Aromatic sulphonamides of aziridine-2-carboxylic acid derivatives as novel PDIA1 and PDIA3 inhibitors
In this study, we report a series of newly synthesised sulphonamides of aziridine-2-carboxylic acid (Az-COOH) ester and amide analogues as potent protein disulphide isomerase (PDI, EC 5.3.4.1) inhibitors. The inhibitory activity on PDI was determined against recombinant human PDIA1 and PDIA3 protein...
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| Veröffentlicht in: | Journal of enzyme inhibition and medicinal chemistry 2023-12, Vol.38 (1), p.2158187-2158187 |
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| creator | Zelencova-Gopejenko, D. Andrianov, V. Domracheva, I. Kanepe-Lapsa, I. Milczarek, M. Stojak, M. Przyborowski, K. Fedak, F. A. Walczak, M. Kramkowski, K. Wietrzyk, J. Chlopicki, S. Kalvins, I. |
| description | In this study, we report a series of newly synthesised sulphonamides of aziridine-2-carboxylic acid (Az-COOH) ester and amide analogues as potent protein disulphide isomerase (PDI, EC 5.3.4.1) inhibitors. The inhibitory activity on PDI was determined against recombinant human PDIA1 and PDIA3 proteins using an insulin reduction assay. These compounds in low micromolar to low nanomolar concentrations showed the effective in vitro inhibitory properties of PDIA1 with weaker effects on PDIA3. Complexes of
15
N- and
15
N,
13
C- uniformly labelled recombinant human PDIA1a with two PDIA1 inhibitors were produced and investigated by a protein nuclear magnetic resonance (NMR) spectroscopy. It was found that both C53 and C56 of the PDIA1 enzyme were involved in covalent binding. Finally, in a range of pharmacological studies, we demonstrated that investigated compounds displayed anti-cancer and anti-thrombotic activity. These findings demonstrate that sulphonamides of Az-COOH derivatives are promising candidates for the development of novel anti-cancer and anti-thrombotic agents. |
| doi_str_mv | 10.1080/14756366.2022.2158187 |
| format | Article |
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N- and
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C- uniformly labelled recombinant human PDIA1a with two PDIA1 inhibitors were produced and investigated by a protein nuclear magnetic resonance (NMR) spectroscopy. It was found that both C53 and C56 of the PDIA1 enzyme were involved in covalent binding. Finally, in a range of pharmacological studies, we demonstrated that investigated compounds displayed anti-cancer and anti-thrombotic activity. These findings demonstrate that sulphonamides of Az-COOH derivatives are promising candidates for the development of novel anti-cancer and anti-thrombotic agents.</description><identifier>ISSN: 1475-6366</identifier><identifier>EISSN: 1475-6374</identifier><identifier>DOI: 10.1080/14756366.2022.2158187</identifier><identifier>PMID: 37070480</identifier><language>eng</language><publisher>England: Taylor & Francis</publisher><subject>Acids ; aziridine ; Aziridines - pharmacology ; Cancer ; Carboxylic acids ; Chemistry ; Disulphide ; Enzymes ; Humans ; inhibitor ; isomerase ; Ligands ; NMR ; Nuclear magnetic resonance ; PDI ; Protein Disulfide-Isomerases - antagonists & inhibitors ; Protein Disulfide-Isomerases - chemistry ; Proteins ; Research Paper ; Spectroscopy ; Sulfonamides ; Sulfonamides - pharmacology</subject><ispartof>Journal of enzyme inhibition and medicinal chemistry, 2023-12, Vol.38 (1), p.2158187-2158187</ispartof><rights>2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. 2023</rights><rights>2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This work is licensed under the Creative Commons Attribution – Non-Commercial License http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. 2023 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c563t-a091b278c7da32fd7678fc0b0af2976185890575d2fa704fe9aaa70afe27f6743</citedby><cites>FETCH-LOGICAL-c563t-a091b278c7da32fd7678fc0b0af2976185890575d2fa704fe9aaa70afe27f6743</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10120451/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC10120451/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,27479,27901,27902,53766,53768,59116,59117</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37070480$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zelencova-Gopejenko, D.</creatorcontrib><creatorcontrib>Andrianov, V.</creatorcontrib><creatorcontrib>Domracheva, I.</creatorcontrib><creatorcontrib>Kanepe-Lapsa, I.</creatorcontrib><creatorcontrib>Milczarek, M.</creatorcontrib><creatorcontrib>Stojak, M.</creatorcontrib><creatorcontrib>Przyborowski, K.</creatorcontrib><creatorcontrib>Fedak, F. A.</creatorcontrib><creatorcontrib>Walczak, M.</creatorcontrib><creatorcontrib>Kramkowski, K.</creatorcontrib><creatorcontrib>Wietrzyk, J.</creatorcontrib><creatorcontrib>Chlopicki, S.</creatorcontrib><creatorcontrib>Kalvins, I.</creatorcontrib><title>Aromatic sulphonamides of aziridine-2-carboxylic acid derivatives as novel PDIA1 and PDIA3 inhibitors</title><title>Journal of enzyme inhibition and medicinal chemistry</title><addtitle>J Enzyme Inhib Med Chem</addtitle><description>In this study, we report a series of newly synthesised sulphonamides of aziridine-2-carboxylic acid (Az-COOH) ester and amide analogues as potent protein disulphide isomerase (PDI, EC 5.3.4.1) inhibitors. The inhibitory activity on PDI was determined against recombinant human PDIA1 and PDIA3 proteins using an insulin reduction assay. These compounds in low micromolar to low nanomolar concentrations showed the effective in vitro inhibitory properties of PDIA1 with weaker effects on PDIA3. Complexes of
15
N- and
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N,
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C- uniformly labelled recombinant human PDIA1a with two PDIA1 inhibitors were produced and investigated by a protein nuclear magnetic resonance (NMR) spectroscopy. It was found that both C53 and C56 of the PDIA1 enzyme were involved in covalent binding. Finally, in a range of pharmacological studies, we demonstrated that investigated compounds displayed anti-cancer and anti-thrombotic activity. These findings demonstrate that sulphonamides of Az-COOH derivatives are promising candidates for the development of novel anti-cancer and anti-thrombotic agents.</description><subject>Acids</subject><subject>aziridine</subject><subject>Aziridines - pharmacology</subject><subject>Cancer</subject><subject>Carboxylic acids</subject><subject>Chemistry</subject><subject>Disulphide</subject><subject>Enzymes</subject><subject>Humans</subject><subject>inhibitor</subject><subject>isomerase</subject><subject>Ligands</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>PDI</subject><subject>Protein Disulfide-Isomerases - antagonists & inhibitors</subject><subject>Protein Disulfide-Isomerases - chemistry</subject><subject>Proteins</subject><subject>Research Paper</subject><subject>Spectroscopy</subject><subject>Sulfonamides</subject><subject>Sulfonamides - pharmacology</subject><issn>1475-6366</issn><issn>1475-6374</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>0YH</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNp9kk9vEzEQxVcIREvhI4BW4sJlgz3rXXtPEJUCkSrBAc7WrP80jnbtYG9Swqev06QR5cDJo_FvnudZryheUzKjRJD3lPGmrdt2BgRgBrQRVPAnxfm-X7U1Z09PddueFS9SWhECFCh7XpzVnHDCBDkvzDyGESenyrQZ1svgcXTapDLYEv-46LTzpoJKYezD792QOVROl9pEt81j24xiKn3YmqH8_mkxpyV6fV_VpfNL17spxPSyeGZxSObV8bwofn6--nH5tbr-9mVxOb-uVPYyVUg62gMXimuswWrecmEV6Qla6HhLRSM60vBGg8W8vzUdYi7QGuC25ay-KBYHXR1wJdfRjRh3MqCT940QbyTGbHYwsu3QElGj6E3PNEAHjRZQK6wt4wJ51vpw0Fpv-tFoZfwUcXgk-vjGu6W8CVtJCQXCGpoV3h0VYvi1MWmSo0vKDAN6EzZJgiAgBOOsy-jbf9BV2ESf_0pCR3nDOLC9veZAqRhSisaetqFE7lMhH1Ih96mQx1TkuTd_WzlNPcQgAx8PgPM2xBFvQxy0nHA3hGgjeuWSrP__xh1HHcYa</recordid><startdate>202312</startdate><enddate>202312</enddate><creator>Zelencova-Gopejenko, D.</creator><creator>Andrianov, V.</creator><creator>Domracheva, I.</creator><creator>Kanepe-Lapsa, I.</creator><creator>Milczarek, M.</creator><creator>Stojak, M.</creator><creator>Przyborowski, K.</creator><creator>Fedak, F. A.</creator><creator>Walczak, M.</creator><creator>Kramkowski, K.</creator><creator>Wietrzyk, J.</creator><creator>Chlopicki, S.</creator><creator>Kalvins, I.</creator><general>Taylor & Francis</general><general>Taylor & Francis Ltd</general><general>Taylor & Francis Group</general><scope>0YH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</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>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>202312</creationdate><title>Aromatic sulphonamides of aziridine-2-carboxylic acid derivatives as novel PDIA1 and PDIA3 inhibitors</title><author>Zelencova-Gopejenko, D. ; Andrianov, V. ; Domracheva, I. ; Kanepe-Lapsa, I. ; Milczarek, M. ; Stojak, M. ; Przyborowski, K. ; Fedak, F. 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A.</au><au>Walczak, M.</au><au>Kramkowski, K.</au><au>Wietrzyk, J.</au><au>Chlopicki, S.</au><au>Kalvins, I.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Aromatic sulphonamides of aziridine-2-carboxylic acid derivatives as novel PDIA1 and PDIA3 inhibitors</atitle><jtitle>Journal of enzyme inhibition and medicinal chemistry</jtitle><addtitle>J Enzyme Inhib Med Chem</addtitle><date>2023-12</date><risdate>2023</risdate><volume>38</volume><issue>1</issue><spage>2158187</spage><epage>2158187</epage><pages>2158187-2158187</pages><issn>1475-6366</issn><eissn>1475-6374</eissn><abstract>In this study, we report a series of newly synthesised sulphonamides of aziridine-2-carboxylic acid (Az-COOH) ester and amide analogues as potent protein disulphide isomerase (PDI, EC 5.3.4.1) inhibitors. The inhibitory activity on PDI was determined against recombinant human PDIA1 and PDIA3 proteins using an insulin reduction assay. 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15
N- and
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C- uniformly labelled recombinant human PDIA1a with two PDIA1 inhibitors were produced and investigated by a protein nuclear magnetic resonance (NMR) spectroscopy. It was found that both C53 and C56 of the PDIA1 enzyme were involved in covalent binding. Finally, in a range of pharmacological studies, we demonstrated that investigated compounds displayed anti-cancer and anti-thrombotic activity. These findings demonstrate that sulphonamides of Az-COOH derivatives are promising candidates for the development of novel anti-cancer and anti-thrombotic agents.</abstract><cop>England</cop><pub>Taylor & Francis</pub><pmid>37070480</pmid><doi>10.1080/14756366.2022.2158187</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Taylor & Francis Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Acids aziridine Aziridines - pharmacology Cancer Carboxylic acids Chemistry Disulphide Enzymes Humans inhibitor isomerase Ligands NMR Nuclear magnetic resonance PDI Protein Disulfide-Isomerases - antagonists & inhibitors Protein Disulfide-Isomerases - chemistry Proteins Research Paper Spectroscopy Sulfonamides Sulfonamides - pharmacology |
| title | Aromatic sulphonamides of aziridine-2-carboxylic acid derivatives as novel PDIA1 and PDIA3 inhibitors |
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