title: (-)-Tarchonanthuslactone: Design of New Analogues, Evaluation of their Antiproliferative Activity on Cancer Cell Lines, and Preliminary Mechanistic Studies.
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.
authors: Institute of Chemistry, University of Campinas (Unicamp), C.P. 6154, 13084-971, Campinas, SP (Brazil).
authors: Luiz Fernando
authors: LF
authors: Toneto Novaes
authors: Institute of Chemistry, University of Campinas (Unicamp), C.P. 6154, 13084-971, Campinas, SP (Brazil).
authors: Carolina
authors: C
authors: Martins Avila
authors: Department of Biochemistry, Biology Institute, University of Campinas (Unicamp), 13083-862, Campinas, SP (Brazil).
authors: Karin Juliane
authors: KJ
authors: Pelizzaro-Rocha
authors: Division of Pharmacology and Toxicology-CPQBA, University of Campinas (Unicamp), 13083-970, Campinas, SP (Brazil).
authors: Débora Barbosa
authors: DB
authors: Vendramini-Costa
authors: Department of Biochemistry, Biology Institute, University of Campinas (Unicamp), 13083-862, Campinas, SP (Brazil).
authors: Marina
authors: M
authors: Pereira Dias
authors: Brazilian Biosciences National Laboratory, National Center for Research in Energy and Material, 13083-970, Campinas, SP (Brazil).
authors: Daniela Barreto
authors: DB
authors: Barbosa Trivella
authors: Division of Pharmacology and Toxicology-CPQBA, University of Campinas (Unicamp), 13083-970, Campinas, SP (Brazil).
authors: João
authors: J
authors: Ernesto de Carvalho
authors: Department of Biochemistry, Biology Institute, University of Campinas (Unicamp), 13083-862, Campinas, SP (Brazil).
authors: Carmen Veríssima
authors: CV
authors: Ferreira-Halder
authors: Institute of Chemistry, University of Campinas (Unicamp), C.P. 6154, 13084-971, Campinas, SP (Brazil). pilli@iqm.unicamp.br.
authors: Ronaldo Aloise
authors: RA
authors: Pilli
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001688:Biological Products; D011753:Pyrones; C427965:tarchonanthuslactone
keywords: antitumor agents; cancer; natural products; reactive oxygen species; tarchonanthuslactone