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。

IF 3.597 Q2 Pharmacology, Toxicology and Pharmaceutics
MedChemComm Pub Date : 2025-03-07 DOI:10.1039/D4MD01007H
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
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引用次数: 0

摘要

探索了乙酰胆碱与抗肿瘤脂质(ATLs)杂交以获得新的潜在抗癌药物。与2-硬脂氧苯基片段的结合显著增强了乙酰胆碱杂交体的抗癌活性。化合物6、8、9和10的抗癌活性明显高于雪草碱、stPEPC和NSC43067。化合物6、8、9和10还显示出广谱的抗肿瘤活性,包括肺癌、卵巢癌、肾癌、前列腺癌、白血病、结肠癌、中枢神经系统、黑色素瘤和乳腺癌细胞。化合物6和8是诱发个位数低微摩尔GI50值的有效化合物。化合物6对非小细胞肺癌、卵巢癌、肾癌和前列腺癌最有效。同时,化合物8对白血病、结肠癌、中枢神经系统癌、黑色素瘤和乳腺癌最有效。对化合物6在A549非小细胞肺癌细胞中的作用机制的探索表明,化合物6通过破坏CDK4/6-Rb通路,在G0/G1期触发细胞周期阻滞,通过激活caspase、上调BAX和裂解PARP诱导细胞凋亡。总之,结果表明乙酰胆碱- atl杂种6和8是潜在的抗癌药物,可能进一步开发。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

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来源期刊
MedChemComm
MedChemComm BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL
CiteScore
4.70
自引率
0.00%
发文量
0
审稿时长
2.2 months
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.
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