Current Cancer Drug Targets

Ruiwen Zhang 
Texas Tech University Health Sciences Center
1300 Coulter Drive
Amarillo, TX 79106
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Structure-Activity Studies on Arylamides and Arysulfonamides Ras Inhibitors

Author(s): S. Colombo, A. Palmioli, C. Airoldi, R. Tisi, S. Fantinato, S. Olivieri, L. De Gioia, E. Martegani, F. Peri.

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 The inhibitor potency is lower in molecules in which either the hydroxylamine has been replaced by other functional groups or the sulfonamide has been replaced by an amide.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.

Keywords: Ras, anticancer agents, computational chemistry, structure-activity relationship

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Article Details

VOLUME: 10
ISSUE: 2
Year: 2010
Page: [192 - 199]
Pages: 8
DOI: 10.2174/156800910791054185
Price: $58