Objective: To synthesize a novel chemotype based on the naphthoquinone scaffold with retained
cytotoxicity and provisionally low intracellular oxidation potential.
Background: Derivatives of naphthoquinone, although potent anticancer agents, can exert heart toxicity due to
generation of free oxygen species.
Methods: 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 spatial structure was determined by X-ray analysis. New compounds were tested for the
ability to form stable complexes with double stranded DNA by spectroscopy and molecular docking and to
induce death of tumor cell lines and non-malignant counterparts.
Results: 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).
Conclusion: Thus, our chemical modifications yielded a new chemotype with good cytotoxic properties and
yet-to-be-identified intracellular target(s).