肽醛类前药衍生物作为蛋白酶体抑制剂的研究(英文)

为了提高经典的肽醛类蛋白酶体抑制剂的稳定性和生物利用度,我们设计合成了4个肽缩醛和2个肽杂缩醛衍生物,并对其进行了酶水平和体外抗肿瘤实验。结果显示,4个肽缩醛化合物几乎没有显示任何活性,表明此类化合物有用作前药的潜质。而2个肽杂缩醛化合物在酶水平和细胞水平均表现出明显的活性,则表明此类化合物可能不是通过前药的形式而发挥作用,进一步优化杂环的结构,有可能发现更好的蛋白酶体抑制剂。

Study of the prodrugs of peptide aldehydes as proteasome inhibitors

To improve the stability of peptide aldehyde proteasome inhibitors,four peptide cycioacetal derivatives and two peptide heterocycle compounds were designed and synthesized.Their proteasome inhibition and in vitro anticancer activities were evaluated.The four peptide cycioacetal derivatives did not showed any activities,which demonstrated that this kind of cycioacetal derivatives might be suitable as prodrugs.The two peptide heterocycle compounds were found to show obvious activities at both enzyme and cell levels.These results provide us a new clue for the modification of peptide aldehyde proteasome inhibitors.