title: New anticancer agents mimicking protein recognition motifs.
abstract: The novel tetrasubstituted pyrrole derivatives 8g, 8h, and 8i showed selective cytotoxicity against M14 melanoma cells at low micromolar concentration. Structure-activity relationships (SARs) indicated the presence of three aromatic substituents on the pyrrole core as necessary for biological activity. Computational studies strongly suggest that the peculiar 3D orientation of these substituents is able to reproduce the hydrophobic side chains in LxxLL-like protein recognition motifs. Biological results showed altered p53 expression and nuclear translocation in cells sensitive to the compounds, suggesting p53 involvement in their anticancer mechanism of action. Unfortunately, because of poor solubility of the active analogues, it was not possible to perform further investigation by NMR techniques. Pharmacophore models were generated and used to perform 3D searches in molecular databases. Results indicated that two compounds share the same pharmacological profile and the same pharmacophoric features with our new derivatives, and one of them inhibited MDM2-MDM4 heterodimer formation.
authors.affiliation: Dipartimento di Farmacia, Università di Napoli "Federico II" , Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Persico
authors.forename: Anna
authors.initials: A
authors.lastname: Ramunno
authors.forename: Vita
authors.initials: V
authors.lastname: Maglio
authors.forename: Silvia
authors.initials: S
authors.lastname: Franceschelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Esposito
authors.forename: Alfonso
authors.initials: A
authors.lastname: Carotenuto
authors.forename: Diego
authors.initials: D
authors.lastname: Brancaccio
authors.forename: Valeria
authors.initials: V
authors.lastname: De Pasquale
authors.forename: Luigi Michele
authors.initials: LM
authors.lastname: Pavone
authors.forename: Michela
authors.initials: M
authors.lastname: Varra
authors.forename: Nausicaa
authors.initials: N
authors.lastname: Orteca
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Caterina
authors.initials: C
authors.lastname: Fattorusso
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D018716:Molecular Mimicry; D011506:Proteins / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D011506:Proteins