The Oxime Derivatives of 1-R-1H-Naphtho[2,3-d][1,2,3]triazole-4,9-dione 2-oxides: Synthesis and Properties

Author(s): 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, Alexander A. Shtil*.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 17 , Issue 13 , 2017

Become EABM
Become Reviewer

Graphical Abstract:


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).

Keywords: Quinones, naphtho[2, 3-d][1, 2, 3]triazole-4, 9-dione 2-oxide, oxime, molecular docking, tumor cells, cytotoxicity.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2017
Page: [1814 - 1823]
Pages: 10
DOI: 10.2174/1871520617666170327112216
Price: $65

Article Metrics

PDF: 22