Schiffrer Eva Shannon, Sosič Izidor, Šterman Andrej, Mravljak Janez, Raščan Irena Mlinarič, Gobec Stanislav, Gobec Martina
Faculty of Pharmacy , Chair of Pharmaceutical Chemistry , University of Ljubljana , Aškerčeva 7 , 1000 Ljubljana , Slovenia.
Faculty of Pharmacy , Chair of Clinical Biochemistry , University of Ljubljana , Aškerčeva 7 , 1000 Ljubljana , Slovenia . Email:
Medchemcomm. 2019 Sep 13;10(11):1958-1965. doi: 10.1039/c9md00365g. eCollection 2019 Nov 1.
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.
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、各种类型的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。在此，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'位具有不同的取代基。通过补骨脂素环3位的变化对最有前景的化合物进行了进一步评估。尽管与母体化合物相比抑制效力略有下降，但我们能够提高对免疫蛋白酶体和组成型蛋白酶体其他亚基的选择性。最有效的化合物能够区分细胞裂解物中的两种蛋白酶体类型，并且在外周血单核细胞中也显示出细胞因子分泌减少。
