Antiproliferative and proapoptotic activities of aza-annulated naphthoquinone analogs.
Toxicol In Vitro
; 54: 375-390, 2019 Feb.
Article
em En
| MEDLINE
| ID: mdl-30389605
ABSTRACT
1,4-Naphthoquinone derivatives have been widely documented with regard to their biological properties, and particularly their anticancer activities. In the 9,10-anthraquinone family, aza-annulation involving one of the carbonyl oxygen atoms has afforded more potent, possibly less toxic analogues. We recently carried out different modifications on the naphthoquinone skeleton to generate 3-chloro-2-amino- and 3-chloro-2-(N-acetamido)-1,4-naphthoquinone and 3,4-dihydrobenzo[f]quinoxalin-6(2H)-one derivatives. These three series of compounds were now tested against normal human fibroblasts and six human cancer cell lines. Some of the dihydrobenzoquinoxalinone derivatives were not only more potent than their 1,4-naphthoquinone counterparts, but also exhibited 10- to 14-fold selectivity between bladder carcinoma and normal cells and were equipotent with the non-selective reference drug used (etoposide). The fusion of an additional azaheterocycle to the 1,4-naphthoquinone nucleus modulates both the activity, selectivity and mechanism of action of the compounds. The electrochemical properties of selected compounds were evaluated in an attempt to correlate them with cytotoxic activity and mechanism of action. Finally, 3D-QSAR CoMFA and CoMSIA models were built on the AGS, J82, and HL-60 cell lines. The best models had values of r2predâ¯=â¯0.815; 0.823 and 0.925. The main structural relationships found, suggest that acetylation and alkylation of the amino group with large groups would be beneficial for cytotoxic activity.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Naftoquinonas
/
Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Toxicol In Vitro
Assunto da revista:
TOXICOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Chile