygenase 1) by specific iron chelators. Therefore, in the present work, we prepared a series of pyrrolopyrrole derivatives with hydrazide (1) or hydrazone (2–6) iron-binding groups. As a result, we determined that the basic pyrrolo[3,2-b]pyrrole derivative 1 was a strong inhibitor of the TET1 protein (IC50 = 1.33 μM), supported by microscale thermophoresis and molecular docking. Pyrrolo[3,2-b]pyrroles 2–6, bearing substituted 2-hydroxybenzylidene moieties, displayed no significant inhibitory activity. In addition, in vitro studies demonstrated that derivative 1 exhibits potent anticancer activity and an exclusive mitochondrial localization, confirmed by Pearson’s correlation coefficient of 0.92.</abstract><cop>Basel</cop><pub>MDPI AG</pub><pmid>36142763</pmid><doi>10.3390/ijms231810850</doi><orcidid>https://orcid.org/0000-0001-6184-2947</orcidid><orcidid>https://orcid.org/0000-0001-7323-3903</orcidid><orcidid>https://orcid.org/0000-0003-3715-6626</orcidid><orcidid>https://orcid.org/0000-0002-1922-5707</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1422-0067
ispartof International journal of molecular sciences, 2022-09, Vol.23 (18), p.10850
issn 1422-0067
1661-6596
1422-0067
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9505425
source Publicly Available Content Database; PubMed Central
subjects Acids
Antitumor activity
Cancer
Cell growth
Chelating agents
Correlation coefficients
Dioxygenase
DNA methylation
Enzymes
Epigenetics
Gene expression
Hydrazones
Iron
Leukemia
Ligands
Localization
Medical prognosis
Mitochondria
Mitochondrial DNA
Molecular docking
Protein transport
Proteins
Pyrroles
Thermophoresis
title Targeting of the Mitochondrial TET1 Protein by Pyrrolo[3,2-b]pyrrole Chelators
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-30T23%3A41%3A34IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Targeting%20of%20the%20Mitochondrial%20TET1%20Protein%20by%20Pyrrolo%5B3,2-b%5Dpyrrole%20Chelators&rft.jtitle=International%20journal%20of%20molecular%20sciences&rft.au=Antonyov%C3%A1,%20Veronika&rft.date=2022-09-16&rft.volume=23&rft.issue=18&rft.spage=10850&rft.pages=10850-&rft.issn=1422-0067&rft.eissn=1422-0067&rft_id=info:doi/10.3390/ijms231810850&rft_dat=%3Cproquest_pubme%3E2717684691%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c392t-bfffb257812029d5ac6e8f5cc8b010785c3ea2fb953e82e36056b071a6a2727d3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2716556693&rft_id=info:pmid/36142763&rfr_iscdi=true