Design, synthesis, and evaluation of novel quindoline derivatives with fork-shaped side chains as RNA G-quadruplex stabilizers for repressing oncogene NRAS translation
NRAS mutation is the second most common oncogenic factor in cutaneous melanoma. Inhibiting NRAS translation by stabilizing the G-quadruplex (G4) structure with small molecules seems to be a potential strategy for cancer therapy due to the NRAS protein's lack of a druggable pocket. To enhance th...
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| Veröffentlicht in: | European journal of medicinal chemistry 2024-05, Vol.271, p.116406-116406, Article 116406 |
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| container_title | European journal of medicinal chemistry |
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| creator | Sun, Jia-Wei Zou, Jing Zheng, Ying Yuan, Hao Xie, Yuan-Ze-Yu Wang, Xiao-Na Ou, Tian-Miao |
| description | NRAS mutation is the second most common oncogenic factor in cutaneous melanoma. Inhibiting NRAS translation by stabilizing the G-quadruplex (G4) structure with small molecules seems to be a potential strategy for cancer therapy due to the NRAS protein's lack of a druggable pocket. To enhance the effects of previously reported G4 stabilizers quindoline derivatives, we designed and synthesized a novel series of quindoline derivatives with fork-shaped side chains by introducing (alkylamino)alkoxy side chains. Panels of experimental results showed that introducing a fork-shaped (alkylamino)alkoxy side chain could enhance the stabilizing abilities of the ligands against NRAS RNA G-quadruplexes and their anti-melanoma activities. One of them, 10b, exhibited good antitumor activity in the NRAS-mutant melanoma xenograft mouse model, showing the therapeutic potential of this kind of compounds.
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•Quindoline derivatives with fork-shaped chains combated NRASmut melanoma.•Derivatives strongly stabilized NRAS rG4, with most showing ΔTm > 18 °C.•Hit compound 10b stabilized NRAS rG4 and repressed NRAS translation.•10b showed good antitumor activity in the NRASmut melanoma xenograft mouse model. |
| doi_str_mv | 10.1016/j.ejmech.2024.116406 |
| format | Article |
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[Display omitted]
•Quindoline derivatives with fork-shaped chains combated NRASmut melanoma.•Derivatives strongly stabilized NRAS rG4, with most showing ΔTm > 18 °C.•Hit compound 10b stabilized NRAS rG4 and repressed NRAS translation.•10b showed good antitumor activity in the NRASmut melanoma xenograft mouse model.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2024.116406</identifier><identifier>PMID: 38688064</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Alkaloids ; Animals ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Dose-Response Relationship, Drug ; Drug Design ; Drug Screening Assays, Antitumor ; G-Quadruplexes - drug effects ; GTP Phosphohydrolases - metabolism ; Humans ; Indoles - chemical synthesis ; Indoles - chemistry ; Indoles - pharmacology ; Melanoma ; Melanoma - drug therapy ; Melanoma - pathology ; Membrane Proteins - antagonists & inhibitors ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Mice ; Molecular Structure ; NRAS ; Protein Biosynthesis - drug effects ; Quindoline derivative ; Quinolines ; RNA - chemistry ; RNA - metabolism ; RNA G-quadruplex ; Structure-Activity Relationship</subject><ispartof>European journal of medicinal chemistry, 2024-05, Vol.271, p.116406-116406, Article 116406</ispartof><rights>2024 Elsevier Masson SAS</rights><rights>Copyright © 2024 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c311t-ba110e6cb6c4ad15d20d4804422c3567119b1cf1b7d44c55f6407e6f96dc27053</cites><orcidid>0000-0002-8176-4576</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejmech.2024.116406$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38688064$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sun, Jia-Wei</creatorcontrib><creatorcontrib>Zou, Jing</creatorcontrib><creatorcontrib>Zheng, Ying</creatorcontrib><creatorcontrib>Yuan, Hao</creatorcontrib><creatorcontrib>Xie, Yuan-Ze-Yu</creatorcontrib><creatorcontrib>Wang, Xiao-Na</creatorcontrib><creatorcontrib>Ou, Tian-Miao</creatorcontrib><title>Design, synthesis, and evaluation of novel quindoline derivatives with fork-shaped side chains as RNA G-quadruplex stabilizers for repressing oncogene NRAS translation</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>NRAS mutation is the second most common oncogenic factor in cutaneous melanoma. Inhibiting NRAS translation by stabilizing the G-quadruplex (G4) structure with small molecules seems to be a potential strategy for cancer therapy due to the NRAS protein's lack of a druggable pocket. To enhance the effects of previously reported G4 stabilizers quindoline derivatives, we designed and synthesized a novel series of quindoline derivatives with fork-shaped side chains by introducing (alkylamino)alkoxy side chains. Panels of experimental results showed that introducing a fork-shaped (alkylamino)alkoxy side chain could enhance the stabilizing abilities of the ligands against NRAS RNA G-quadruplexes and their anti-melanoma activities. One of them, 10b, exhibited good antitumor activity in the NRAS-mutant melanoma xenograft mouse model, showing the therapeutic potential of this kind of compounds.
[Display omitted]
•Quindoline derivatives with fork-shaped chains combated NRASmut melanoma.•Derivatives strongly stabilized NRAS rG4, with most showing ΔTm > 18 °C.•Hit compound 10b stabilized NRAS rG4 and repressed NRAS translation.•10b showed good antitumor activity in the NRASmut melanoma xenograft mouse model.</description><subject>Alkaloids</subject><subject>Animals</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Design</subject><subject>Drug Screening Assays, Antitumor</subject><subject>G-Quadruplexes - drug effects</subject><subject>GTP Phosphohydrolases - metabolism</subject><subject>Humans</subject><subject>Indoles - chemical synthesis</subject><subject>Indoles - chemistry</subject><subject>Indoles - pharmacology</subject><subject>Melanoma</subject><subject>Melanoma - drug therapy</subject><subject>Melanoma - pathology</subject><subject>Membrane Proteins - antagonists & inhibitors</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Molecular Structure</subject><subject>NRAS</subject><subject>Protein Biosynthesis - drug effects</subject><subject>Quindoline derivative</subject><subject>Quinolines</subject><subject>RNA - chemistry</subject><subject>RNA - metabolism</subject><subject>RNA G-quadruplex</subject><subject>Structure-Activity Relationship</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcFu1DAQhi0EokvhDRDykUOz2I7jZC9IqxYKUlWkAmfLsScbL1k760kC5YV4TbKkcOTkkfz_88_MR8hLztaccfVmv4b9AWy7FkzINedKMvWIrHipqiwXhXxMVkyIPCtELs_IM8Q9Y6xQjD0lZ3mlqoopuSK_rgD9LlxQvA9DO9d4QU1wFCbTjWbwMdDY0BAn6Ohx9MHFzgegDpKf5u8JkH73Q0ubmL5l2JoeHEXvgNrW-IDUIL273dLr7Dgal8a-gx8UB1P7zv-EhCcfTdAnQPRhR2OwcQdzwO3d9jMdkgnY_ZniOXnSmA7hxcN7Tr6-f_fl8kN28-n64-X2JrM550NWG84ZKFsrK43jhRPMyYpJKYTNC1Vyvqm5bXhdOiltUTTz1UpQzUY5K0pW5Ofk9dK3T_E4Ag764NFC15kAcUSdM7kpeVlINkvlIrUpIiZodJ_8waR7zZk-IdJ7vSDSJ0R6QTTbXj0kjPUB3D_TXyaz4O0igHnPyUPSaD0EC84nsIN20f8_4Tcooqb0</recordid><startdate>20240505</startdate><enddate>20240505</enddate><creator>Sun, Jia-Wei</creator><creator>Zou, Jing</creator><creator>Zheng, Ying</creator><creator>Yuan, Hao</creator><creator>Xie, Yuan-Ze-Yu</creator><creator>Wang, Xiao-Na</creator><creator>Ou, Tian-Miao</creator><general>Elsevier Masson SAS</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><orcidid>https://orcid.org/0000-0002-8176-4576</orcidid></search><sort><creationdate>20240505</creationdate><title>Design, synthesis, and evaluation of novel quindoline derivatives with fork-shaped side chains as RNA G-quadruplex stabilizers for repressing oncogene NRAS translation</title><author>Sun, Jia-Wei ; Zou, Jing ; Zheng, Ying ; Yuan, Hao ; Xie, Yuan-Ze-Yu ; Wang, Xiao-Na ; Ou, Tian-Miao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c311t-ba110e6cb6c4ad15d20d4804422c3567119b1cf1b7d44c55f6407e6f96dc27053</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Alkaloids</topic><topic>Animals</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Design</topic><topic>Drug Screening Assays, Antitumor</topic><topic>G-Quadruplexes - drug effects</topic><topic>GTP Phosphohydrolases - metabolism</topic><topic>Humans</topic><topic>Indoles - chemical synthesis</topic><topic>Indoles - chemistry</topic><topic>Indoles - pharmacology</topic><topic>Melanoma</topic><topic>Melanoma - drug therapy</topic><topic>Melanoma - pathology</topic><topic>Membrane Proteins - antagonists & inhibitors</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Molecular Structure</topic><topic>NRAS</topic><topic>Protein Biosynthesis - drug effects</topic><topic>Quindoline derivative</topic><topic>Quinolines</topic><topic>RNA - chemistry</topic><topic>RNA - metabolism</topic><topic>RNA G-quadruplex</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sun, Jia-Wei</creatorcontrib><creatorcontrib>Zou, Jing</creatorcontrib><creatorcontrib>Zheng, Ying</creatorcontrib><creatorcontrib>Yuan, Hao</creatorcontrib><creatorcontrib>Xie, Yuan-Ze-Yu</creatorcontrib><creatorcontrib>Wang, Xiao-Na</creatorcontrib><creatorcontrib>Ou, Tian-Miao</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><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sun, Jia-Wei</au><au>Zou, Jing</au><au>Zheng, Ying</au><au>Yuan, Hao</au><au>Xie, Yuan-Ze-Yu</au><au>Wang, Xiao-Na</au><au>Ou, Tian-Miao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, synthesis, and evaluation of novel quindoline derivatives with fork-shaped side chains as RNA G-quadruplex stabilizers for repressing oncogene NRAS translation</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2024-05-05</date><risdate>2024</risdate><volume>271</volume><spage>116406</spage><epage>116406</epage><pages>116406-116406</pages><artnum>116406</artnum><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>NRAS mutation is the second most common oncogenic factor in cutaneous melanoma. Inhibiting NRAS translation by stabilizing the G-quadruplex (G4) structure with small molecules seems to be a potential strategy for cancer therapy due to the NRAS protein's lack of a druggable pocket. To enhance the effects of previously reported G4 stabilizers quindoline derivatives, we designed and synthesized a novel series of quindoline derivatives with fork-shaped side chains by introducing (alkylamino)alkoxy side chains. Panels of experimental results showed that introducing a fork-shaped (alkylamino)alkoxy side chain could enhance the stabilizing abilities of the ligands against NRAS RNA G-quadruplexes and their anti-melanoma activities. One of them, 10b, exhibited good antitumor activity in the NRAS-mutant melanoma xenograft mouse model, showing the therapeutic potential of this kind of compounds.
[Display omitted]
•Quindoline derivatives with fork-shaped chains combated NRASmut melanoma.•Derivatives strongly stabilized NRAS rG4, with most showing ΔTm > 18 °C.•Hit compound 10b stabilized NRAS rG4 and repressed NRAS translation.•10b showed good antitumor activity in the NRASmut melanoma xenograft mouse model.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>38688064</pmid><doi>10.1016/j.ejmech.2024.116406</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-8176-4576</orcidid></addata></record> |
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| subjects | Alkaloids Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cell Line, Tumor Cell Proliferation - drug effects Dose-Response Relationship, Drug Drug Design Drug Screening Assays, Antitumor G-Quadruplexes - drug effects GTP Phosphohydrolases - metabolism Humans Indoles - chemical synthesis Indoles - chemistry Indoles - pharmacology Melanoma Melanoma - drug therapy Melanoma - pathology Membrane Proteins - antagonists & inhibitors Membrane Proteins - genetics Membrane Proteins - metabolism Mice Molecular Structure NRAS Protein Biosynthesis - drug effects Quindoline derivative Quinolines RNA - chemistry RNA - metabolism RNA G-quadruplex Structure-Activity Relationship |
| title | Design, synthesis, and evaluation of novel quindoline derivatives with fork-shaped side chains as RNA G-quadruplex stabilizers for repressing oncogene NRAS translation |
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