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 and Alexander A. Shtil*   Pages 1814 - 1823 ( 10 )

Abstract:

Objective: To synthesize a novel chemotype based on the naphthoquinone scaffold with retained cytotoxicity and provisionally low intracellular oxidation potential. </P><P> Background: Derivatives of naphthoquinone, although potent anticancer agents, can exert heart toxicity due to generation of free oxygen species. </P><P> 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. </P><P> 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). </P><P> 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.

Affiliation:

V.P. Astaf'ev Krasnoyarsk State Pedagogical University, 89 A. Lebedeva Street, Krasnoyarsk, 660060, A.V.Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences. 29 Leninsky Avenue, 119991 Moscow, A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov Street, Moscow 119991, V.P. Astaf'ev Krasnoyarsk State Pedagogical University, 89 A. Lebedeva Street, Krasnoyarsk, 660060, V.P. Astaf'ev Krasnoyarsk State Pedagogical University, 89 A. Lebedeva Street, Krasnoyarsk, 660060, V.P. Astaf'ev Krasnoyarsk State Pedagogical University, 89 A. Lebedeva Street, Krasnoyarsk, 660060, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Pirogov Russian National Research Medical University, 1 Ostrovitianov Street, Moscow 117997, Blokhin Cancer Center, 24 Kashirskoye shosse, Moscow 115478, Blokhin Cancer Center, 24 Kashirskoye shosse, Moscow 115478, Department of Chemistry, Moscow State University, 1-3 Leninskie Gory, Moscow 119991, Blokhin Cancer Center, 24 Kashirskoye shosse, Moscow 115478

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