Structure simplification of the Securinine skeleton reveals the importance of BCD ring system for the cytotoxic activity on HCT116 and HL60 cell lines
[Display omitted] Function-oriented molecular editing of the polycyclic scaffold of securinine led to the preparation of a library of simplified analogs that have been evaluated for their cytotoxicity potential against HCT116 and HL60 human cell lines. Chemical diversity at the C14 position (securin...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2022-03, Vol.58, p.116658-116658, Article 116658 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Le Roch, Myriam Afonso, Damien Chirkin, Egor Guillory, Xavier Porée, François-Hugues |
| description | [Display omitted]
Function-oriented molecular editing of the polycyclic scaffold of securinine led to the preparation of a library of simplified analogs that have been evaluated for their cytotoxicity potential against HCT116 and HL60 human cell lines. Chemical diversity at the C14 position (securinine numbering) was generated through the site-selective γ-iodination followed by Pd-catalyzed Sonogashira and Suzuki-Miyaura reactions. To explain the selectivity in the iodination step, a reaction mechanism has been proposed. Surprisingly, the piperidine ring (ring A) of the securinine skeleton has been found to be irrelevant for the cytotoxic activity. Based on this finding, the pharmacophoric core of securinine could be simplified to the key BCD motif. The nature of the substituent at the nitrogen can vary from a methyl or an isobutyl group to a benzyl or a carbamate moiety. Interestingly, the N-benzyl substituted simplified analog exhibited the same cytotoxic activity as the parent compound securinine. This functional group tolerance paves the way for the installation of reactive handles for the synthesis of molecular probes for target identification. |
| doi_str_mv | 10.1016/j.bmc.2022.116658 |
| format | Article |
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Function-oriented molecular editing of the polycyclic scaffold of securinine led to the preparation of a library of simplified analogs that have been evaluated for their cytotoxicity potential against HCT116 and HL60 human cell lines. Chemical diversity at the C14 position (securinine numbering) was generated through the site-selective γ-iodination followed by Pd-catalyzed Sonogashira and Suzuki-Miyaura reactions. To explain the selectivity in the iodination step, a reaction mechanism has been proposed. Surprisingly, the piperidine ring (ring A) of the securinine skeleton has been found to be irrelevant for the cytotoxic activity. Based on this finding, the pharmacophoric core of securinine could be simplified to the key BCD motif. The nature of the substituent at the nitrogen can vary from a methyl or an isobutyl group to a benzyl or a carbamate moiety. Interestingly, the N-benzyl substituted simplified analog exhibited the same cytotoxic activity as the parent compound securinine. This functional group tolerance paves the way for the installation of reactive handles for the synthesis of molecular probes for target identification.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2022.116658</identifier><identifier>PMID: 35183880</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Azepines - chemical synthesis ; Azepines - chemistry ; Azepines - pharmacology ; Cancer ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Chemical Sciences ; Cytotoxicity ; Density Functional Theory ; Dose-Response Relationship, Drug ; Drug Screening Assays, Antitumor ; HCT116 ; HCT116 Cells ; Heterocyclic Compounds, Bridged-Ring - chemical synthesis ; Heterocyclic Compounds, Bridged-Ring - chemistry ; Heterocyclic Compounds, Bridged-Ring - pharmacology ; HL-60 Cells ; HL60 ; Humans ; Lactones - chemical synthesis ; Lactones - chemistry ; Lactones - pharmacology ; Life Sciences ; Molecular Conformation ; Molecular editing ; Organic chemistry ; Piperidines - chemical synthesis ; Piperidines - chemistry ; Piperidines - pharmacology ; Securinega ; Simplified analogs ; Structure-Activity Relationship ; Tumor Cells, Cultured</subject><ispartof>Bioorganic & medicinal chemistry, 2022-03, Vol.58, p.116658-116658, Article 116658</ispartof><rights>2022 Elsevier Ltd</rights><rights>Copyright © 2022 Elsevier Ltd. 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><cites>FETCH-LOGICAL-c382t-e41995ca388d354d7c4c94b97c4249b2f5eade9de98d624846ec6e1f3b75759e3</cites><orcidid>0000-0001-5989-3833</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmc.2022.116658$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35183880$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://univ-rennes.hal.science/hal-03683055$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Le Roch, Myriam</creatorcontrib><creatorcontrib>Afonso, Damien</creatorcontrib><creatorcontrib>Chirkin, Egor</creatorcontrib><creatorcontrib>Guillory, Xavier</creatorcontrib><creatorcontrib>Porée, François-Hugues</creatorcontrib><title>Structure simplification of the Securinine skeleton reveals the importance of BCD ring system for the cytotoxic activity on HCT116 and HL60 cell lines</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
Function-oriented molecular editing of the polycyclic scaffold of securinine led to the preparation of a library of simplified analogs that have been evaluated for their cytotoxicity potential against HCT116 and HL60 human cell lines. Chemical diversity at the C14 position (securinine numbering) was generated through the site-selective γ-iodination followed by Pd-catalyzed Sonogashira and Suzuki-Miyaura reactions. To explain the selectivity in the iodination step, a reaction mechanism has been proposed. Surprisingly, the piperidine ring (ring A) of the securinine skeleton has been found to be irrelevant for the cytotoxic activity. Based on this finding, the pharmacophoric core of securinine could be simplified to the key BCD motif. The nature of the substituent at the nitrogen can vary from a methyl or an isobutyl group to a benzyl or a carbamate moiety. Interestingly, the N-benzyl substituted simplified analog exhibited the same cytotoxic activity as the parent compound securinine. This functional group tolerance paves the way for the installation of reactive handles for the synthesis of molecular probes for target identification.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Azepines - chemical synthesis</subject><subject>Azepines - chemistry</subject><subject>Azepines - pharmacology</subject><subject>Cancer</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Chemical Sciences</subject><subject>Cytotoxicity</subject><subject>Density Functional Theory</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Screening Assays, Antitumor</subject><subject>HCT116</subject><subject>HCT116 Cells</subject><subject>Heterocyclic Compounds, Bridged-Ring - chemical synthesis</subject><subject>Heterocyclic Compounds, Bridged-Ring - chemistry</subject><subject>Heterocyclic Compounds, Bridged-Ring - pharmacology</subject><subject>HL-60 Cells</subject><subject>HL60</subject><subject>Humans</subject><subject>Lactones - chemical synthesis</subject><subject>Lactones - chemistry</subject><subject>Lactones - pharmacology</subject><subject>Life Sciences</subject><subject>Molecular Conformation</subject><subject>Molecular editing</subject><subject>Organic chemistry</subject><subject>Piperidines - chemical synthesis</subject><subject>Piperidines - chemistry</subject><subject>Piperidines - pharmacology</subject><subject>Securinega</subject><subject>Simplified analogs</subject><subject>Structure-Activity Relationship</subject><subject>Tumor Cells, Cultured</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kctu1DAUhi0EokPhAdggL2GRwY4vY4tVO1wGaSQWLWvLcU6ohyQebGfEvAjPi9OULpEsHcnnO_-5_Ai9pmRNCZXvD-tmcOua1PWaUimFeoJWlEteMabpU7QiWqqKKC0v0IuUDoSQmmv6HF0wQRVTiqzQn5scJ5enCDj54dj7zjubfRhx6HC-A3wDbop-9GMBfkIPuaQinMD26T5fikLMdnQwV1xvP-JC_8DpnDIMuAvxnnLnHHL47R22LvuTz2dcdHbb2zI3tmOLd3tJsIO-x31plV6iZ13pAK8e4iX6_vnT7XZX7b99-bq92leOqTpXwKnWwtmyS8sEbzeOO80bXWLZtKk7AbYFXZ5qZc0Vl-Ak0I41G7ERGtglerfo3tneHKMfbDybYL3ZXe3N_EeYVIwIcaKFfbuwxxh-TZCyGXyaR7YjhCmZWjIqqSJqRumCuhhSitA9alNiZuvMwRTrzGydWawrNW8e5KdmgPax4p9XBfiwAFAOcvIQTXIeyuFbH8Fl0wb_H_m_LsCpnw</recordid><startdate>20220315</startdate><enddate>20220315</enddate><creator>Le Roch, Myriam</creator><creator>Afonso, Damien</creator><creator>Chirkin, Egor</creator><creator>Guillory, Xavier</creator><creator>Porée, François-Hugues</creator><general>Elsevier Ltd</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><scope>VOOES</scope><orcidid>https://orcid.org/0000-0001-5989-3833</orcidid></search><sort><creationdate>20220315</creationdate><title>Structure simplification of the Securinine skeleton reveals the importance of BCD ring system for the cytotoxic activity on HCT116 and HL60 cell lines</title><author>Le Roch, Myriam ; Afonso, Damien ; Chirkin, Egor ; Guillory, Xavier ; Porée, François-Hugues</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c382t-e41995ca388d354d7c4c94b97c4249b2f5eade9de98d624846ec6e1f3b75759e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Azepines - chemical synthesis</topic><topic>Azepines - chemistry</topic><topic>Azepines - pharmacology</topic><topic>Cancer</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Chemical Sciences</topic><topic>Cytotoxicity</topic><topic>Density Functional Theory</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Screening Assays, Antitumor</topic><topic>HCT116</topic><topic>HCT116 Cells</topic><topic>Heterocyclic Compounds, Bridged-Ring - chemical synthesis</topic><topic>Heterocyclic Compounds, Bridged-Ring - chemistry</topic><topic>Heterocyclic Compounds, Bridged-Ring - pharmacology</topic><topic>HL-60 Cells</topic><topic>HL60</topic><topic>Humans</topic><topic>Lactones - chemical synthesis</topic><topic>Lactones - chemistry</topic><topic>Lactones - pharmacology</topic><topic>Life Sciences</topic><topic>Molecular Conformation</topic><topic>Molecular editing</topic><topic>Organic chemistry</topic><topic>Piperidines - chemical synthesis</topic><topic>Piperidines - chemistry</topic><topic>Piperidines - pharmacology</topic><topic>Securinega</topic><topic>Simplified analogs</topic><topic>Structure-Activity Relationship</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Le Roch, Myriam</creatorcontrib><creatorcontrib>Afonso, Damien</creatorcontrib><creatorcontrib>Chirkin, Egor</creatorcontrib><creatorcontrib>Guillory, Xavier</creatorcontrib><creatorcontrib>Porée, François-Hugues</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><collection>Hyper Article en Ligne (HAL) (Open Access)</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Le Roch, Myriam</au><au>Afonso, Damien</au><au>Chirkin, Egor</au><au>Guillory, Xavier</au><au>Porée, François-Hugues</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure simplification of the Securinine skeleton reveals the importance of BCD ring system for the cytotoxic activity on HCT116 and HL60 cell lines</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2022-03-15</date><risdate>2022</risdate><volume>58</volume><spage>116658</spage><epage>116658</epage><pages>116658-116658</pages><artnum>116658</artnum><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
Function-oriented molecular editing of the polycyclic scaffold of securinine led to the preparation of a library of simplified analogs that have been evaluated for their cytotoxicity potential against HCT116 and HL60 human cell lines. Chemical diversity at the C14 position (securinine numbering) was generated through the site-selective γ-iodination followed by Pd-catalyzed Sonogashira and Suzuki-Miyaura reactions. To explain the selectivity in the iodination step, a reaction mechanism has been proposed. Surprisingly, the piperidine ring (ring A) of the securinine skeleton has been found to be irrelevant for the cytotoxic activity. Based on this finding, the pharmacophoric core of securinine could be simplified to the key BCD motif. The nature of the substituent at the nitrogen can vary from a methyl or an isobutyl group to a benzyl or a carbamate moiety. Interestingly, the N-benzyl substituted simplified analog exhibited the same cytotoxic activity as the parent compound securinine. This functional group tolerance paves the way for the installation of reactive handles for the synthesis of molecular probes for target identification.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>35183880</pmid><doi>10.1016/j.bmc.2022.116658</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0001-5989-3833</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry, 2022-03, Vol.58, p.116658-116658, Article 116658 |
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| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Azepines - chemical synthesis Azepines - chemistry Azepines - pharmacology Cancer Cell Proliferation - drug effects Cell Survival - drug effects Chemical Sciences Cytotoxicity Density Functional Theory Dose-Response Relationship, Drug Drug Screening Assays, Antitumor HCT116 HCT116 Cells Heterocyclic Compounds, Bridged-Ring - chemical synthesis Heterocyclic Compounds, Bridged-Ring - chemistry Heterocyclic Compounds, Bridged-Ring - pharmacology HL-60 Cells HL60 Humans Lactones - chemical synthesis Lactones - chemistry Lactones - pharmacology Life Sciences Molecular Conformation Molecular editing Organic chemistry Piperidines - chemical synthesis Piperidines - chemistry Piperidines - pharmacology Securinega Simplified analogs Structure-Activity Relationship Tumor Cells, Cultured |
| title | Structure simplification of the Securinine skeleton reveals the importance of BCD ring system for the cytotoxic activity on HCT116 and HL60 cell lines |
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