Synthesis, modeling, and biological evaluation of anti-tubulin indole-substituted furanones
[Display omitted] Due to the central role of tubulin in various cellular functions, it is a validated target for anti-cancer therapeutics. However, many of the current tubulin inhibitors are derived from complex natural products and suffer from multidrug resistance, low solubility, toxicity issues,...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2023-06, Vol.90, p.129347-129347, Article 129347 |
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| creator | Hurysz, Brianna Evans, Blake A. Laryea, Reuben N. Boyer, Brooke E. Coburn, Taylor E. Dexter, Molly S. Edwards, Marissa A. Faulkner, Grace V. Huss, Rebecca L. Lafferty, Megan M. Manning, Maegan McNulty, Matthew Melvin, Sophia J. Mitrow, Christina M. Patel, Roslyn R. Pierce, Kelsey Russo, Jack Seminer, Allie M. Sockett, Kaitlynn A. Webster, Nathan R. Cole, Kathryn E. Mowery, Patricia Pelkey, Erin T. |
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Due to the central role of tubulin in various cellular functions, it is a validated target for anti-cancer therapeutics. However, many of the current tubulin inhibitors are derived from complex natural products and suffer from multidrug resistance, low solubility, toxicity issues, and/or the lack of multi-cancer efficacy. As such, there is a continued need for the discovery and development of new anti-tubulin drugs to enter the pipeline. Herein we report on a group of indole-substituted furanones that were prepared and tested for anti-cancer activity. Molecular docking studies showed positive correlations between favorable binding in the colchicine binding site (CBS) of tubulin and anti-proliferative activity, and the most potent compound was found to inhibit tubulin polymerization. These compounds represent a promising new structural motif in the search for small heterocyclic CBS cancer inhibitors. |
| doi_str_mv | 10.1016/j.bmcl.2023.129347 |
| format | Article |
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Due to the central role of tubulin in various cellular functions, it is a validated target for anti-cancer therapeutics. However, many of the current tubulin inhibitors are derived from complex natural products and suffer from multidrug resistance, low solubility, toxicity issues, and/or the lack of multi-cancer efficacy. As such, there is a continued need for the discovery and development of new anti-tubulin drugs to enter the pipeline. Herein we report on a group of indole-substituted furanones that were prepared and tested for anti-cancer activity. Molecular docking studies showed positive correlations between favorable binding in the colchicine binding site (CBS) of tubulin and anti-proliferative activity, and the most potent compound was found to inhibit tubulin polymerization. These compounds represent a promising new structural motif in the search for small heterocyclic CBS cancer inhibitors.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2023.129347</identifier><identifier>PMID: 37236376</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Antineoplastic Agents - chemistry ; Antiproliferative ; Antitubulin ; Binding Sites ; Cell Line, Tumor ; Cell Proliferation ; Colchicine - chemistry ; Drug Screening Assays, Antitumor ; Heterocyclic ; Indole ; Indoles - chemistry ; Molecular Docking Simulation ; Structure-Activity Relationship ; Tubulin - metabolism ; Tubulin Modulators - chemistry</subject><ispartof>Bioorganic & medicinal chemistry letters, 2023-06, Vol.90, p.129347-129347, Article 129347</ispartof><rights>2023 Elsevier Ltd</rights><rights>Copyright © 2023 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c400t-103ffd16edbf5b3f7b770c50a5b9964307fce538536ac1fad3e52f444cadc04d3</citedby><cites>FETCH-LOGICAL-c400t-103ffd16edbf5b3f7b770c50a5b9964307fce538536ac1fad3e52f444cadc04d3</cites><orcidid>0009-0000-3133-5872 ; 0000-0002-5430-6959 ; 0000-0002-9454-9234 ; 0009-0009-2452-3758 ; 0000-0003-3059-384X ; 0009-0008-4523-9759 ; 0009-0001-8395-8278 ; 0000-0001-8882-9128</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X23002251$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37236376$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hurysz, Brianna</creatorcontrib><creatorcontrib>Evans, Blake A.</creatorcontrib><creatorcontrib>Laryea, Reuben N.</creatorcontrib><creatorcontrib>Boyer, Brooke E.</creatorcontrib><creatorcontrib>Coburn, Taylor E.</creatorcontrib><creatorcontrib>Dexter, Molly S.</creatorcontrib><creatorcontrib>Edwards, Marissa A.</creatorcontrib><creatorcontrib>Faulkner, Grace V.</creatorcontrib><creatorcontrib>Huss, Rebecca L.</creatorcontrib><creatorcontrib>Lafferty, Megan M.</creatorcontrib><creatorcontrib>Manning, Maegan</creatorcontrib><creatorcontrib>McNulty, Matthew</creatorcontrib><creatorcontrib>Melvin, Sophia J.</creatorcontrib><creatorcontrib>Mitrow, Christina M.</creatorcontrib><creatorcontrib>Patel, Roslyn R.</creatorcontrib><creatorcontrib>Pierce, Kelsey</creatorcontrib><creatorcontrib>Russo, Jack</creatorcontrib><creatorcontrib>Seminer, Allie M.</creatorcontrib><creatorcontrib>Sockett, Kaitlynn A.</creatorcontrib><creatorcontrib>Webster, Nathan R.</creatorcontrib><creatorcontrib>Cole, Kathryn E.</creatorcontrib><creatorcontrib>Mowery, Patricia</creatorcontrib><creatorcontrib>Pelkey, Erin T.</creatorcontrib><title>Synthesis, modeling, and biological evaluation of anti-tubulin indole-substituted furanones</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Due to the central role of tubulin in various cellular functions, it is a validated target for anti-cancer therapeutics. However, many of the current tubulin inhibitors are derived from complex natural products and suffer from multidrug resistance, low solubility, toxicity issues, and/or the lack of multi-cancer efficacy. As such, there is a continued need for the discovery and development of new anti-tubulin drugs to enter the pipeline. Herein we report on a group of indole-substituted furanones that were prepared and tested for anti-cancer activity. Molecular docking studies showed positive correlations between favorable binding in the colchicine binding site (CBS) of tubulin and anti-proliferative activity, and the most potent compound was found to inhibit tubulin polymerization. These compounds represent a promising new structural motif in the search for small heterocyclic CBS cancer inhibitors.</description><subject>Antineoplastic Agents - chemistry</subject><subject>Antiproliferative</subject><subject>Antitubulin</subject><subject>Binding Sites</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Colchicine - chemistry</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Heterocyclic</subject><subject>Indole</subject><subject>Indoles - chemistry</subject><subject>Molecular Docking Simulation</subject><subject>Structure-Activity Relationship</subject><subject>Tubulin - metabolism</subject><subject>Tubulin Modulators - chemistry</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1LHTEUhoNU9Gr7B1yUWXbhXE8-ZuYOuCnSakHoohWELkI-TjSXTGInieC_71yudunqLN7nfeE8hJxRWFOg_cV2rScT1gwYX1M2cjEckBUVvWi5gO4DWcHYQ7sZxf0xOcl5C0AFCHFEjvnAeM-HfkX-_HqJ5RGzz-fNlCwGHx_OGxVto30K6cEbFRp8VqGq4lNsklvC4ttSdV3YxkebAra56lx8qQVt4-qsYoqYP5JDp0LGT6_3lNx9__b76qa9_Xn94-rrbWsEQGkpcOcs7dFq12nuBj0MYDpQnR7HXnAYnMGObzreK0Odshw75oQQRlkDwvJT8mW_-zSnvxVzkZPPBkNQEVPNkm0YABtg3Cwo26NmTjnP6OTT7Cc1v0gKcidVbuVOqtxJlXupS-nz637VE9r_lTeLC3C5B3D58tnjLLPxGA1aP6Mp0ib_3v4_CSSKEg</recordid><startdate>20230615</startdate><enddate>20230615</enddate><creator>Hurysz, Brianna</creator><creator>Evans, Blake A.</creator><creator>Laryea, Reuben N.</creator><creator>Boyer, Brooke E.</creator><creator>Coburn, Taylor E.</creator><creator>Dexter, Molly S.</creator><creator>Edwards, Marissa A.</creator><creator>Faulkner, Grace V.</creator><creator>Huss, Rebecca L.</creator><creator>Lafferty, Megan M.</creator><creator>Manning, Maegan</creator><creator>McNulty, Matthew</creator><creator>Melvin, Sophia J.</creator><creator>Mitrow, Christina M.</creator><creator>Patel, Roslyn R.</creator><creator>Pierce, Kelsey</creator><creator>Russo, Jack</creator><creator>Seminer, Allie M.</creator><creator>Sockett, Kaitlynn A.</creator><creator>Webster, Nathan R.</creator><creator>Cole, Kathryn E.</creator><creator>Mowery, Patricia</creator><creator>Pelkey, Erin T.</creator><general>Elsevier Ltd</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/0009-0000-3133-5872</orcidid><orcidid>https://orcid.org/0000-0002-5430-6959</orcidid><orcidid>https://orcid.org/0000-0002-9454-9234</orcidid><orcidid>https://orcid.org/0009-0009-2452-3758</orcidid><orcidid>https://orcid.org/0000-0003-3059-384X</orcidid><orcidid>https://orcid.org/0009-0008-4523-9759</orcidid><orcidid>https://orcid.org/0009-0001-8395-8278</orcidid><orcidid>https://orcid.org/0000-0001-8882-9128</orcidid></search><sort><creationdate>20230615</creationdate><title>Synthesis, modeling, and biological evaluation of anti-tubulin indole-substituted furanones</title><author>Hurysz, Brianna ; Evans, Blake A. ; Laryea, Reuben N. ; Boyer, Brooke E. ; Coburn, Taylor E. ; Dexter, Molly S. ; Edwards, Marissa A. ; Faulkner, Grace V. ; Huss, Rebecca L. ; Lafferty, Megan M. ; Manning, Maegan ; McNulty, Matthew ; Melvin, Sophia J. ; Mitrow, Christina M. ; Patel, Roslyn R. ; Pierce, Kelsey ; Russo, Jack ; Seminer, Allie M. ; Sockett, Kaitlynn A. ; Webster, Nathan R. ; Cole, Kathryn E. ; Mowery, Patricia ; Pelkey, Erin T.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c400t-103ffd16edbf5b3f7b770c50a5b9964307fce538536ac1fad3e52f444cadc04d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Antineoplastic Agents - chemistry</topic><topic>Antiproliferative</topic><topic>Antitubulin</topic><topic>Binding Sites</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Colchicine - chemistry</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Heterocyclic</topic><topic>Indole</topic><topic>Indoles - chemistry</topic><topic>Molecular Docking Simulation</topic><topic>Structure-Activity Relationship</topic><topic>Tubulin - metabolism</topic><topic>Tubulin Modulators - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hurysz, Brianna</creatorcontrib><creatorcontrib>Evans, Blake A.</creatorcontrib><creatorcontrib>Laryea, Reuben N.</creatorcontrib><creatorcontrib>Boyer, Brooke E.</creatorcontrib><creatorcontrib>Coburn, Taylor E.</creatorcontrib><creatorcontrib>Dexter, Molly S.</creatorcontrib><creatorcontrib>Edwards, Marissa A.</creatorcontrib><creatorcontrib>Faulkner, Grace V.</creatorcontrib><creatorcontrib>Huss, Rebecca L.</creatorcontrib><creatorcontrib>Lafferty, Megan M.</creatorcontrib><creatorcontrib>Manning, Maegan</creatorcontrib><creatorcontrib>McNulty, Matthew</creatorcontrib><creatorcontrib>Melvin, Sophia J.</creatorcontrib><creatorcontrib>Mitrow, Christina M.</creatorcontrib><creatorcontrib>Patel, Roslyn R.</creatorcontrib><creatorcontrib>Pierce, Kelsey</creatorcontrib><creatorcontrib>Russo, Jack</creatorcontrib><creatorcontrib>Seminer, Allie M.</creatorcontrib><creatorcontrib>Sockett, Kaitlynn A.</creatorcontrib><creatorcontrib>Webster, Nathan R.</creatorcontrib><creatorcontrib>Cole, Kathryn E.</creatorcontrib><creatorcontrib>Mowery, Patricia</creatorcontrib><creatorcontrib>Pelkey, Erin T.</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>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hurysz, Brianna</au><au>Evans, Blake A.</au><au>Laryea, Reuben N.</au><au>Boyer, Brooke E.</au><au>Coburn, Taylor E.</au><au>Dexter, Molly S.</au><au>Edwards, Marissa A.</au><au>Faulkner, Grace V.</au><au>Huss, Rebecca L.</au><au>Lafferty, Megan M.</au><au>Manning, Maegan</au><au>McNulty, Matthew</au><au>Melvin, Sophia J.</au><au>Mitrow, Christina M.</au><au>Patel, Roslyn R.</au><au>Pierce, Kelsey</au><au>Russo, Jack</au><au>Seminer, Allie M.</au><au>Sockett, Kaitlynn A.</au><au>Webster, Nathan R.</au><au>Cole, Kathryn E.</au><au>Mowery, Patricia</au><au>Pelkey, Erin T.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis, modeling, and biological evaluation of anti-tubulin indole-substituted furanones</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2023-06-15</date><risdate>2023</risdate><volume>90</volume><spage>129347</spage><epage>129347</epage><pages>129347-129347</pages><artnum>129347</artnum><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
Due to the central role of tubulin in various cellular functions, it is a validated target for anti-cancer therapeutics. However, many of the current tubulin inhibitors are derived from complex natural products and suffer from multidrug resistance, low solubility, toxicity issues, and/or the lack of multi-cancer efficacy. As such, there is a continued need for the discovery and development of new anti-tubulin drugs to enter the pipeline. Herein we report on a group of indole-substituted furanones that were prepared and tested for anti-cancer activity. Molecular docking studies showed positive correlations between favorable binding in the colchicine binding site (CBS) of tubulin and anti-proliferative activity, and the most potent compound was found to inhibit tubulin polymerization. These compounds represent a promising new structural motif in the search for small heterocyclic CBS cancer inhibitors.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>37236376</pmid><doi>10.1016/j.bmcl.2023.129347</doi><tpages>1</tpages><orcidid>https://orcid.org/0009-0000-3133-5872</orcidid><orcidid>https://orcid.org/0000-0002-5430-6959</orcidid><orcidid>https://orcid.org/0000-0002-9454-9234</orcidid><orcidid>https://orcid.org/0009-0009-2452-3758</orcidid><orcidid>https://orcid.org/0000-0003-3059-384X</orcidid><orcidid>https://orcid.org/0009-0008-4523-9759</orcidid><orcidid>https://orcid.org/0009-0001-8395-8278</orcidid><orcidid>https://orcid.org/0000-0001-8882-9128</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2023-06, Vol.90, p.129347-129347, Article 129347 |
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| subjects | Antineoplastic Agents - chemistry Antiproliferative Antitubulin Binding Sites Cell Line, Tumor Cell Proliferation Colchicine - chemistry Drug Screening Assays, Antitumor Heterocyclic Indole Indoles - chemistry Molecular Docking Simulation Structure-Activity Relationship Tubulin - metabolism Tubulin Modulators - chemistry |
| title | Synthesis, modeling, and biological evaluation of anti-tubulin indole-substituted furanones |
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