| Summary: | 碩士 === 國立陽明大學 === 生物藥學研究所 === 101 === Abstract
Ubiquitin specific protease 7(USP7) is an important deubiquitylating enzyme (DUB) in human. It was reported that USP7 could reduce the transcriptional activity of FOXO4 and regulate the progress of cell cycle arrest and apoptosis. USP7 regulated apoptosis through inhibition of translocation of PTEN. Knockdown of USP7 enhanced expression of p53 and activated p53, result in the apoptosis in cancer cells. The recent studies told that knockdown of USP7 gene reduced expression of HIF-1ɑ and inhibited metastasis in cancer cells. In brief, targeting USP7 is a potential therapeutic therapy of cancer.
The USP7 inhibitors as HBX 41108 could down-regulate USP7 activity, reduce Mdm2 expression, activate p53, and induce the apoptosis, but HBX 41108 is not highly specific to USP7. HBX 19818 is the USP7-specific inhibitor, but its inhibitory effect is too low to be considered as a promising drug. Thus, the aim of our work is to synthesize the novel USP7 inhibitors based on the chemical structures of HBX 41108 and HBX 19818, and identify the potential compounds though the bioassay.
The HBX 41108 derivatives (series A) are synthesized from cyclization of indandione and aromatic diamine. The compound 4a-g and 14a-f with pyrazine ring are oxidized as compound 5a-g and a5a-d with ketone group. The HBX 19818 derivatives (series B), compound 24a-d are synthesized as 2,3-dimethoxyquinoxaline and carbon chain with tertiary amine in the terminal. We have successfully synthesized total 30 compounds (26 for series A and 4 for series B).
Depend on the results of the invasion assay, migration assay and Western blotting of HIF-1ɑ, we might identify compounds of series A: (1) five-member ring with ketone groups shows better inhibitory effect; (2) pyrido[2,3-b]pyrazine is better than quinoxaline; (3) electron donating group is more effective in inhibition of cancer cells. Compound 5c with pyrido[2,3-b]pyrazine has better inhibitory effect than HBX 41108 in 0.25µM and 0.5µM. It shows that the structure of pyrido[2,3-b]pyrazine plays a role in USP7 inhibitors.
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