A focused structure-activity relationship study of psoralen-based immunoproteasome inhibitors.,RSC Medicinal Chemistry

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A focused structure-activity relationship study of psoralen-based immunoproteasome inhibitors.
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2019-09-13 , DOI: 10.1039/c9md00365g
Eva Shannon Schiffrer ₁ , Izidor Sosič ₁ , Andrej Šterman ₁ , Janez Mravljak ₁ , Irena Mlinarič Raščan ₂ , Stanislav Gobec ₁ , Martina Gobec ₂

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The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types of cancer, and inflammatory diseases. The development of immunoproteasome-selective inhibitors with non-peptidic scaffolds remains a challenging task. Here, we describe a focused series of psoralen-based inhibitors of the β5i subunit of the immunoproteasome with different substituents placed at position 4′. The most promising compound was further evaluated through changes at position 3 of the psoralen ring. Despite a small decrease in the inhibitory potency in comparison with the parent compound, we were able to improve the selectivity against other subunits of both the immunoproteasome and the constitutive proteasome. The most potent compounds discriminated between both proteasome types in cell lysates and also showed a decrease in cytokine secretion in peripheral blood mononuclear cells.

中文翻译：

基于补骨脂素的免疫蛋白酶体抑制剂的重点结构-活性关系研究。

免疫蛋白酶体是一种多催化蛋白酶，主要在造血来源的细胞中表达。其表达升高与自身免疫性疾病、各种癌症和炎症性疾病有关。开发具有非肽支架的免疫蛋白酶体选择性抑制剂仍然是一项具有挑战性的任务。在这里，我们描述了一系列基于补骨脂素的免疫蛋白酶体 β5i 亚基抑制剂，在 4' 位置放置了不同的取代基。通过补骨脂素环第 3 位的变化进一步评估了最有前途的化合物。尽管与母体化合物相比，抑制效力略有下降，但我们能够提高免疫蛋白酶体和组成型蛋白酶体对其他亚基的选择性。最有效的化合物可以区分细胞裂解物中的两种蛋白酶体类型，并且还显示外周血单核细胞中细胞因子分泌的减少。

更新日期：2019-09-13

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