title: Design and synthesis of N-acylated aza-goniothalamin derivatives and evaluation of their in vitro and in vivo antitumor activity.
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 Annexin V/7-aminoactinomycin D double staining, which indicated apoptosis, and also led to G2 /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.
authors.affiliation: Departamento de Química Orgânica, Instituto de Química, Universidade Estadual de Campinas, CP 6154, 13083-970, Campinas, SP (Brazil).
authors.forename: Rosimeire Coura
authors.initials: RC
authors.lastname: Barcelos
authors.forename: Julio Cezar
authors.initials: JC
authors.lastname: Pastre
authors.forename: Débora Barbosa
authors.initials: DB
authors.lastname: Vendramini-Costa
authors.forename: Vanessa
authors.initials: V
authors.lastname: Caixeta
authors.forename: Giovanna Barbarini
authors.initials: GB
authors.lastname: Longato
authors.forename: Paula Araújo
authors.initials: PA
authors.lastname: Monteiro
authors.forename: João Ernesto
authors.initials: JE
authors.lastname: de Carvalho
authors.forename: Ronaldo Aloise
authors.initials: RA
authors.lastname: Pilli
mesh_terms: D000215:Acylation; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001372:Aza Compounds / Q000737:chemistry*; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D011753:Pyrones / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D001372:Aza Compounds; D011753:Pyrones; D017382:Reactive Oxygen Species; C103280:goniothalamin
keywords: acylation; antitumor agents; aza compounds; cytotoxicity; goniothalamin