This paper reports the synthesis of a panel of small molecules with arylamides and arylsulfonamides groups and their biological activity in inhibiting nucleotide exchange on human Ras. The design of these molecules was guided by experimental and molecular modelling data previously collected on similar compounds. Aim of this work is the validation of the hypothesis that a phenyl hydroxylamine group linked to a second aromatic moiety generates a pharmacophore capable to interact with Ras and to inhibit its activation. In vitro experiments on purified human Ras clearly show that the presence of an aromatic hydroxylamine and a sulfonamide group in the same molecule is a necessary condition for Ras binding and nucleotide exchange inhibition. The inhibitor potency is lower in molecules in which either the hydroxylamine has been replaced by other functional groups or the sulfonamide has been replaced by an amide. In the case both these moieties, the hydroxylamine and sulfonamide are absent, inactive compounds are obtained.

Colombo, S., Palmioli, A., Airoldi, C., Tisi, R., Fantinato, S., Olivieri, S., et al. (2010). Structure-Activity Studies on Arylamides and Arysulfonamides Ras Inhibitors. CURRENT CANCER DRUG TARGETS, 10(2), 192-199 [10.2174/156800910791054185].

Structure-Activity Studies on Arylamides and Arysulfonamides Ras Inhibitors

COLOMBO, SONIA
;
PALMIOLI, ALESSANDRO;AIROLDI, CRISTINA;TISI, RENATA ANITA;DE GIOIA, LUCA;MARTEGANI, ENZO;PERI, FRANCESCO
2010

Abstract

This paper reports the synthesis of a panel of small molecules with arylamides and arylsulfonamides groups and their biological activity in inhibiting nucleotide exchange on human Ras. The design of these molecules was guided by experimental and molecular modelling data previously collected on similar compounds. Aim of this work is the validation of the hypothesis that a phenyl hydroxylamine group linked to a second aromatic moiety generates a pharmacophore capable to interact with Ras and to inhibit its activation. In vitro experiments on purified human Ras clearly show that the presence of an aromatic hydroxylamine and a sulfonamide group in the same molecule is a necessary condition for Ras binding and nucleotide exchange inhibition. The inhibitor potency is lower in molecules in which either the hydroxylamine has been replaced by other functional groups or the sulfonamide has been replaced by an amide. In the case both these moieties, the hydroxylamine and sulfonamide are absent, inactive compounds are obtained.
Articolo in rivista - Articolo scientifico
Anticancer agents; Computational chemistry; Ras; Structure-activity relationship;
English
2010
10
2
192
199
none
Colombo, S., Palmioli, A., Airoldi, C., Tisi, R., Fantinato, S., Olivieri, S., et al. (2010). Structure-Activity Studies on Arylamides and Arysulfonamides Ras Inhibitors. CURRENT CANCER DRUG TARGETS, 10(2), 192-199 [10.2174/156800910791054185].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/12446
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