Synthesis, Characterization, and Optimization for in Vivo Delivery of a Nonselective Isopeptidase Inhibitor as New Antineoplastic Agent
Synthesis, Characterization, and Optimization for in Vivo Delivery of a Nonselective Isopeptidase Inhibitor as New Antineoplastic Agent
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DOI：
10.1021/jm501336h
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发表时间：
2015-02-26
影响因子：
7.3
通讯作者：
Brancolini, Claudio
中科院分区：
文献类型：
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作者：
Cersosimo, Ulma;Sgorbissa, Andrea;Brancolini, Claudio
合成了与非选择性异肽酶抑制剂G5结构相关的双芳基环烷酮，并测试了其对胶质母细胞瘤细胞的细胞毒活性。细胞毒性与取代芳基基团的Hammett常数密切相关，证实了所提出的抑制机制。一种新的基于4-羟基环己酮支架的抑制剂（2c）被选择用于进一步开发，它有利于细胞凋亡而不是坏死。2c以微摩尔IC50抑制代表性去泛素酶，并在几种癌细胞上研究了其促凋亡活性。抑制剂2c通过二氨基甲酸酯和二酯连接物与PEG偶联。二氨基甲酸酯是无活性的，二酯（2cPE）表现为前药，通过分泌酯酶活性转化为活性物质2c。最后，对小鼠A549肺癌异种移植物进行体内实验。静脉注射2cPE可显著降低原发肿瘤生长，对小鼠无明显毒性。
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 s 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.