Design, synthesis and biological evaluation of carboxy analogues of arginine methyltransferase inhibitor 1 (AMI-1).
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.
Castellano
Sabrina
S
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, Via Ponte Don Melillo, 84084 Fisciano SA, Italy.
Milite
Ciro
C
Ragno
Rino
R
Simeoni
Silvia
S
Mai
Antonello
A
Limongelli
Vittorio
V
Novellino
Ettore
E
Bauer
Ingo
I
Brosch
Gerald
G
Spannhoff
Astrid
A
Cheng
Donghang
D
Bedford
Mark T
MT
Sbardella
Gianluca
G
D001233:Aspergillus nidulans / Q000201:enzymology; D001665:Binding Sites; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D009282:Naphthalenesulfonates / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D011484:Protein-Arginine N-Methyltransferases; D021281:Quantitative Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
C535077:7,7'-carbonylbis(azanediyl) bis(4-hydroxynaphthalene-2-sulfonic acid; D005656:Fungal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009282:Naphthalenesulfonates; D014508:Urea; D008780:Methyltransferases; C077013:PRMT2 protein, human; D011484:Protein-Arginine N-Methyltransferases; D011495:Histone-Lysine N-Methyltransferase