Derivatives of naphthoquinone, although potent anticancer agents,
can exert heart toxicity due to generation of free oxygen species. In this
study we modified the scaffold by replacing one carbonyl group with the
oxime moiety. Interestingly, only one carbonyl group in
1-R-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione 2-oxides reacted with
hydroxylamine. The resulting 1-R-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione
4-oxime 2-oxides were further acylated to produce a series of
1-R-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione 4-(O-acyloxime) 2-oxides.
Newly synthesized compounds demonstrated a higher (in submicromolar or low
micromolar range) cytotoxic potency against human colon and breast
adenocarcinoma cell lines than to non-malignant skin fibroblasts.
Spectroscopic measurements revealed that, unlike other classes of quinone
derivatives, new naphthotriazoledione oxides did not form stable complexes
with double stranded DNA regardless of their fitting to the DNA minor groove
(as determined by molecular modeling). Thus, our chemical modifications
yielded a new chemotype with good cytotoxic properties and
yet-to-be-identified intracellular target(s).
Keywords: Quinones, naphtho[2, 3-d][1, 2, 3]triazole-4, 9-dione 2-oxide, oxime,
molecular docking, tumor cells, cytotoxicity.
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