Design and Synthesis of N-Acylated Aza-Goniothalamin Derivatives and Evaluation of Their in vitro and in vivo Antitumor Activity

Author(s)

Barcelos, Rosimeire Coura ^[1] ; Pastre, Julio Cezar ^[1] ; Vendramini-Costa, Debora Barbosa ^{[1, 2]} ; Caixeta, Vanessa ^[1] ; Longato, Giovanna Barbarini ^{[2, 3]} ; Monteiro, Paula Araujo ^{[2, 3]} ; de Carvalho, Joao Ernesto ^{[2, 3]} ; Pilli, Ronaldo Aloise ^[1]

Affiliation

^[1] Univ Estadual Campinas, Inst Quim, Dept Quim Organ, BR-13083970 Campinas, SP - Brazil

^[2] Univ Estadual Campinas, Ctr Pluridisciplinar Pesquisas Quim Biol & Agr CP, Div Farmacol & Toxicol, BR-13083970 Campinas, SP - Brazil

^[3] Univ Estadual Campinas, Inst Biol, Programa Posgrad Biol Celular & Estrutural, BR-13083970 Campinas, SP - Brazil

• Document type: Journal article
• Source: CHEMMEDCHEM; v. 9, n. 12, p. 2725-2743, DEC 2014.
• Web of Science Citations: 14

Abstract

Herein we describe the synthesis of a focused library of compounds based on the structure of goniothalamin (1) and the evaluation of the potential antitumor activity of the compounds. N-Acylation of aza-goniothalamin (2) restored the in vitro antiproliferative activity of this family of compounds. 1-(E)-But-2-enoyl-6-styryl-5,6-dihydropyridin-2(1H)-one (18) displayed enhanced antiproliferative activity. Both goniothalamin (1) and derivative 18 led to reactive oxygen species generation in PC-3 cells, which was probably a signal for caspase-dependent apoptosis. Treatment with derivative 18 promoted AnnexinV/7-aminoactinomycinD double staining, which indicated apoptosis, and also led to G(2)/M cell-cycle arrest. In vivo studies in Ehrlich ascitic and solid tumor models confirmed the antitumor activity of goniothalamin (1), without signs of toxicity. However, derivative 18 exhibited an unexpectedly lower in vivo antitumor activity, despite the treatments being administered at the same site of inoculation. Contrary to its in vitro profile, aza-goniothalamin (2) inhibited Ehrlich tumor growth, both on the ascitic and solid forms. Our findings highlight the importance of in vivo studies in the search for new candidates for cancer treatment. (AU)

• FAPESP's process: 12/18281-3 - Mechanism of action of goniothalamin and derivatives: the use of fluorescent probes and folate receptors
• Grantee: Débora Barbosa Vendramini Costa
• 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: 10/16990-1 - Synthesis and evaluation of cytotoxic activity of gama-dihydropyrones: goniothalamin and abyssinone II analogues
• Grantee: Júlio Cezar Pastre
• Support Opportunities: Scholarships in Brazil - Post-Doctoral