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, 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, Yong Sup Lee","doi":"10.1039/d4md01007h","DOIUrl":null,"url":null,"abstract":"<p><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 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 GI<sub>50</sub> 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 G<sub>0</sub>/G<sub>1</sub> phase <i>via</i> disruption of the CDK4/6-Rb pathway and induces apoptosis <i>via</i> 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.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":4.1000,"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, Yong Sup Lee\",\"doi\":\"10.1039/d4md01007h\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><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 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 GI<sub>50</sub> 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 G<sub>0</sub>/G<sub>1</sub> phase <i>via</i> disruption of the CDK4/6-Rb pathway and induces apoptosis <i>via</i> 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.</p>\",\"PeriodicalId\":21462,\"journal\":{\"name\":\"RSC medicinal chemistry\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":4.1000,\"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\":\"RSC medicinal chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1039/d4md01007h\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"RSC medicinal chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1039/d4md01007h","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","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.