Université Rennes 1, Institut des Sciences Chimiques de Rennes, CNRS UMR 6226, Bâtiment 10A, Campus de Beaulieu, 35042 Rennes, Cedex, France.
Sorbonne Universités, UPMC Univ Paris 06-CNRS, IBPS, UMR 8256, Inserm ERL1164, B2A, 7 Quai Saint Bernard, F75005 Paris, France.
Eur J Med Chem. 2018 Feb 10;145:570-587. doi: 10.1016/j.ejmech.2018.01.013. Epub 2018 Jan 8.
Starting from the X-ray structure of our previous tripeptidic linear mimics of TMC-95A in complex with yeast 20S proteasome, we introduced new structural features to induce a differential inhibition between human constitutive and immunoproteasome 20S particles. Libraries of 24 tripeptidic and 6 dipeptidic derivatives were synthesized. The optimized preparation of 3-hydroxyoxindolyl alanine residues from tryptophan and their incorporation in peptides were described. Several potent inhibitors of human constitutive proteasome and immunoproteasome acting at the nanomolar level (IC = 7.1 nM against the chymotrypsin-like activity for the best inhibitor) were obtained. A cytotoxic effect at the submicromolar level was observed against 6 human cancer cell lines.
从我们之前与酵母 20S 蛋白酶体复合物的 TMC-95A 三肽线性模拟物的 X 射线结构出发，我们引入了新的结构特征，以诱导人类组成型和免疫蛋白酶体 20S 颗粒之间的差异抑制。合成了 24 个三肽和 6 个二肽衍生物文库。描述了色氨酸 3-羟基吲哚基丙氨酸残基的优化制备及其在肽中的掺入。获得了几种对人组成型蛋白酶体和免疫蛋白酶体具有纳米级抑制作用的有效抑制剂（对最佳抑制剂的胰凝乳蛋白酶样活性的 IC = 7.1 nM）。对 6 个人类癌细胞系观察到亚微摩尔级别的细胞毒性作用。
