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 (IC₅₀ = 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.

从我们先前的TMC-95A与酵母20S蛋白酶体复合的三肽线性模拟物的X射线结构开始，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种三肽衍生物和6种二肽衍生物的文库。描述了从色氨酸的3-羟基氧代吲哚基丙氨酸残基的优化制备及其在肽中的掺入。获得了几种有效的人组成型蛋白酶体和免疫蛋白酶体抑制剂，它们的浓度为纳摩尔水平（IC ₅₀ 为最佳抑制剂的胰凝乳蛋白酶样活性，IC ₅₀ = 7.1 nM）。观察到针对6种人类癌细胞系的亚微摩尔水平的细胞毒性作用。