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恶唑烷酮衍生物:细胞毒素-利奈唑胺杂合体诱导 DU145 前列腺癌细胞凋亡和衰老。

Oxazolidinone derivatives: cytoxazone-linezolid hybrids induces apoptosis and senescence in DU145 prostate cancer cells.

机构信息

Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.

Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.

出版信息

Eur J Med Chem. 2014 Jun 10;80:295-307. doi: 10.1016/j.ejmech.2014.04.062. Epub 2014 Apr 24.

Abstract

In this study, we report the synthesis of novel oxazolidinone derivatives derived from linezolid 3 having p-methoxyphenyl group at C-4 position. In vitro evaluation for their anticancer activity toward cultured A549, DU145, HELA, and MCF7 were carried out. The series of compounds prepared displayed wide range of cytotoxicity in MTT assays (10-70 μM) across the cell lines tested. Of the all tested compounds 16 and 17 displayed good anticancer potential against A549 (lung) and DU145 (prostate) cancer cells. Further, to determine their anticancer potential, in the present study we have assessed effect of 17 on DU145 cells growth in in vitro assays. The results clearly demonstrated that the exposure of DU145 cells to 17 inhibits cell proliferation and induces apoptosis by activation of caspase-3 and -9. Long term exposure of DU145 cells to 17 induced cellular senescence confirmed by senescence marker β-galactosidase staining of cells on post exposure to 17. The results from this current report support that the oxazolidinone derivatives with ethyl and acryl substitutions showed promising anticancer activity which will be helpful to develop further novel anticancer agents with better therapeutic potential.

摘要

在这项研究中,我们报告了新型恶唑烷酮衍生物的合成,这些衍生物源自 C-4 位带有对甲氧基苯基的利奈唑胺 3。对其针对培养的 A549、DU145、HELA 和 MCF7 的抗癌活性进行了体外评估。所制备的一系列化合物在 MTT 测定中(10-70 μM)在测试的细胞系中表现出广泛的细胞毒性。在所测试的所有化合物中,化合物 16 和 17 对 A549(肺)和 DU145(前列腺)癌细胞表现出良好的抗癌潜力。此外,为了确定它们的抗癌潜力,在本研究中,我们评估了化合物 17 对 DU145 细胞在体外实验中的生长的影响。结果清楚地表明,DU145 细胞暴露于 17 会通过激活 caspase-3 和 -9 来抑制细胞增殖并诱导细胞凋亡。长期暴露于 17 诱导 DU145 细胞衰老,通过暴露于 17 后细胞β-半乳糖苷酶染色来证实细胞衰老标志物。本报告的结果支持具有乙基和丙烯酰基取代的恶唑烷酮衍生物表现出有希望的抗癌活性,这将有助于开发具有更好治疗潜力的新型抗癌药物。

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