I类组蛋白脱乙酰酶抑制剂生物还原前药的设计和合成及其在病毒转染的急性髓系白血病细胞中的生物学评价。
Design and synthesis of bioreductive prodrugs of class I histone deacetylase inhibitors and their biological evaluation in virally transfected acute myeloid leukemia cells.
发表日期：2023 Nov 06
作者：
Mohamed Abdelsalam, Mariia Zmyslia, Karin Schmidtkunz, Anita Vecchio, Sebastian Hilscher, Hany S Ibrahim, Mike Schutkowski, Manfred Jung, Claudia Jessen-Trefzer, Wolfgang Sippl
来源：
Epigenetics & Chromatin
摘要：
尽管组蛋白脱乙酰酶 (HDAC) 抑制剂在治疗各种类型的血液恶性肿瘤方面显示出良好的前景，但它们也有一些局限性，包括药代动力学较差和脱靶副作用。前药设计已显示出作为改善药代动力学特性和提高靶组织特异性的方法的前景。在这项工作中，基于已知的选择性 HDAC 抑制剂设计了几种 I 类 HDAC 的生物还原性前药。 HDAC 抑制剂的锌结合基团被各种硝基芳基甲基残基掩蔽，使其成为硝基还原酶 (NTR) 的底物。与其母体抑制剂相比，所开发的前药显示出较弱的 HDAC 抑制活性。这些前药针对野生型和 NTR 转染的 THP1 细胞进行了测试。细胞测定表明，基于 2-硝基咪唑的前药 5 和 6 均最能被 NTR 激活，并表现出针对 NTR-THP1 细胞的有效活性。化合物6表现出最高的细胞活性(GI50= 77 nM)并且表现出中等的选择性。此外，通过液相色谱-质谱分析证实了NTR对前药6的激活，表明与大肠杆菌NTR孵育后母体抑制剂的释放。因此，化合物 6 可以被认为是一种对 I 类 HDAC 具有选择性的新型前药，它可以作为提高选择性和进一步优化的良好起点。© 2023 作者。 Archiv der Pharmazie 由 Wiley-VCH GmbH 代表 Deutsche Pharmazeutische Gesellschaft 出版。
Although histone deacetylase (HDAC) inhibitors show promise in treating various types of hematologic malignancies, they have some limitations, including poor pharmacokinetics and off-target side effects. Prodrug design has shown promise as an approach to improve pharmacokinetic properties and to improve target tissue specificity. In this work, several bioreductive prodrugs for class I HDACs were designed based on known selective HDAC inhibitors. The zinc-binding group of the HDAC inhibitors was masked with various nitroarylmethyl residues to make them substrates of nitroreductase (NTR). The developed prodrugs showed weak HDAC inhibitory activity compared to their parent inhibitors. The prodrugs were tested against wild-type and NTR-transfected THP1 cells. Cellular assays showed that both 2-nitroimidazole-based prodrugs 5 and 6 were best activated by the NTR and exhibited potent activity against NTR-THP1 cells. Compound 6 showed the highest cellular activity (GI50 = 77 nM) and exhibited moderate selectivity. Moreover, activation of prodrug 6 by NTR was confirmed by liquid chromatography-mass spectrometry analysis, which showed the release of the parent inhibitor after incubation with Escherichia coli NTR. Thus, compound 6 can be considered a novel prodrug selective for class I HDACs, which could be used as a good starting point for increasing selectivity and for further optimization.© 2023 The Authors. Archiv der Pharmazie published by Wiley-VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.