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Structure-Activity Studies on Arylamides and Arysulfonamides Ras Inhibitors
- Source :
- Current Cancer Drug Targets. 10:192-199
- Publication Year :
- 2010
- Publisher :
- Bentham Science Publishers Ltd., 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 The inhibitor potency is lower in molecules in which either the hydroxylamine has been replaced by other functional groups or the sulfonamide has been replaced by an amide.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.
- Subjects :
- Cyclin-Dependent Kinase Inhibitor p21
Computational chemistry
Cancer Research
Stereochemistry
Hydroxylamines
Guanosine Diphosphate
Inhibitory Concentration 50
Mice
chemistry.chemical_compound
Hydroxylamine
Two-Hybrid System Techniques
Amide
Drug Discovery
Animals
Humans
Structure–activity relationship
Nucleotide
Ra
Cell Proliferation
Pharmacology
chemistry.chemical_classification
Sulfonamides
Molecular Structure
ras-GRF1
Biological activity
Structure-activity relationship
Small molecule
Sulfonamide
Cell Transformation, Neoplastic
Anticancer agent
Oncology
chemistry
Biochemistry
Drug Design
Mutation
NIH 3T3 Cells
ras Proteins
Guanosine Triphosphate
Pharmacophore
Subjects
Details
- ISSN :
- 15680096
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Current Cancer Drug Targets
- Accession number :
- edsair.doi.dedup.....a4dfb0abcfbe2767b2bc3ecf9b3b271e