N-(2-{3-[3,5-Bis(trifluoromethyl)phenyl]ureido}ethyl)-glycyrrhetinamide (6b): A Novel Anticancer Glycyrrhetinic Acid Derivative that Targets the Proteasome and Displays Anti-Kinase Activity
N-(2-{3-[3,5-Bis(trifluoromethyl)phenyl]ureido}ethyl)-glycyrrhetinamide (6b): A Novel Anticancer Glycyrrhetinic Acid Derivative that Targets the Proteasome and Displays Anti-Kinase Activity
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DOI：
10.1021/jm200285z
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发表时间：
2011-10-13
影响因子：
7.3
通讯作者：
Kiss, Robert
中科院分区：
文献类型：
--
作者：
Lallemand, Benjamin;Chaix, Fabien;Kiss, Robert
18-β-大黄酸（GA; 1）及其许多衍生物在癌细胞中具有细胞毒性。本研究的目的是表征17个新的1衍生物的抗癌作用。在这些研究的基础上，N-（2-{3-[3，5-双（三氟甲基）苯基]脲基}乙基）-大黄酸酰胺（6 b）似乎是最有效的化合物，在一组8种癌细胞系中具有单位数微摩尔浓度的IC 50体外生长抑制浓度。化合物6 b具有细胞抑制作用，并且至少部分地通过抑制与癌细胞增殖和控制有关的十几种激酶的活性，在细胞凋亡敏感性癌细胞系与抗细胞凋亡癌细胞系中显示出相似的效率。肌动蛋白细胞骨架组织。化合物6 b还抑制蛋白酶体的3个蛋白水解单元的活性。因此，化合物6 b代表了一个有趣的打击，未来的化合物可以从中衍生出来，以改善旨在对抗与不良预后相关的癌症的化疗方案。
18-beta-Glycyrrhetinic acid (GA; 1) and many of its derivatives are cytotoxic in cancer cells. The current study aims to characterize the anticancer effects of 17 novel 1 derivatives. On the basis of these studies, N-(2-{3-[3,5-bis(trifluoromethyl)phenyl]ureido}ethyl)-glycyrrhetinamide (6b) appeared to be the most potent compound, with IC50 in vitro growth inhibitory concentrations in single-digit micromolarity in a panel of 8 cancer cell lines. Compound 6b is cytostatic and displays similar efficiency in apoptosis-sensitive versus apoptosis-resistant cancer cell lines through, at least partly, the inhibition of the activity of a cluster of a dozen kinases that are implicated in cancer cell proliferation and in the control of the actin cytoskeleton organization. Compound 6b also inhibits the activity of the 3 proteolytic units of the proteasome. Compound 6b thus represents an interesting hit from which future compounds could be derived to improve chemotherapeutic regimens that aim to combat cancers associated with poor prognoses.