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.

Design, Synthesis and Biological Evaluation of Carboxy Analogues of Arginine Methyltransferase Inhibitor 1 (AMI-1) / Castellano, S.; Milite, C.; Ragno, R.; Simeoni, S.; Mai, A.; Limongelli, Vittorio; Novellino, E.; Bauer, I.; Brosch, G.; Spannhoff, A.; Cheng, D.; Bedford, M. T.; Sbardella, G.. - In: CHEMMEDCHEM. - ISSN 1860-7179. - ELETTRONICO. - 5:(2010), pp. 398-414. [10.1002/cmdc.200900459]

Design, Synthesis and Biological Evaluation of Carboxy Analogues of Arginine Methyltransferase Inhibitor 1 (AMI-1)

LIMONGELLI, VITTORIO;E. Novellino;
2010

Abstract

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.
2010
Design, Synthesis and Biological Evaluation of Carboxy Analogues of Arginine Methyltransferase Inhibitor 1 (AMI-1) / Castellano, S.; Milite, C.; Ragno, R.; Simeoni, S.; Mai, A.; Limongelli, Vittorio; Novellino, E.; Bauer, I.; Brosch, G.; Spannhoff, A.; Cheng, D.; Bedford, M. T.; Sbardella, G.. - In: CHEMMEDCHEM. - ISSN 1860-7179. - ELETTRONICO. - 5:(2010), pp. 398-414. [10.1002/cmdc.200900459]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/426081
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