Ahmed H. E. Hassan, Eun Seo Bae, Youngdo Jeong, Chae Won Ock, Selwan M. El-Sayed, Minji Kim, Mohamed F. Radwan, Tarek S. Ibrahim, Jun-Young Cho, Boyoung Y. Park, Jaehoon Sim, Sang Kook Lee and Yong Sup Lee
{"title":"乙酰胆碱-抗肿瘤脂质杂合体的设计、合成和评价导致了一种潜在的抗癌药物在肺癌中破坏CDK4/6-Rb通路。","authors":"Ahmed H. E. Hassan, Eun Seo Bae, Youngdo Jeong, Chae Won Ock, Selwan M. El-Sayed, Minji Kim, Mohamed F. Radwan, Tarek S. Ibrahim, Jun-Young Cho, Boyoung Y. Park, Jaehoon Sim, Sang Kook Lee and Yong Sup Lee","doi":"10.1039/D4MD01007H","DOIUrl":null,"url":null,"abstract":"<p >Hybridization of acetylcholine with antitumor lipids (ATLs) was explored to achieve novel potential anticancer agents. The combination with a 2-stearoxyphenyl moiety substantially enhanced the anticancer activity of the acetylcholine hybrids. Compounds <strong>6</strong>, <strong>8</strong>, <strong>9</strong> and <strong>10</strong> exhibited pronounced anticancer activities higher than edelfosine and stPEPC and NSC43067. Compounds <strong>6</strong>, <strong>8</strong>, <strong>9</strong> and <strong>10</strong> also showed broad-spectrum anticancer activity against diverse cancer cells including lung, ovarian, renal, prostate, leukaemia, colon, CNS, melanoma, and breast cancer cells. Compounds <strong>6</strong> and <strong>8</strong> were potent compounds eliciting single digit low micromolar GI<small><sub>50</sub></small> values. Compound <strong>6</strong> was the most potent against non-small cell lung cancer, ovarian cancer, renal cancer, and prostate cancer. Meanwhile, compound <strong>8</strong> was the most potent against leukaemia, colon cancer, CNS cancer, melanoma, and breast cancer. Exploration of the mechanism of action of compound <strong>6</strong> in A549 non-small cell lung cancer cells showed that it triggers cell cycle arrest in the G<small><sub>0</sub></small>/G<small><sub>1</sub></small> phase <em>via</em> disruption of the CDK4/6-Rb pathway and induces apoptosis <em>via</em> the activation of caspases, upregulation of BAX and cleavage of PARP. Overall, the results present acetylcholine-ATL hybrids <strong>6</strong> and <strong>8</strong> as potential anticancer agents for possible further development.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 5","pages":" 2281-2296"},"PeriodicalIF":3.5970,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931566/pdf/","citationCount":"0","resultStr":"{\"title\":\"Design, synthesis and evaluation of acetylcholine-antitumor lipid hybrids led to identification of a potential anticancer agent disrupting the CDK4/6-Rb pathway in lung cancer†\",\"authors\":\"Ahmed H. E. Hassan, Eun Seo Bae, Youngdo Jeong, Chae Won Ock, Selwan M. El-Sayed, Minji Kim, Mohamed F. Radwan, Tarek S. Ibrahim, Jun-Young Cho, Boyoung Y. Park, Jaehoon Sim, Sang Kook Lee and Yong Sup Lee\",\"doi\":\"10.1039/D4MD01007H\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Hybridization of acetylcholine with antitumor lipids (ATLs) was explored to achieve novel potential anticancer agents. The combination with a 2-stearoxyphenyl moiety substantially enhanced the anticancer activity of the acetylcholine hybrids. Compounds <strong>6</strong>, <strong>8</strong>, <strong>9</strong> and <strong>10</strong> exhibited pronounced anticancer activities higher than edelfosine and stPEPC and NSC43067. Compounds <strong>6</strong>, <strong>8</strong>, <strong>9</strong> and <strong>10</strong> also showed broad-spectrum anticancer activity against diverse cancer cells including lung, ovarian, renal, prostate, leukaemia, colon, CNS, melanoma, and breast cancer cells. Compounds <strong>6</strong> and <strong>8</strong> were potent compounds eliciting single digit low micromolar GI<small><sub>50</sub></small> values. Compound <strong>6</strong> was the most potent against non-small cell lung cancer, ovarian cancer, renal cancer, and prostate cancer. Meanwhile, compound <strong>8</strong> was the most potent against leukaemia, colon cancer, CNS cancer, melanoma, and breast cancer. Exploration of the mechanism of action of compound <strong>6</strong> in A549 non-small cell lung cancer cells showed that it triggers cell cycle arrest in the G<small><sub>0</sub></small>/G<small><sub>1</sub></small> phase <em>via</em> disruption of the CDK4/6-Rb pathway and induces apoptosis <em>via</em> the activation of caspases, upregulation of BAX and cleavage of PARP. Overall, the results present acetylcholine-ATL hybrids <strong>6</strong> and <strong>8</strong> as potential anticancer agents for possible further development.</p>\",\"PeriodicalId\":88,\"journal\":{\"name\":\"MedChemComm\",\"volume\":\" 5\",\"pages\":\" 2281-2296\"},\"PeriodicalIF\":3.5970,\"publicationDate\":\"2025-03-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931566/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"MedChemComm\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://pubs.rsc.org/en/content/articlelanding/2025/md/d4md01007h\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"Pharmacology, Toxicology and Pharmaceutics\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"MedChemComm","FirstCategoryId":"1085","ListUrlMain":"https://pubs.rsc.org/en/content/articlelanding/2025/md/d4md01007h","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Pharmacology, Toxicology and Pharmaceutics","Score":null,"Total":0}
Design, synthesis and evaluation of acetylcholine-antitumor lipid hybrids led to identification of a potential anticancer agent disrupting the CDK4/6-Rb pathway in lung cancer†
Hybridization of acetylcholine with antitumor lipids (ATLs) was explored to achieve novel potential anticancer agents. The combination with a 2-stearoxyphenyl moiety substantially enhanced the anticancer activity of the acetylcholine hybrids. Compounds 6, 8, 9 and 10 exhibited pronounced anticancer activities higher than edelfosine and stPEPC and NSC43067. Compounds 6, 8, 9 and 10 also showed broad-spectrum anticancer activity against diverse cancer cells including lung, ovarian, renal, prostate, leukaemia, colon, CNS, melanoma, and breast cancer cells. Compounds 6 and 8 were potent compounds eliciting single digit low micromolar GI50 values. Compound 6 was the most potent against non-small cell lung cancer, ovarian cancer, renal cancer, and prostate cancer. Meanwhile, compound 8 was the most potent against leukaemia, colon cancer, CNS cancer, melanoma, and breast cancer. Exploration of the mechanism of action of compound 6 in A549 non-small cell lung cancer cells showed that it triggers cell cycle arrest in the G0/G1 phase via disruption of the CDK4/6-Rb pathway and induces apoptosis via the activation of caspases, upregulation of BAX and cleavage of PARP. Overall, the results present acetylcholine-ATL hybrids 6 and 8 as potential anticancer agents for possible further development.
期刊介绍:
Research and review articles in medicinal chemistry and related drug discovery science; the official journal of the European Federation for Medicinal Chemistry.
In 2020, MedChemComm will change its name to RSC Medicinal Chemistry. Issue 12, 2019 will be the last issue as MedChemComm.