title: In vivo phase II-enzymes inducers, as potential chemopreventive agents, based on the chalcone and furoxan skeletons.
abstract: Cancer chemoprevention involves prevention/delay/reverse of the carcinogenic process through administration of cancer chemopreventive agents (CCA). Compounds which are able to induce detoxification-enzymes, especially monofunctional phase II enzymes, have become in excellent approaches for new CCA. Herein, we report the synthesis of new furoxanyl chalcone-like hybrid compounds as CCA. In vitro studies showed that phenylfuroxanyl derivatives 6 and 9 displayed the best activities being 9 the greatest monofunctional-inducer. Additionally, compounds were non-mutagenic against TA98 Salmonella typhimurium strain (Ames test) and could be used in the prevention of the progression of pre-malignant lesions for their cytotoxic activity against tumoral cells. In vivo proof of concept showed increment on phase II-enzymes activities in liver, colon and mammary gland having derivative 9 the best induction profiles. We probed Nrf2 nuclear translocation is operative for both compounds allowing to exert protective effects via expression of downstream phase-II enzymes.
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Cabrera
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay; Laboratorio de I + D de Moléculas Bioactivas, Centro Universitario Paysandú, CenUR Litoral Norte, Universidad de la República, Uruguay; Departamento de Neurociencias, Laboratorio de Neurobiología Celular y Molecular, IIBCE, 11600 Montevideo, Uruguay.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Mastandrea
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay; Laboratorio de I + D de Moléculas Bioactivas, Centro Universitario Paysandú, CenUR Litoral Norte, Universidad de la República, Uruguay; Departamento de Neurociencias, Laboratorio de Neurobiología Celular y Molecular, IIBCE, 11600 Montevideo, Uruguay.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Otero
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay. Electronic address: hcerecetto@cin.edu.uy.
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay. Electronic address: megonzal@fq.edu.uy.
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002599:Chalcone / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C528141:1,2,5-oxadiazole 2-oxide; D000970:Antineoplastic Agents; D010069:Oxadiazoles; D002599:Chalcone; D003577:Cytochrome P-450 Enzyme System; D016660:NAD(P)H Dehydrogenase (Quinone); D005982:Glutathione Transferase
keywords: Cancer; Chalcone; Chemoprevention; Furoxan; Phase II enzymes