Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, Regensburg, Germany.
Arch Pharm (Weinheim). 2019 Jun;352(6):e1900026. doi: 10.1002/ardp.201900026. Epub 2019 May 6.
Aberrant epigenetic changes in DNA methylation and histone modification by acetylation or deacetylation regulate the pathogenesis of many diseases. Especially selective inhibitors are getting more and more attention. We recently reported on a new class of potent and selective anti-inflammatory and antirheumatic histone deacetylase 6 (HDAC6) inhibitors (e.g., Marbostat-100). The attachment of a morpholinoethoxy part to the head group dramatically enhances the solubility, in particular the solubility in aqueous solutions, of the lead compound Marbostat-100. Here, we present the enantioselective synthesis of small-molecule compounds based on the tetrahydro-β-carboline core system with improved solubility, and the influence of the stereochemistry on the biological activity. The enantiomers were synthesized in good enantiomeric excess (ee) purity and were potent and selective HDAC6 inhibitors, whereas the S-derivative S-21 is clearly the eutomer. The potency of our selective HDAC6 inhibitors is demonstrated by K values in the range of 0.5-2 nM toward HDAC6, and the selectivity was proved in cellular assays by Western blot analysis taking ac-tubulin as surrogate parameter.
DNA 甲基化和组蛋白修饰的表观遗传改变通过乙酰化或去乙酰化来调节许多疾病的发病机制。特别是选择性抑制剂越来越受到关注。我们最近报道了一类新型强效和选择性抗炎和抗风湿组蛋白去乙酰化酶 6（HDAC6）抑制剂（例如，Marbostat-100）。将吗啉乙氧基部分连接到头基团上，可大大提高先导化合物 Marbostat-100 的溶解度，特别是在水溶液中的溶解度。在这里，我们提出了基于四氢-β-咔啉核心系统的小分子化合物的对映选择性合成，该化合物具有改善的溶解度，以及立体化学对生物活性的影响。对映异构体以良好的对映体过量（ee）纯度合成，并具有强效和选择性的 HDAC6 抑制活性，而 S-构型 S-21 显然是优势对映体。我们的选择性 HDAC6 抑制剂的效力通过 K 值在 0.5-2 nM 范围内对 HDAC6 进行证明，并且通过 Western blot 分析以 ac-tubulin 作为替代参数的细胞测定证明了选择性。
