Design and synthesis of peptide-MCA substrates for a novel assay of histone methyltransferases and their inhibitors
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- 作者：Hongfang Chi ; Yasushi Takemoto ; Tienabe K. Nsiama ; Tamaki Kato ; Norikazu Nishino ; Akihiro Ito ; Minoru Yoshida
- 关键词：AcOH ; acetic acid ; Ac2O ; acetic anhydride ; AcOEt ; ethyl acetate ; AMC ; 7-amino-4-methylcoumarin ; DCM ; dichloromethane ; DCC ; dicyclohexylcarbodiimide ; DIEA ; N ; N-diisopropylethylamine ; DMF ; N ; N-dimethylformamide ; Fmoc ; fluorenylmethyloxycarbonyl ; HOBt· ; H2O ; 1-hydroxybenzotriazole hydrate ; HBTU ; O-(benzotriazol-1-yl)-N ; N ; N&prime ; N&prime ; -tetramethyluronium hexafluorophosphate ; MCA ; 4-methylcoumaryl-7-amide ; HPLC ; high performance liquid chromategraphy ; HRMS (FAB) ; high resolution fast atom bo
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：15 February, 2014
- 年：2014
- 卷：22
- 期：4
- 页码：1268-1275
- 全文大小：968 K
文摘
Histone methyltransferases (HMTs) play an important role in controlling gene expression through site-specific methylation of lysines in core and linker histones within chromatin. As the typical HMTs, G9a and Set7/9 have been intensively studied that G9a is specific to the methylation at H3K9 and H3K27 and represses transcription, while Set7/9 methylates at H3K4. In this report we prepared various peptide-MCAs (4-methylcoumaryl-7-amides) related to histone tail and protein-substrates such as p53 and estrogen receptor-伪. The fluorogenic substrates are applied for the assay of HMTs and an inhibitor, for example. The most sensitive and specific MCA-substrates to G9a and Set7/9 are discovered. The peptide-MCAs corresponding to the methylation sequences are promising for screening of HMT inhibitors.