title: Synthesis and evaluation of spiroisoxazoline oxindoles as anticancer agents.
abstract: Restoring p53 levels through disruption of p53-MDM2 interaction has been proved to be a valuable approach in fighting cancer. We herein report the synthesis and evaluation of eighteen spiroisoxazoline oxindoles derivatives as p53-MDM2 interaction inhibitors. Seven compounds showed an antiproliferative profile superior to the p53-MDM2 interaction inhibitor nutlin-3, and induced cell death by apoptosis. Moreover, proof-of-concept was demonstrated by inhibition of the interaction between p53 and MDM2 in a live-cell bimolecular fluorescence complementation assay.
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
authors.forename: Carlos J A
authors.initials: CJ
authors.lastname: Ribeiro
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
authors.forename: Joana D
authors.initials: JD
authors.lastname: Amaral
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
authors.forename: Cecília M P
authors.initials: CM
authors.lastname: Rodrigues
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal. Electronic address: mariasantos@ff.ul.pt.
authors.forename: Maria M M
authors.initials: MM
authors.lastname: Santos
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis; D049109:Cell Proliferation; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D000078183:Oxindoles; D013141:Spiro Compounds
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D000078183:Oxindoles; D013141:Spiro Compounds; C022960:2-oxindole
keywords: Cancer; MDM2; Protein–protein interactions; Spiro compounds; p53