Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste , Via Giorgieri 1, 34127 Trieste, Italy.
J Med Chem. 2015 Feb 26;58(4):1691-704. doi: 10.1021/jm501336h. Epub 2015 Feb 12.
Bis-arylidenecycloalkanones structurally related to the nonselective isopeptidase inhibitor G5 were synthesized and tested for cytotoxic activity against glioblastoma cells. Cytotoxicities correlate well with Hammett σ constants for substituted arylidene groups, confirming the proposed inhibition mechanism. A new inhibitor (2c) based on the 4-hydroxycyclohexanone scaffold, which favors apoptosis over necrosis, was selected for further development. 2c inhibited representative deubiquitinases with micromolar IC50, and its proapoptotic activity was studied on several cancer cell lines. Inhibitor 2c was conjugated to PEG via dicarbamate and diester linkers. While the dicarbamate was inactive, the diester (2cPE) behaves like a prodrug and is converted into the active species 2c by secreted esterase activities. Finally, 2cPE was also tested in vivo on A549 lung carcinoma xenografts generated in mice. Intravenous treatment with 2cPE led to a significant reduction in primary tumor growth, without appreciable toxicity to mice.
合成了与非选择性异肽酶抑制剂 G5 结构相关的双芳亚甲基环烷酮，并测试了它们对神经胶质瘤细胞的细胞毒性。细胞毒性与取代芳基亚甲基基团的哈米特 σ 常数密切相关，证实了所提出的抑制机制。选择基于 4-羟基环己酮支架的新型抑制剂（2c）用于进一步开发，它有利于细胞凋亡而不是坏死。2c 以微摩尔 IC50 抑制代表性去泛素化酶，并且在几种癌细胞系上研究了其促凋亡活性。抑制剂 2c 通过二碳酸酯和二酯接头与 PEG 偶联。虽然二碳酸酯没有活性，但二酯（2cPE）表现为前药，并且通过分泌的酯酶活性转化为活性物质 2c。最后，还在体内对在小鼠中生成的 A549 肺癌异种移植瘤进行了 2cPE 的测试。2cPE 的静脉治疗导致原发性肿瘤生长显著减少，而对小鼠没有明显毒性。
