The Oxime Derivatives of 1-R-1H-Naphtho[2.3-d][1.2.3]triazole-4.9-dione 2-oxides: Synthesis and Properties

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Author(s): Alexander A. Shtil*, Leonid M. Gornostaev, Vladimir B. Tsvetkov, Alina A. Markova, Tatyana I. Lavrikova, Yulia G. Khalyavina, Anastasia S. Kuznetsova, Dmitry N. Kaluzhny, Alexei V. Shunayev, Maria V. Tsvetkova, Valeria A. Glazunova, Vladimir V. Chernyshev.

Journal Name:Anti-Cancer Agents in Medicinal Chemistry

Volume 17 , 2017


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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Year: 2017
(E-pub Ahead of Print)
DOI: 10.2174/1871520617666170327112216
Price: $95

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