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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,
Pastre Julio Cezar,
VendraminiCosta Débora Barbosa,
Caixeta Vanessa,
Longato Giovanna Barbarini,
Monteiro Paula Araújo,
de Carvalho João Ernesto,
Pilli Ronaldo Aloise
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402292
Subject(s) - in vivo , apoptosis , in vitro , chemistry , annexin , pharmacology , acylation , cell growth , cell cycle , cell cycle checkpoint , stereochemistry , biochemistry , biology , microbiology and biotechnology , catalysis
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(1 H )‐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 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.