title: Design, synthesis and biological evaluation of sugar-derived Ras inhibitors.
abstract: The design and synthesis of novel Ras inhibitors with a bicyclic scaffold derived from the natural sugar D-arabinose are presented. Molecular modelling showed that these ligands can bind Ras by accommodating the aromatic moieties and the phenylhydroxylamino group in a cavity near the Switch II region of the protein. All the synthetic compounds were active in inhibiting nucleotide exchange on p21 human Ras in vitro, and two of them selectively inhibited Ras-dependent cell growth in vivo.
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy. francesco.peri@unimib.it
authors.forename: Francesco
authors.initials: F
authors.lastname: Peri
authors.forename: Cristina
authors.initials: C
authors.lastname: Airoldi
authors.forename: Sonia
authors.initials: S
authors.lastname: Colombo
authors.forename: Enzo
authors.initials: E
authors.lastname: Martegani
authors.forename: Anske Stephanie
authors.initials: AS
authors.lastname: van Neuren
authors.forename: Matthias
authors.initials: M
authors.lastname: Stein
authors.forename: Chiara
authors.initials: C
authors.lastname: Marinzi
authors.forename: Francesco
authors.initials: F
authors.lastname: Nicotra
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001089:Arabinose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D041681:NIH 3T3 Cells; D015689:Oncogene Protein p21(ras) / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015003:Yeasts / Q000187:drug effects; D020687:cdc25 Phosphatases / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018797:Cell Cycle Proteins; D001089:Arabinose; C517009:CDC25C protein, human; C517010:Cdc25c protein, mouse; D020687:cdc25 Phosphatases; D015689:Oncogene Protein p21(ras)