期刊
CHEMMEDCHEM
卷 5, 期 3, 页码 398-414出版社
WILEY-BLACKWELL
DOI: 10.1002/cmdc.200900459
关键词
enzymes; epigenetics; histone methylation; inhibitors; transferases
资金
- Regione Compania 2003 [LR 5102]
- Ministero dell'Universita e della Ricerca Scientifica e Tecnologica -PRIN 2007
- Universita di Salerno
- Ministero, dell'Universita e della Ricerco Scientifica e Tecnologica -PRIN
- RETI FIRB
- Fondazione Roma
- Welch Foundation [G-1495]
Here we report the synthesis of a number of compounds structurally related to arginine methyltransferase inhibitor 1 (AMI-1). The structural alterations that we made included: 1) the substitution of the sulfonic groups with the bioisosteric carboxylic groups; 2) the replacement of the ureidic function with a bis-amidic moiety; 3) the introduction of a N-containing basic moiety; and 4) the positional isomerization of the aminohydroxynaphthoic moiety. We have assessed the biological activity of these compounds against a panel of arginine methyltransferases (fungal RmtA, hPRMT1, hCARM1, hPRMT3, hPRMT6) and a lysine methyltransferase (SET7/9) using histone and nonhistone proteins as substrates. Molecular modeling studies for a deep binding-mode analysis of test compounds were also performed. The bis-carboxylic acid derivatives 1 b and 7 b emerged as the most effective PRMT inhibitors, both in vitro and in vivo, being comparable or even better than the reference compound (AMI-1) and practically inactive against the lysine methyltransferase SET7/9.
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