Nur Farisya Shamsudin, Sze-Wei Leong, Andreas Koeberle, Utid Suriya, Thanyada Rungrotmongkol, Suet Lin Chia, Muhammad Taher, Muhammad Salahuddin Haris, Hussah Abdullah Alshwyeh, Areej A Alosaimi, Ahmed Mediani, Muna Abdulsalam Ilowefah, Deri Islami, Siti Munirah Mohd Faudzi, Mohd Fadhlizil Fasihi Mohd Aluwi, Lam Kok Wai, Kamal Rullah
{"title":"一种基于色酮的新型 ULK1 潜在抑制剂，可调节自噬并诱导结肠癌细胞凋亡。","authors":"Nur Farisya Shamsudin, Sze-Wei Leong, Andreas Koeberle, Utid Suriya, Thanyada Rungrotmongkol, Suet Lin Chia, Muhammad Taher, Muhammad Salahuddin Haris, Hussah Abdullah Alshwyeh, Areej A Alosaimi, Ahmed Mediani, Muna Abdulsalam Ilowefah, Deri Islami, Siti Munirah Mohd Faudzi, Mohd Fadhlizil Fasihi Mohd Aluwi, Lam Kok Wai, Kamal Rullah","doi":"10.1080/17568919.2024.2363668","DOIUrl":null,"url":null,"abstract":"<p><p><b>Aim:</b> Chromones are promising for anticancer drug development.<b>Methods & results:</b> 12 chromone-based compounds were synthesized and tested against cancer cell lines. Compound <b>8</b> showed the highest cytotoxicity (LC<sub>50</sub> 3.2 μM) against colorectal cancer cells, surpassing 5-fluorouracil (LC<sub>50</sub> 4.2 μM). It suppressed colony formation, induced cell cycle arrest and triggered apoptotic cell death, confirmed by staining and apoptosis markers. Cell death was accompanied by enhanced reactive oxygen species formation and modulation of the autophagic machinery (autophagy marker light chain 3B (LC3B); adenosine monophosphate-activated protein kinase (AMPK); protein kinase B (PKB); UNC-51-like kinase (ULK)-1; and ULK2). Molecular docking and dynamic simulations revealed that compound <b>8</b> directly binds to ULK1.<b>Conclusion:</b> Compound <b>8</b> is a promising lead for autophagy-modulating anti-colon cancer drugs.</p>","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"1499-1517"},"PeriodicalIF":3.2000,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370956/pdf/","citationCount":"0","resultStr":"{\"title\":\"A novel chromone-based as a potential inhibitor of ULK1 that modulates autophagy and induces apoptosis in colon cancer.\",\"authors\":\"Nur Farisya Shamsudin, Sze-Wei Leong, Andreas Koeberle, Utid Suriya, Thanyada Rungrotmongkol, Suet Lin Chia, Muhammad Taher, Muhammad Salahuddin Haris, Hussah Abdullah Alshwyeh, Areej A Alosaimi, Ahmed Mediani, Muna Abdulsalam Ilowefah, Deri Islami, Siti Munirah Mohd Faudzi, Mohd Fadhlizil Fasihi Mohd Aluwi, Lam Kok Wai, Kamal Rullah\",\"doi\":\"10.1080/17568919.2024.2363668\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Aim:</b> Chromones are promising for anticancer drug development.<b>Methods & results:</b> 12 chromone-based compounds were synthesized and tested against cancer cell lines. Compound <b>8</b> showed the highest cytotoxicity (LC<sub>50</sub> 3.2 μM) against colorectal cancer cells, surpassing 5-fluorouracil (LC<sub>50</sub> 4.2 μM). It suppressed colony formation, induced cell cycle arrest and triggered apoptotic cell death, confirmed by staining and apoptosis markers. Cell death was accompanied by enhanced reactive oxygen species formation and modulation of the autophagic machinery (autophagy marker light chain 3B (LC3B); adenosine monophosphate-activated protein kinase (AMPK); protein kinase B (PKB); UNC-51-like kinase (ULK)-1; and ULK2). Molecular docking and dynamic simulations revealed that compound <b>8</b> directly binds to ULK1.<b>Conclusion:</b> Compound <b>8</b> is a promising lead for autophagy-modulating anti-colon cancer drugs.</p>\",\"PeriodicalId\":12475,\"journal\":{\"name\":\"Future medicinal chemistry\",\"volume\":\" \",\"pages\":\"1499-1517\"},\"PeriodicalIF\":3.2000,\"publicationDate\":\"2024-08-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370956/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Future medicinal chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/17568919.2024.2363668\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/7/1 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Future medicinal chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/17568919.2024.2363668","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/1 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
A novel chromone-based as a potential inhibitor of ULK1 that modulates autophagy and induces apoptosis in colon cancer.
Aim: Chromones are promising for anticancer drug development.Methods & results: 12 chromone-based compounds were synthesized and tested against cancer cell lines. Compound 8 showed the highest cytotoxicity (LC50 3.2 μM) against colorectal cancer cells, surpassing 5-fluorouracil (LC50 4.2 μM). It suppressed colony formation, induced cell cycle arrest and triggered apoptotic cell death, confirmed by staining and apoptosis markers. Cell death was accompanied by enhanced reactive oxygen species formation and modulation of the autophagic machinery (autophagy marker light chain 3B (LC3B); adenosine monophosphate-activated protein kinase (AMPK); protein kinase B (PKB); UNC-51-like kinase (ULK)-1; and ULK2). Molecular docking and dynamic simulations revealed that compound 8 directly binds to ULK1.Conclusion: Compound 8 is a promising lead for autophagy-modulating anti-colon cancer drugs.
期刊介绍：
Future Medicinal Chemistry offers a forum for the rapid publication of original research and critical reviews of the latest milestones in the field. Strong emphasis is placed on ensuring that the journal stimulates awareness of issues that are anticipated to play an increasingly central role in influencing the future direction of pharmaceutical chemistry. Where relevant, contributions are also actively encouraged on areas as diverse as biotechnology, enzymology, green chemistry, genomics, immunology, materials science, neglected diseases and orphan drugs, pharmacogenomics, proteomics and toxicology.
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