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

• Published in: ChemMedChem 2014-12, Vol.9 (12), p.2725-2743
• Main Authors: Barcelos, Rosimeire Coura, Pastre, Julio Cezar, Vendramini-Costa, Débora Barbosa, Caixeta, Vanessa, Longato, Giovanna Barbarini, Monteiro, Paula Araújo, de Carvalho, João Ernesto, Pilli, Ronaldo Aloise
• Format: Article
• Language: English
• Subjects: Acylation; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - therapeutic use; Antineoplastic Agents - toxicity; antitumor agents; Apoptosis; Apoptosis - drug effects; aza compounds; Aza Compounds - chemistry; Carcinoma, Ehrlich Tumor - drug therapy; Cell Line, Tumor; Cell Proliferation - drug effects; cytotoxicity; Drug Screening Assays, Antitumor; Female; G2 Phase Cell Cycle Checkpoints - drug effects; goniothalamin; Humans; M Phase Cell Cycle Checkpoints - drug effects; Medical research; Mice; Mice, Inbred BALB C; Pyrones - chemistry; Reactive Oxygen Species - metabolism; Structure-Activity Relationship; Transplantation, Heterologous
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201402292

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. In vivo l′importance! We conducted antiproliferation assays of a library of aza derivatives of goniothalamin (1) against a panel of tumor cell lines. The most potent compound, 18, led to reactive oxygen species generation, apoptosis, and G2/M cell‐cycle arrest in prostate PC‐3 cells, but it failed to inhibit tumor growth. Surprisingly, aza‐goniothalamin (2), which was shown to be much less toxic in vitro, inhibited Ehrlich tumor development in mice.