Novel naphtho[2,1-d]oxazole-4,5-diones as NQO1 substrates with improved aqueous solubility: Design, synthesis, and in vivo antitumor evaluation.
Bioorg Med Chem
; 24(5): 1006-13, 2016 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-26803578
ABSTRACT
A new series of ortho-naphthoquinone analogs of ß-lapachone were designed, synthesized and evaluated. The biological results indicated that most of our compounds were efficient substrates for NQO1. The new scaffold with water-soluble side chain resulted in greater solubility under acidic condition compared to ß-lapachone. Thus avoiding the use of hydroxylpropyl ß-cyclodextrin which would finally cause the rapid drug clearance from the blood and dose-limiting toxicity in the form of hemolytic anemia. The most soluble and promising compound in this series was 2-((4-benzylpiperazin-1-yl)methyl)naphtho[2,1-d]oxazole-4,5-dione (3k), which inhibited cancer cell (NQO1-rich A549 cell line) growth at IC50 values of 4.6±1.0µmol·L(-1). Furthermore, compound 3k had in vivo antitumor activity in an A549 tumor xenografts mouse model comparable to the activity obtained with ß-lapachone. The results indicated that these ortho-naphthoquinones could serve as promising leads for further optimization as novel substrates for NQO1.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Naftoquinonas
/
NAD(P)H Desidrogenase (Quinona)
/
Neoplasias Pulmonares
/
Antineoplásicos
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article