Humboldt Universität zu Berlin, Institute for Chemistry, Brook-Taylor-Str. 2, 12489 Berlin, Germany.
Bioorg Med Chem. 2012 Oct 15;20(20):6162-70. doi: 10.1016/j.bmc.2012.08.031. Epub 2012 Aug 31.
In the present study we describe the design and synthesis of a series of amide- and sulfonamide-based compounds as inhibitor of recombinant acid and neutral ceramidases. Inhibition of ceramidases has been shown to induce apoptosis and to increase the efficacy of conventional chemotherapy in several cancer models. B-13, lead in vitro inhibitor of acid ceramidase has been recently shown to be virtually inactive towards lysosomal acid ceramidase in living cells at lower concentrations and for a shorter time of treatment, suggesting the development of more potent inhibitors. In this study, a detailed SAR investigation has been performed to understand the effect of different substituents on the phenyl ring of amide- and sulfonamide-based compounds that partially resemble the structure of well-known inhibitors such as B-13, D-e-MAPP as well as NOE. Our results suggest that the electronic effects of the substituents on phenyl ring in B-13 and D-e-MAPP analogues have negligible effects either in enhancing the inhibition potencies or for selectivity towards aCDase over nCDase. However, the hydrophobicity and the steric effects of longer alkyl chains (n-Pr, n-Bu or t-Bu groups) at the phenyl ring were found to be important for an enhanced selectivity towards aCDase over nCDase.
在本研究中，我们描述了一系列酰胺和磺酰胺类化合物的设计和合成，这些化合物是重组酸性和中性神经酰胺酶的抑制剂。神经酰胺酶的抑制已被证明能诱导细胞凋亡，并能提高几种癌症模型中常规化疗的疗效。体外酸性神经酰胺酶抑制剂 B-13 最近被证明在较低浓度和较短的治疗时间下，对活细胞中的溶酶体酸性神经酰胺酶几乎没有活性，这表明需要开发更有效的抑制剂。在这项研究中，我们进行了详细的 SAR 研究，以了解不同取代基对酰胺和磺酰胺类化合物苯环的影响，这些化合物部分类似于众所周知的抑制剂，如 B-13、D-e-MAPP 以及 NOE 的结构。我们的结果表明，苯环上取代基的电子效应对 B-13 和 D-e-MAPP 类似物的抑制效力或对 aCDase 相对于 nCDase 的选择性几乎没有影响。然而，在苯环上更长的烷基链（n-Pr、n-Bu 或 t-Bu 基团）的疏水性和空间位阻效应被发现对增强 aCDase 相对于 nCDase 的选择性很重要。
