Synthesis, in vitro evaluation and molecular docking studies of novel naphthoisoxazolequinone carboxamide hybrids as potential antitumor agents

• Published in: Polycyclic aromatic compounds Vol. 43; no. 6; pp. 4960 - 4983
• Main Authors: Maldonado, Javier, Acevedo, Waldo, Molinari, Aurora, Oliva, Alfonso, Knox, Marcela, San Feliciano, Arturo
• Format: Journal Article
• Language: English
• Published: Philadelphia Taylor & Francis 03-07-2023; Taylor & Francis Ltd
• Subjects: Adenocarcinoma; Alanine; Amino acids; Anticancer properties; antiproliferative activity; Antitumor agents; bioisosteric; Carcinogens; Chemical synthesis; Cytotoxicity; Gastric cancer; Glutamic acid; Glycine; Hybrids; Intermediates; L-Alanine; Molecular docking; Naphthoisoxazolequinone; Phenylalanine; Quinones
• ISSN: 1040-6638; 1563-5333
• DOI: 10.1080/10406638.2022.2095410

Based on previous results with benzoindazolequinone (BIZQ) derivatives, a new series of bioisosteric 3-methylnaphtho[2,3-d]isoxazole-4,9-quinones (NIQs), conjugated with C-protected amino acids as glycine (Gly), L-alanine (Ala), L-phenylalanine (Phe) and L-glutamic acid, were synthesized from NIQ 2, and the chemical structures of intermediates and hybrids were elucidated by spectroscopic techniques. The antiproliferative activity of NIQs was evaluated by in vitro assay on cultured MCF-7 breast adenocarcinoma and KATO III gastric carcinoma cells. All the compounds showed to be cytotoxic against both cell lines, with IC
50
values between 22.9 and 215.3 µM. NIQ hybrids 6, 8, and 9, conjugated with Gly, Phe and Glu, respectively, showed to be more cytotoxic, and hybrid 8 also proved to have higher activity than the precursor 2 against MCF-7 cells. Docking studies showed that NIQs exhibited very good binding energies (ΔG
bin
) in the active site of proteins that participate in key carcinogenic pathways.