Expedient synthesis and anticancer evaluation of dual-action 9-anilinoacridine methyl triazene chimeras.
Chem Biol Drug Des
; 97(2): 237-252, 2021 02.
Article
em En
| MEDLINE
| ID: mdl-32772433
ABSTRACT
The efficient synthesis of molecular hybrids including a DNA-intercalating 9-anilinoacridine (9-AnA) core and a methyl triazene DNA-methylating moiety is described. Nucleophilic aromatic substitution (SN Ar) and electrophilic aromatic substitution (EAS) reactions using readily accessible starting materials provide a quick entry to novel bifunctional anticancer molecules. The chimeras were evaluated for their anticancer activity. Chimera 7b presented the highest antitumor activity at low micromolar IC50 values in antiproliferative assays performed with various cancer cell lines. In comparison, compound 7b outperformed DNA-intercalating drugs like amsacrine and AHMA. Mechanistic studies of chimera 7b suggest a dual mechanism of action methylation of the DNA-repairing protein MGMT associated with the triazene structural portion and Topo II inhibition by intercalation of the acridine core.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Triazenos
/
Amsacrina
/
Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Chem Biol Drug Des
Assunto da revista:
BIOQUIMICA
/
FARMACIA
/
FARMACOLOGIA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Israel