This paper describes the design, synthesis, and biological evaluation of 2-thioxoimidazolidin-4-one derivatives as inhibitors of proteasome and immunoproteasome, potential targets for the treatment of hematological malignancies. In particular, we focused our efforts on the design of noncovalent inhibitors, which might be a promising therapeutic option potentially devoid of drawbacks and side-effects related to irreversible inhibition. Among all the synthesized compounds, we identified a panel of active inhibitors with K_i values towards one or two chymotrypsin-like activities of proteasome (β5c) and immunoproteasome (β5i and β1i subunits) in the low micromolar range. Docking studies suggested a unique binding mode of the molecules in the catalytic site of immunoproteasome proteolytic subunits.

本文描述了作为蛋白酶体和免疫蛋白酶体抑制剂的2-thioxoimidazolidin-4-one衍生物的设计，合成和生物学评估，这是血液系统恶性肿瘤治疗的潜在靶标。特别是，我们将精力集中在非共价抑制剂的设计上，这可能是一种有前途的治疗选择，可能会避免与不可逆抑制有关的缺点和副作用。在所有的合成的化合物，我们确定了活性抑制剂与一个面板ķ_我朝值一个或两个胰凝乳蛋白酶样蛋白酶的活性（β 5C）和免疫蛋白酶（β 5i和β1i亚基）在低摩尔浓度范围内。对接研究表明，分子在免疫蛋白酶体蛋白水解亚基催化位点的独特结合方式。