(-)-Tarchonanthuslactone: Design of New Analogues, Evaluation of their Antiproliferative Activity on Cancer Cell Lines, and Preliminary Mechanistic Studies

Author(s)

Toneto Novaes, Luiz Fernando ^[1] ; Avila, Carolina Martins ^[1] ; Pelizzaro-Rocha, Karin Juliane ^[2] ; Vendramini-Costa, Debora Barbosa ^[3] ; Dias, Marina Pereira ^[2] ; Barbosa Trivella, Daniela Barreto ^[4] ; de Carvalho, Joao Ernesto ^[3] ; Ferreira-Halder, Carmen Verissima ^[2] ; Pilli, Ronaldo Aloise ^[1]

Affiliation

^[1] Univ Estadual Campinas, UNICAMP, Inst Chem, BR-13084971 Campinas, SP - Brazil

^[2] Univ Estadual Campinas, Inst Biol, Dept Biochem, BR-13083862 Campinas, SP - Brazil

^[3] Univ Estadual Campinas, UNICAMP, Div Pharmacol & Toxicol CPQBA, BR-13083970 Campinas, SP - Brazil

^[4] Natl Ctr Res Energy & Mat, Brazilian Biosci Natl Lab, BR-13083970 Campinas, SP - Brazil

• Document type: Journal article
• Source: CHEMMEDCHEM; v. 10, n. 10, p. 1687-1699, OCT 2015.
• Web of Science Citations: 5

Abstract

Natural products containing the alpha,beta-unsaturated delta-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. (AU)

• FAPESP's process: 10/17544-5 - Structural and molecular bases of inhibitor recognition by the CDC-25 and LMW-PTP human protein phosphatases involved in cancer
• Grantee: Daniela Barretto Barbosa Trivella
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 12/09254-2 - Synthesis of the tarchonanthuslactone, analogues and evaluation of anticancer and antidiabetic activity
• Grantee: Luiz Fernando Toneto Novaes
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 13/08896-3 - Biochemical mapping of antitumor mechanism of calix[6]arene in human pancreatic cancer cell: investigation of intracellular trafficking, of kinome and microRNA expression
• Grantee: Karin Juliane Pelizzaro Rocha
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 09/51602-5 - Chemical biology: new natural and synthetic molecular targets against cancer, structural studies, biological evaluation and mode of action
• Grantee: Ronaldo Aloise Pilli
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/24385-6 - Influence of protein phosphatases inhibitors in the expression and / or activity of protein kinases in pancreatic cancer
• Grantee: Marina Pereira Dias
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 10/08673-6 - Studies toward the Synthesis of Analogues of Fostriecin and Total Synthesis and Structural Elucidation of Coibacinas A and B
• Grantee: Carolina Martins Avila de Sant'Ana
• Support Opportunities: Scholarships in Brazil - Doctorate