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

Abstract

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 IC₅₀ 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.

Keywords:

• Naphthoisoxazolequinone
• bioisosteric
• antiproliferative activity
• molecular docking

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

We are grateful for the financial support from the Comisión Nacional de Investigación Científica y Tecnológica CONICYT of Chile (Project FONDECYT 1100316) and from the Dirección de Investigación de la Vicerrectoría de Investigación y Estudios Avanzados, Pontificia Universidad Católica de Valparaíso, Chile (Projects DI 125.780/2010-2013, DI 039.471/2020). J. Maldonado is grateful for the support of the Doctoral Fellowship CONICYT-PCHA/Doctorado Nacional/2014-21140688.