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Type: Artigo de periódico
Title: (-)-tarchonanthuslactone: Design Of New Analogues, Evaluation Of Their Antiproliferative Activity On Cancer Cell Lines, And Preliminary Mechanistic Studies.
Author: Toneto Novaes, Luiz Fernando
Martins Avila, Carolina
Pelizzaro-Rocha, Karin Juliane
Vendramini-Costa, Débora Barbosa
Pereira Dias, Marina
Barbosa Trivella, Daniela Barreto
Ernesto de Carvalho, João
Ferreira-Halder, Carmen Veríssima
Pilli, Ronaldo Aloise
Abstract: Natural products containing the α,β-unsaturated δ-lactone skeleton have been shown to possess a variety of biological activities. The natural product (-)-tarchonanthuslactone (1) possessing this privileged scaffold is a popular synthetic target, but its biological activity remains underexplored. Herein, the total syntheses of dihydropyran-2-ones modeled on the structure of 1 were undertaken. These compounds were obtained in overall yields of 17-21 % based on the Keck asymmetric allylation reaction and were evaluated in vitro against eight different cultured human tumor cell lines. We further conducted initial investigation into the mechanism of action of selected analogues. Dihydropyran-2-one 8 [(S,E)-(6-oxo-3,6-dihydro-2H-pyran-2-yl)methyl 3-(3,4-dihydroxyphenyl)acrylate], a simplified analogue of (-)-tarchonanthuslactone (1) bearing an additional electrophilic site and a catechol system, was the most cytotoxic and selective compound against six of the eight cancer cell lines analyzed, including the pancreatic cancer cell line. Preliminary studies on the mechanism of action of compound 8 on pancreatic cancer demonstrated that apoptotic cell death takes place mediated by an increase in the level of reactive oxygen species. It appears as though compound 8, possessing two Michael acceptors and a catechol system, may be a promising scaffold for the selective killing of cancer cells, and thus, it deserves further investigation to determine its potential for cancer therapy.
Subject: Antitumor Agents
Natural Products
Reactive Oxygen Species
Rights: fechado
Identifier DOI: 10.1002/cmdc.201500246
Date Issue: 2015
Appears in Collections:Unicamp - Artigos e Outros Documentos

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