title: Structure-activity studies on arylamides and arysulfonamides Ras inhibitors.
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 The inhibitor potency is lower in molecules in which either the hydroxylamine has been replaced by other functional groups or the sulfonamide has been replaced by an amide.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.
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Colombo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Palmioli
authors.forename: Cristina
authors.initials: C
authors.lastname: Airoldi
authors.forename: Renata
authors.initials: R
authors.lastname: Tisi
authors.forename: Sonia
authors.initials: S
authors.lastname: Fantinato
authors.forename: Sandro
authors.initials: S
authors.lastname: Olivieri
authors.forename: Luca
authors.initials: L
authors.lastname: De Gioia
authors.forename: Enzo
authors.initials: E
authors.lastname: Martegani
authors.forename: Francesco
authors.initials: F
authors.lastname: Peri
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015195:Drug Design; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D006898:Hydroxylamines / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D020798:Two-Hybrid System Techniques; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020666:ras-GRF1 / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006898:Hydroxylamines; D013449:Sulfonamides; D020666:ras-GRF1; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D018631:ras Proteins