Loading…
Enhanced antitumor potential induced by chloroacetate-loaded benzophenones acting as fused tubulin-pyruvate dehydrogenase kinase 1 (PDHK1) ligands
[Display omitted] •34 synthesized benzo(thio)phenones.•Unprecedented dual tubulin/PDHK1 inhibitors identified.•Molecular docking on studied targets.•Cell cycle analysis on DA1-3b cells.•High cytotoxicity effect on NCI-60 cancer cell line panel (GI50
Saved in:
| Published in: | Bioorganic chemistry 2020-03, Vol.96, p.103643-103643, Article 103643 |
|---|---|
| Main Authors: | , , , , , |
| Format: | Article |
| Language: | English |
| Subjects: | |
| 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-c508t-2f9ea4779cb6540bf20a076321f1a74ea02cedcc556b846625a2ec3daa8875bf3 |
|---|---|
| cites | cdi_FETCH-LOGICAL-c508t-2f9ea4779cb6540bf20a076321f1a74ea02cedcc556b846625a2ec3daa8875bf3 |
| container_end_page | 103643 |
| container_issue | |
| container_start_page | 103643 |
| container_title | Bioorganic chemistry |
| container_volume | 96 |
| creator | Ghinet, Alina Thuru, Xavier Floquet, Emilie Dubois, Joëlle Farce, Amaury Rigo, Benoît |
| description | [Display omitted]
•34 synthesized benzo(thio)phenones.•Unprecedented dual tubulin/PDHK1 inhibitors identified.•Molecular docking on studied targets.•Cell cycle analysis on DA1-3b cells.•High cytotoxicity effect on NCI-60 cancer cell line panel (GI50 |
| doi_str_mv | 10.1016/j.bioorg.2020.103643 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_hal_p</sourceid><recordid>TN_cdi_hal_primary_oai_HAL_hal_02873632v1</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0045206819319376</els_id><sourcerecordid>2352637131</sourcerecordid><originalsourceid>FETCH-LOGICAL-c508t-2f9ea4779cb6540bf20a076321f1a74ea02cedcc556b846625a2ec3daa8875bf3</originalsourceid><addsrcrecordid>eNp9kc9u1DAQxi0EokvhDRDysT1k8Z_EyV6QqtKyiJXgAGdr4kw2XrJ2sJOVlsfgieuQ0iOnkWd-3zfWfIS85WzNGVfvD-vaeh_2a8HE3JIql8_IirMNywQX7DlZMZYXmWCquiCvYjwwxnleqpfkQgomC7GpVuTPnevAGWwouNGO09EHOvgR0wN6al0zzbP6TE3X--DB4AgjZr2HZu6j--2HDp13GCmY0bo9hUjbKabpONVTb102nMN0SiraYHdugt-jg4j0p_1bOL369nH7hV_T3u7BNfE1edFCH_HNY70kP-7vvt9us93XT59vb3aZKVg1ZqLdIORluTG1KnJWt4IBK5UUvOVQ5ghMpK8bUxSqrnKlRAECjWwAqqos6lZekuvFt4NeD8EeIZy1B6u3Nzs995ioSpkMTzyxVws7BP9rwjjqo40G-x4c-ilqkc6pZMnljOYLaoKPMWD75M2ZnpPTB70kp-fk9JJckr173DDVR2yeRP-iSsCHBcB0k5PFoKOxOEdnA5pRN97-f8MDOgetdQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2352637131</pqid></control><display><type>article</type><title>Enhanced antitumor potential induced by chloroacetate-loaded benzophenones acting as fused tubulin-pyruvate dehydrogenase kinase 1 (PDHK1) ligands</title><source>ScienceDirect Freedom Collection</source><creator>Ghinet, Alina ; Thuru, Xavier ; Floquet, Emilie ; Dubois, Joëlle ; Farce, Amaury ; Rigo, Benoît</creator><creatorcontrib>Ghinet, Alina ; Thuru, Xavier ; Floquet, Emilie ; Dubois, Joëlle ; Farce, Amaury ; Rigo, Benoît</creatorcontrib><description>[Display omitted]
•34 synthesized benzo(thio)phenones.•Unprecedented dual tubulin/PDHK1 inhibitors identified.•Molecular docking on studied targets.•Cell cycle analysis on DA1-3b cells.•High cytotoxicity effect on NCI-60 cancer cell line panel (GI50 < 10 nM).
The majority of cancers detected every year are treated with anti-cancer compounds. Unfortunately, many tumors become resistant to antineoplastic drugs. One option is to use cocktails of compounds acting on different targets to try to overcome the resistant cells. This type of approach can produce good results, but is often accompanied by a sharp increase of associated side effects.
The strategy presented herein focuses on the use of a single compound acting on two different biological targets enhancing potency and lowering the toxicity of the chemotherapy. In this light, the approach presented in the current study involves the dual inhibition of human pyruvate dehydrogenase kinase-1 (PDHK1) and tubulin polymerization using mono-, di- and tri-chloroacetate-loaded benzophenones and benzothiophenones.
Synthesized molecules were evaluated in vitro on tubulin polymerization and on pyruvate dehydrogenase kinase 1. The cell cycle distribution after treatment of DA1-3b leukemic cells with active compounds was tested.
Twenty-two benzo(thio)phenones have been selected by the National Cancer Institute (USA) for evaluation of their anti-proliferative potential against NCI-60 cancer cell lines including multidrug-resistant tumor cell lines. Seventeen molecules proved to be very effective in combating the growth of tumor cells exhibiting inhibitory activities up to nanomolar range.
The molecular docking of best antitumor molecules in the study was realized with GOLD in the tubulin and PDHK1 binding sites, and allowed to understand the positioning of active molecules.
Chloroacetate-loaded benzo(thio)phenones are dual targeted tubulin- and pyruvate dehydrogenase kinase 1 (PDHK1)-binding antitumor agents and exhibited superior antitumor activity compared to non-chlorinated congeners particularly on leukemia, colon, melanoma and breast cancer cell lines.</description><identifier>ISSN: 0045-2068</identifier><identifier>EISSN: 1090-2120</identifier><identifier>DOI: 10.1016/j.bioorg.2020.103643</identifier><identifier>PMID: 32035298</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Acetates - chemistry ; Acetates - pharmacology ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Benzophenone ; Benzophenones - chemistry ; Benzophenones - pharmacology ; Cell Line, Tumor ; Chemical Sciences ; Chloroacetate ; DCA, dichloroacetic acid ; Drug Screening Assays, Antitumor ; Humans ; Ligands ; Molecular Docking Simulation ; Neoplasms - drug therapy ; Neoplasms - metabolism ; PDHK1 (h), human pyruvate dehydrogenase kinase 1 ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase - antagonists & inhibitors ; Pyruvate Dehydrogenase Acetyl-Transferring Kinase - metabolism ; SAR, structure-activity relationship ; Tubulin - metabolism ; Tubulin Modulators - chemistry ; Tubulin Modulators - pharmacology</subject><ispartof>Bioorganic chemistry, 2020-03, Vol.96, p.103643-103643, Article 103643</ispartof><rights>2020 Elsevier Inc.</rights><rights>Copyright © 2020 Elsevier Inc. All rights reserved.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c508t-2f9ea4779cb6540bf20a076321f1a74ea02cedcc556b846625a2ec3daa8875bf3</citedby><cites>FETCH-LOGICAL-c508t-2f9ea4779cb6540bf20a076321f1a74ea02cedcc556b846625a2ec3daa8875bf3</cites><orcidid>0000-0002-0998-4160 ; 0000-0001-6468-4331</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32035298$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-02873632$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Ghinet, Alina</creatorcontrib><creatorcontrib>Thuru, Xavier</creatorcontrib><creatorcontrib>Floquet, Emilie</creatorcontrib><creatorcontrib>Dubois, Joëlle</creatorcontrib><creatorcontrib>Farce, Amaury</creatorcontrib><creatorcontrib>Rigo, Benoît</creatorcontrib><title>Enhanced antitumor potential induced by chloroacetate-loaded benzophenones acting as fused tubulin-pyruvate dehydrogenase kinase 1 (PDHK1) ligands</title><title>Bioorganic chemistry</title><addtitle>Bioorg Chem</addtitle><description>[Display omitted]
•34 synthesized benzo(thio)phenones.•Unprecedented dual tubulin/PDHK1 inhibitors identified.•Molecular docking on studied targets.•Cell cycle analysis on DA1-3b cells.•High cytotoxicity effect on NCI-60 cancer cell line panel (GI50 < 10 nM).
The majority of cancers detected every year are treated with anti-cancer compounds. Unfortunately, many tumors become resistant to antineoplastic drugs. One option is to use cocktails of compounds acting on different targets to try to overcome the resistant cells. This type of approach can produce good results, but is often accompanied by a sharp increase of associated side effects.
The strategy presented herein focuses on the use of a single compound acting on two different biological targets enhancing potency and lowering the toxicity of the chemotherapy. In this light, the approach presented in the current study involves the dual inhibition of human pyruvate dehydrogenase kinase-1 (PDHK1) and tubulin polymerization using mono-, di- and tri-chloroacetate-loaded benzophenones and benzothiophenones.
Synthesized molecules were evaluated in vitro on tubulin polymerization and on pyruvate dehydrogenase kinase 1. The cell cycle distribution after treatment of DA1-3b leukemic cells with active compounds was tested.
Twenty-two benzo(thio)phenones have been selected by the National Cancer Institute (USA) for evaluation of their anti-proliferative potential against NCI-60 cancer cell lines including multidrug-resistant tumor cell lines. Seventeen molecules proved to be very effective in combating the growth of tumor cells exhibiting inhibitory activities up to nanomolar range.
The molecular docking of best antitumor molecules in the study was realized with GOLD in the tubulin and PDHK1 binding sites, and allowed to understand the positioning of active molecules.
Chloroacetate-loaded benzo(thio)phenones are dual targeted tubulin- and pyruvate dehydrogenase kinase 1 (PDHK1)-binding antitumor agents and exhibited superior antitumor activity compared to non-chlorinated congeners particularly on leukemia, colon, melanoma and breast cancer cell lines.</description><subject>Acetates - chemistry</subject><subject>Acetates - pharmacology</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Benzophenone</subject><subject>Benzophenones - chemistry</subject><subject>Benzophenones - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Chemical Sciences</subject><subject>Chloroacetate</subject><subject>DCA, dichloroacetic acid</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Humans</subject><subject>Ligands</subject><subject>Molecular Docking Simulation</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - metabolism</subject><subject>PDHK1 (h), human pyruvate dehydrogenase kinase 1</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Pyruvate Dehydrogenase Acetyl-Transferring Kinase - antagonists & inhibitors</subject><subject>Pyruvate Dehydrogenase Acetyl-Transferring Kinase - metabolism</subject><subject>SAR, structure-activity relationship</subject><subject>Tubulin - metabolism</subject><subject>Tubulin Modulators - chemistry</subject><subject>Tubulin Modulators - pharmacology</subject><issn>0045-2068</issn><issn>1090-2120</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kc9u1DAQxi0EokvhDRDysT1k8Z_EyV6QqtKyiJXgAGdr4kw2XrJ2sJOVlsfgieuQ0iOnkWd-3zfWfIS85WzNGVfvD-vaeh_2a8HE3JIql8_IirMNywQX7DlZMZYXmWCquiCvYjwwxnleqpfkQgomC7GpVuTPnevAGWwouNGO09EHOvgR0wN6al0zzbP6TE3X--DB4AgjZr2HZu6j--2HDp13GCmY0bo9hUjbKabpONVTb102nMN0SiraYHdugt-jg4j0p_1bOL369nH7hV_T3u7BNfE1edFCH_HNY70kP-7vvt9us93XT59vb3aZKVg1ZqLdIORluTG1KnJWt4IBK5UUvOVQ5ghMpK8bUxSqrnKlRAECjWwAqqos6lZekuvFt4NeD8EeIZy1B6u3Nzs995ioSpkMTzyxVws7BP9rwjjqo40G-x4c-ilqkc6pZMnljOYLaoKPMWD75M2ZnpPTB70kp-fk9JJckr173DDVR2yeRP-iSsCHBcB0k5PFoKOxOEdnA5pRN97-f8MDOgetdQ</recordid><startdate>202003</startdate><enddate>202003</enddate><creator>Ghinet, Alina</creator><creator>Thuru, Xavier</creator><creator>Floquet, Emilie</creator><creator>Dubois, Joëlle</creator><creator>Farce, Amaury</creator><creator>Rigo, Benoît</creator><general>Elsevier Inc</general><general>Elsevier</general><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>7X8</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0002-0998-4160</orcidid><orcidid>https://orcid.org/0000-0001-6468-4331</orcidid></search><sort><creationdate>202003</creationdate><title>Enhanced antitumor potential induced by chloroacetate-loaded benzophenones acting as fused tubulin-pyruvate dehydrogenase kinase 1 (PDHK1) ligands</title><author>Ghinet, Alina ; Thuru, Xavier ; Floquet, Emilie ; Dubois, Joëlle ; Farce, Amaury ; Rigo, Benoît</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c508t-2f9ea4779cb6540bf20a076321f1a74ea02cedcc556b846625a2ec3daa8875bf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Acetates - chemistry</topic><topic>Acetates - pharmacology</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Benzophenone</topic><topic>Benzophenones - chemistry</topic><topic>Benzophenones - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Chemical Sciences</topic><topic>Chloroacetate</topic><topic>DCA, dichloroacetic acid</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Humans</topic><topic>Ligands</topic><topic>Molecular Docking Simulation</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - metabolism</topic><topic>PDHK1 (h), human pyruvate dehydrogenase kinase 1</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Pyruvate Dehydrogenase Acetyl-Transferring Kinase - antagonists & inhibitors</topic><topic>Pyruvate Dehydrogenase Acetyl-Transferring Kinase - metabolism</topic><topic>SAR, structure-activity relationship</topic><topic>Tubulin - metabolism</topic><topic>Tubulin Modulators - chemistry</topic><topic>Tubulin Modulators - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ghinet, Alina</creatorcontrib><creatorcontrib>Thuru, Xavier</creatorcontrib><creatorcontrib>Floquet, Emilie</creatorcontrib><creatorcontrib>Dubois, Joëlle</creatorcontrib><creatorcontrib>Farce, Amaury</creatorcontrib><creatorcontrib>Rigo, Benoît</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Bioorganic chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ghinet, Alina</au><au>Thuru, Xavier</au><au>Floquet, Emilie</au><au>Dubois, Joëlle</au><au>Farce, Amaury</au><au>Rigo, Benoît</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Enhanced antitumor potential induced by chloroacetate-loaded benzophenones acting as fused tubulin-pyruvate dehydrogenase kinase 1 (PDHK1) ligands</atitle><jtitle>Bioorganic chemistry</jtitle><addtitle>Bioorg Chem</addtitle><date>2020-03</date><risdate>2020</risdate><volume>96</volume><spage>103643</spage><epage>103643</epage><pages>103643-103643</pages><artnum>103643</artnum><issn>0045-2068</issn><eissn>1090-2120</eissn><abstract>[Display omitted]
•34 synthesized benzo(thio)phenones.•Unprecedented dual tubulin/PDHK1 inhibitors identified.•Molecular docking on studied targets.•Cell cycle analysis on DA1-3b cells.•High cytotoxicity effect on NCI-60 cancer cell line panel (GI50 < 10 nM).
The majority of cancers detected every year are treated with anti-cancer compounds. Unfortunately, many tumors become resistant to antineoplastic drugs. One option is to use cocktails of compounds acting on different targets to try to overcome the resistant cells. This type of approach can produce good results, but is often accompanied by a sharp increase of associated side effects.
The strategy presented herein focuses on the use of a single compound acting on two different biological targets enhancing potency and lowering the toxicity of the chemotherapy. In this light, the approach presented in the current study involves the dual inhibition of human pyruvate dehydrogenase kinase-1 (PDHK1) and tubulin polymerization using mono-, di- and tri-chloroacetate-loaded benzophenones and benzothiophenones.
Synthesized molecules were evaluated in vitro on tubulin polymerization and on pyruvate dehydrogenase kinase 1. The cell cycle distribution after treatment of DA1-3b leukemic cells with active compounds was tested.
Twenty-two benzo(thio)phenones have been selected by the National Cancer Institute (USA) for evaluation of their anti-proliferative potential against NCI-60 cancer cell lines including multidrug-resistant tumor cell lines. Seventeen molecules proved to be very effective in combating the growth of tumor cells exhibiting inhibitory activities up to nanomolar range.
The molecular docking of best antitumor molecules in the study was realized with GOLD in the tubulin and PDHK1 binding sites, and allowed to understand the positioning of active molecules.
Chloroacetate-loaded benzo(thio)phenones are dual targeted tubulin- and pyruvate dehydrogenase kinase 1 (PDHK1)-binding antitumor agents and exhibited superior antitumor activity compared to non-chlorinated congeners particularly on leukemia, colon, melanoma and breast cancer cell lines.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>32035298</pmid><doi>10.1016/j.bioorg.2020.103643</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-0998-4160</orcidid><orcidid>https://orcid.org/0000-0001-6468-4331</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0045-2068 |
| ispartof | Bioorganic chemistry, 2020-03, Vol.96, p.103643-103643, Article 103643 |
| issn | 0045-2068 1090-2120 |
| language | eng |
| recordid | cdi_hal_primary_oai_HAL_hal_02873632v1 |
| source | ScienceDirect Freedom Collection |
| subjects | Acetates - chemistry Acetates - pharmacology Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Benzophenone Benzophenones - chemistry Benzophenones - pharmacology Cell Line, Tumor Chemical Sciences Chloroacetate DCA, dichloroacetic acid Drug Screening Assays, Antitumor Humans Ligands Molecular Docking Simulation Neoplasms - drug therapy Neoplasms - metabolism PDHK1 (h), human pyruvate dehydrogenase kinase 1 Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Pyruvate Dehydrogenase Acetyl-Transferring Kinase - antagonists & inhibitors Pyruvate Dehydrogenase Acetyl-Transferring Kinase - metabolism SAR, structure-activity relationship Tubulin - metabolism Tubulin Modulators - chemistry Tubulin Modulators - pharmacology |
| title | Enhanced antitumor potential induced by chloroacetate-loaded benzophenones acting as fused tubulin-pyruvate dehydrogenase kinase 1 (PDHK1) ligands |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-29T07%3A01%3A01IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_hal_p&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Enhanced%20antitumor%20potential%20induced%20by%20chloroacetate-loaded%20benzophenones%20acting%20as%20fused%20tubulin-pyruvate%20dehydrogenase%20kinase%201%20(PDHK1)%20ligands&rft.jtitle=Bioorganic%20chemistry&rft.au=Ghinet,%20Alina&rft.date=2020-03&rft.volume=96&rft.spage=103643&rft.epage=103643&rft.pages=103643-103643&rft.artnum=103643&rft.issn=0045-2068&rft.eissn=1090-2120&rft_id=info:doi/10.1016/j.bioorg.2020.103643&rft_dat=%3Cproquest_hal_p%3E2352637131%3C/proquest_hal_p%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c508t-2f9ea4779cb6540bf20a076321f1a74ea02cedcc556b846625a2ec3daa8875bf3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2352637131&rft_id=info:pmid/32035298&rfr_iscdi=true |