Premium
Expedient synthesis and anticancer evaluation of dual‐action 9‐anilinoacridine methyl triazene chimeras
Author(s) -
Walunj Dipak,
Egarmina Katarina,
Tuchinsky Helena,
Shpilberg Ofer,
HershkovitzRokah Oshrat,
Grynszpan Flavio,
Gellerman Gary
Publication year - 2021
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13776
Subject(s) - triazene , chimera (genetics) , chemistry , stereochemistry , moiety , dna , anticancer drug , intercalation (chemistry) , alkylation , acridine , mechanism of action , biochemistry , combinatorial chemistry , biology , drug , pharmacology , gene , inorganic chemistry , in vitro , catalysis , organic chemistry
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 (S N 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 IC 50 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.