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Title: Design, synthesis and biological evaluation of new small molecule modulators of Arginine methyltransferases
Authors: Milite, Ciro
De Tommasi, Nunziatina
Sbardella, Gianluca
Keywords: Medicinal chemistry
Issue Date: 21-Feb-2011
Publisher: Universita degli studi di Salerno
Abstract: The methylation of arginine residues is a prevalent post-translational modification, found on both nuclear and cytoplasmic proteins, catalyzed by the protein arginine N-methyltransferase (PRMT) family of enzymes. To date there have been only a few publications describing small-molecule chemical modulators of the PRMTs. In this thesis are 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 bisamidic and mixed urea-amidic moiety; 3) the introduction of a N-containing basic moiety; 4) the positional isomerization of the amino- hydroxynaphthoic moiety; and 5) bioisosteric substitution of naphthol with indol. The biological activity of these compounds has been assessed against a panel of arginine methyltransferases (fungal RmtA, hPRMT1, hCARM1, hPRMT3, hPRMT6) and lysine methyltransferase (SET7/9 and G9a) 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 1b and 7b 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. We also identified 33a as the first powerful and selective activator of CARM-1. Moreover an enantioselective α-amination of aryl oxindoles catalyzed by a dimeric quinidine has been developed. This procedure is general, broad in substrate scope, and affords the desired products in good yields with good to excellent enantioselectivities. [edited by author]
Description: 2009 - 2010
Appears in Collections:Scienze farmaceutiche

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tesi C. Milite.pdftesi di dottorato3,79 MBAdobe PDFView/Open
tesi - copertina C. Milite.pdftesi di dottorato - copertina1,76 MBAdobe PDFView/Open
abstract in inglese C. Milite.pdfabstract in inglese a cura dell’autore24,67 kBAdobe PDFView/Open
abstract in italiano C. Milite.pdfabstract in italiano a cura dell’autore50,32 kBAdobe PDFView/Open

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