Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres, 31, 98166 Messina, Italy.
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres, 31, 98166 Messina, Italy.
Bioorg Med Chem Lett. 2022 Jan 1;55:128478. doi: 10.1016/j.bmcl.2021.128478. Epub 2021 Nov 24.
The inhibition of immunoproteasome is considered nowadays a promising strategy for the treatment of hematologic malignancies. In this paper we report the design, synthesis, and biological evaluation as immunoproteasome inhibitors of a new series of isoquinolinone derivatives characterized by a (E)-prop-1-ene fragment that connects the heterocycle to a distal amide functionality. Among all the synthesized compounds, we identified an inhibitor with K values in the low micromolar or submicromolar range towards the chymotrypsin-like activities of both proteasome and immunoproteasome (β5c, β5i and β1i subunits). Molecular modeling studies suggest that the most potent compound of the series may act a single-site binder. In particular, through its isopentyl group, it might dock into P1 site in the case of the β1i catalytic subunit, while in the case of β5c and β5i subunits, the P3 site might be the preferred binding site.
目前，抑制免疫蛋白酶体被认为是治疗血液恶性肿瘤的一种有前途的策略。在本文中，我们报告了一系列新型异喹啉酮衍生物的设计、合成和作为免疫蛋白酶体抑制剂的生物学评价，这些衍生物的特点是具有将杂环与远端酰胺官能团连接的（E）-丙烯-1-基片段。在所合成的所有化合物中，我们鉴定出一种抑制剂，其对蛋白酶体和免疫蛋白酶体（β5c、β5i 和 β1i 亚基）的糜蛋白酶样活性的 K 值在低微摩尔或亚微摩尔范围内。分子建模研究表明，该系列中最有效的化合物可能是一种单一位点结合物。特别是，通过其异戊基部分，它可能在β1i 催化亚基的情况下结合到 P1 位，而在β5c 和β5i 亚基的情况下，P3 位可能是首选的结合位。
