Effective inhibition of acid and neutral ceramidases by novel B-13 and LCL-464 analogues
Effective inhibition of acid and neutral ceramidases by novel B-13 and LCL-464 analogues
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DOI：
10.1016/j.bmc.2012.12.014
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发表时间：
2013-02-15
影响因子：
3.5
通讯作者：
Arenz, Christoph
中科院分区：
文献类型：
--
作者：
Bhabak, Krishna P.;Kleuser, Burkhard;Arenz, Christoph
通过抑制神经酰胺酶介导的细胞凋亡的诱导已经显示出在几种癌症模型中增强常规化疗的功效。在文献报道的神经酰胺酶抑制剂中，B-13被认为是对酸性神经酰胺酶具有良好体外效力的先导化合物。此外，由于B-13对活细胞中的溶酶体酸性神经酰胺酶的活性差，据报道LCL-464（在脂肪酸处含有碱性ω-氨基的B-13的修饰衍生物）对活细胞中的溶酶体酸性神经酰胺酶具有更高的效力。为了寻找更有效的神经酰胺酶抑制剂，我们设计了一系列结构修饰B-13和LCL-464的化合物。在这项研究中，我们表明，B-13在体外以及在完整的细胞中的功效可以通过适当的官能团修饰来增强。此外，对LCL-464类似物的详细SAR研究揭示了新的有希望的aCD酶和nCD酶抑制剂。在使用乳腺癌细胞系MDA-MB-231的细胞培养研究中，一些新开发的化合物升高了内源性神经酰胺水平，同时也诱导了凋亡性细胞死亡。总之，本研究表明，已知神经酰胺酶抑制剂B-13和LCL-464的结构修饰产生更有效的神经酰胺酶抑制剂，其在完整细胞中具有活性，不仅提高细胞神经酰胺水平，而且增强细胞死亡。(C)2012爱思唯尔有限公司保留所有权利。
Induction of apoptosis mediated by the inhibition of ceramidases has been shown to enhance the efficacy of conventional chemotherapy in several cancer models. Among the inhibitors of ceramidases reported in the literature, B-13 is considered as a lead compound having good in vitro potency towards acid ceramidase. Furthermore, owing to the poor activity of B-13 on lysosoamal acid ceramidase in living cells, LCL-464 a modified derivative of B-13 containing a basic omega-amino group at the fatty acid was reported to have higher potency towards lysosomal acid ceramidase in living cells. In a search for more potent inhibitors of ceramidases, we have designed a series of compounds with structural modifications of B-13 and LCL-464. In this study, we show that the efficacy of B-13 in vitro as well as in intact cells can be enhanced by suitable modification of functional groups. Furthermore, a detailed SAR investigation on LCL-464 analogues revealed novel promising inhibitors of aCDase and nCDase. In cell culture studies using the breast cancer cell line MDA-MB-231, some of the newly developed compounds elevated endogenous ceramide levels and in parallel, also induced apoptotic cell death. In summary, this study shows that structural modification of the known ceramidase inhibitors B-13 and LCL-464 generates more potent ceramidase inhibitors that are active in intact cells and not only elevates the cellular ceramide levels, but also enhances cell death. (C) 2012 Elsevier Ltd. All rights reserved.