TY - JOUR
T1 - Antiproliferative benzoindazolequinones as potential cyclooxygenase-2 inhibitors
AU - Molinari, Aurora
AU - Oliva, Alfonso
AU - Arismendi-Macuer, Marlene
AU - Guzmán, Leda
AU - Acevedo, Waldo
AU - Aguayo, Daniel
AU - Vinet, Raúl
AU - Feliciano, Arturo San
N1 - Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
PY - 2019/6/18
Y1 - 2019/6/18
N2 - Quinones and nitrogen heterocyclic moieties have been recognized as important pharmacophores in the development of antitumor agents. This study aimed to establish whether there was any correlation between the in silico predicted parameters and the in vitro antiproliferative activity of a family of benzoindazolequinones (BIZQs), and to evaluate overexpressed proteins in human cancer cells as potential biomolecular targets of these compounds. For this purpose, this study was carried out using KATO-III and MCF-7 cell lines as in vitro models. Docking results showed that these BIZQs present better binding energies (∆Gbin) values for cyclooxygenase-2 (COX-2) than for other cancer-related proteins. The predicted ∆Gbin values of these BIZQs, classified in three series, positively correlated with IC50 measured in both cell lines (KATO-III: 0.72, 0.41, and 0.90; MCF-7: 0.79, 0.55, and 0.87 for Series I, II, and III, respectively). The results also indicated that compounds 2a, 2c, 6g, and 6k are the most prominent BIZQs, because they showed better IC50 and ∆Gbin values than the other derivatives. In silico drug absorption, distribution, metabolism, and excretion (ADME) properties of the three series were also analyzed and showed that several BIZQs could be selected as potential candidates for cancer pre-clinical assays.
AB - Quinones and nitrogen heterocyclic moieties have been recognized as important pharmacophores in the development of antitumor agents. This study aimed to establish whether there was any correlation between the in silico predicted parameters and the in vitro antiproliferative activity of a family of benzoindazolequinones (BIZQs), and to evaluate overexpressed proteins in human cancer cells as potential biomolecular targets of these compounds. For this purpose, this study was carried out using KATO-III and MCF-7 cell lines as in vitro models. Docking results showed that these BIZQs present better binding energies (∆Gbin) values for cyclooxygenase-2 (COX-2) than for other cancer-related proteins. The predicted ∆Gbin values of these BIZQs, classified in three series, positively correlated with IC50 measured in both cell lines (KATO-III: 0.72, 0.41, and 0.90; MCF-7: 0.79, 0.55, and 0.87 for Series I, II, and III, respectively). The results also indicated that compounds 2a, 2c, 6g, and 6k are the most prominent BIZQs, because they showed better IC50 and ∆Gbin values than the other derivatives. In silico drug absorption, distribution, metabolism, and excretion (ADME) properties of the three series were also analyzed and showed that several BIZQs could be selected as potential candidates for cancer pre-clinical assays.
KW - 1H-benzo[f]indazole-4,9-diones
KW - Antiproliferative activity
KW - Benzoindazolequinones
KW - COX-2 inhibitors
KW - Docking
UR - http://www.scopus.com/inward/record.url?scp=85068493801&partnerID=8YFLogxK
U2 - 10.3390/molecules24122261
DO - 10.3390/molecules24122261
M3 - Article
C2 - 31216654
AN - SCOPUS:85068493801
SN - 1420-3049
VL - 24
JO - Molecules
JF - Molecules
IS - 12
M1 - 2261
ER -
