Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia.
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia.
Molecules. 2021 Jan 12;26(2):356. doi: 10.3390/molecules26020356.
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. Selective inhibition of its catalytic activities is therefore a viable approach for the treatment of these diseases. However, the development of immunoproteasome-selective inhibitors with non-peptidic scaffolds remains a challenging task. We previously reported 7-furo[3,2-]chromen-7-one (psoralen)-based compounds with an oxathiazolone warhead as selective inhibitors of the chymotrypsin-like (β5i) subunit of immunoproteasome. Here, we describe the influence of the electrophilic warhead variations at position 3 of the psoralen core on the inhibitory potencies. Despite mapping the chemical space with different warheads, all compounds showed decreased inhibition of the β5i subunit of immunoproteasome in comparison to the parent oxathiazolone-based compound. Although suboptimal, these results provide crucial information about structure-activity relationships that will serve as guidance for the further design of (immuno)proteasome inhibitors.
免疫蛋白酶体是一种多催化蛋白酶，主要在造血细胞中表达。其表达水平的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。因此，选择性抑制其催化活性是治疗这些疾病的一种可行方法。然而，开发具有非肽骨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。我们之前报道了基于 7-呋喃[3,2-]色烯-7-酮（补骨脂素）的化合物，其具有氧杂噻唑啉酮弹头，是免疫蛋白酶体的胰凝乳蛋白酶样（β5i）亚基的选择性抑制剂。在这里，我们描述了补骨脂素核心 3 位上的亲电弹头变化对抑制效力的影响。尽管用不同的弹头绘制了化学空间，但与基于氧杂噻唑啉酮的母体化合物相比，所有化合物对免疫蛋白酶体的β5i 亚基的抑制作用都降低了。尽管效果不理想，但这些结果提供了关于构效关系的重要信息，这将为（免疫）蛋白酶体抑制剂的进一步设计提供指导。
