title: The Oxime Derivatives of 1-R-1H-Naphtho[2,3-d][1,2,3]triazole-4,9-dione 2-oxides: Synthesis and Properties.
abstract: To synthesize a novel chemotype based on the naphthoquinone scaffold with retained cytotoxicity and provisionally low intracellular oxidation potential.
  
  
  
  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 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.
  
  
  
  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).
authors.affiliation: V.P. Astaf'ev Krasnoyarsk State Pedagogical University, 89 A. Lebedeva Street, Krasnoyarsk, 660060. Russian Federation.
authors.forename: Leonid M
authors.initials: LM
authors.lastname: Gornostaev
authors.affiliation: A.V.Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences. 29 Leninsky Avenue, 119991 Moscow. Russian Federation.
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Tsvetkov
authors.affiliation: A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov Street, Moscow 119991. Russian Federation.
authors.forename: Alina A
authors.initials: AA
authors.lastname: Markova
authors.affiliation: V.P. Astaf'ev Krasnoyarsk State Pedagogical University, 89 A. Lebedeva Street, Krasnoyarsk, 660060. Russian Federation.
authors.forename: Tatyana I
authors.initials: TI
authors.lastname: Lavrikova
authors.affiliation: V.P. Astaf'ev Krasnoyarsk State Pedagogical University, 89 A. Lebedeva Street, Krasnoyarsk, 660060. Russian Federation.
authors.forename: Yulia G
authors.initials: YG
authors.lastname: Khalyavina
authors.affiliation: V.P. Astaf'ev Krasnoyarsk State Pedagogical University, 89 A. Lebedeva Street, Krasnoyarsk, 660060. Russian Federation.
authors.forename: Anastasia S
authors.initials: AS
authors.lastname: Kuznetsova
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991. Russian Federation.
authors.forename: Dmitry N
authors.initials: DN
authors.lastname: Kaluzhny
authors.affiliation: Pirogov Russian National Research Medical University, 1 Ostrovitianov Street, Moscow 117997. Russian Federation.
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Shunayev
authors.affiliation: Blokhin Cancer Center, 24 Kashirskoye shosse, Moscow 115478. Russian Federation.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Tsvetkova
authors.affiliation: Blokhin Cancer Center, 24 Kashirskoye shosse, Moscow 115478. Russian Federation.
authors.forename: Valeria A
authors.initials: VA
authors.lastname: Glazunova
authors.affiliation: Department of Chemistry, Moscow State University, 1-3 Leninskie Gory, Moscow 119991. Russian Federation.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Chernyshev
authors.affiliation: Blokhin Cancer Center, 24 Kashirskoye shosse, Moscow 115478. Russian Federation.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Shtil
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D062105:Molecular Docking Simulation; D010091:Oximes / Q000737:chemistry*; D013057:Spectrum Analysis / Q000379:methods; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D010091:Oximes; D014230:Triazoles
keywords: 2; 3-d][1; 3]triazole-4; 9-dione 2-oxide; Quinones; cytotoxicity; molecular docking; naphtho[2; oxime; tumor cells