10$\textit{H}$-1,9-diazaphenothiazine and its 10-derivatives: synthesis, characterisation and biological evaluation as potential anticancer agents

  • Beata Morak-Młodawska (Creator)
  • Krystian Pluta (Creator)
  • Małgorzata Latocha (Creator)
  • Małgorzata Jeleń (Creator)
  • Dariusz Kuśmierz (Creator)
  • Kinga Suwińska (Creator)
  • Aleksander Shkurenko (Creator)
  • Zenon Czuba (Creator)
  • Magdalena Jurzak (Creator)



10$\textit{H}$-1,9-diazaphenothiazine was obtained in the sulphurisation reaction of diphenylamine with elemental sulphur and transformed into new 10-substituted derivatives, containing alkyl and dialkylaminoalkyl groups at the thiazine nitrogen atom. The 1,9-diazaphenothiazine ring system was identified with advanced $^{1}$H and $^{13}$C NMR techniques (COSY, NOESY, HSQC and HMBC) and confirmed by X-ray diffraction analysis of the methyl derivative. The compounds exhibited significant anticancer activities against the human glioblastoma SNB-19, melanoma C-32 and breast cancer MDA-MB-231 cell lines. The most active 1,9-diazaphenothiazines were the derivatives with the propynyl and $\textit{N}$, $\textit{N}$-diethylaminoethyl groups being more potent than cisplatin. For those two compounds, the expression of $\textit{H3}$, $\textit{TP53}$, $\textit{CDKN1A}$, $\textit{BCL-2}$ and $\textit{BAX}$ genes was detected by the RT-QPCR method. The proteome profiling study showed the most probable compound action on SNB-19 cells through the intrinsic mitochondrial pathway of apoptosis. The 1,9-diazaphenotiazine system seems to be more potent than known isomeric ones (1,6-diaza-, 1,8-diaza-, 2,7-diaza- and 3,6-diazaphenothiazine).
Date made available2019
PublisherTaylor & Francis

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