10H-1, 9-diazaphenothiazine and its 10-derivatives: synthesis, characterisation and biological evaluation as potential anticancer agents. (1st January 2019)

• Record Type: Journal Article
• Authors: Morak-Młodawska, Beata; Pluta, Krystian; Latocha, Małgorzata; Jeleń, Małgorzata; Kuśmierz, Dariusz; Suwińska, Kinga; Shkurenko, Aleksander; Czuba, Zenon; Jurzak, Magdalena
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 34:Number 1(2019)
• Page Start: 1298
• Page End: 1306
• Publication Date: 2019-01-01
• Subjects: Phenothiazines -- dipyridothiazines -- anticancer activity -- gene expressions -- 2D NMR spectra; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2019.1639695
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: 10 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 N, N -diethylaminoethyl groups being more potent than cisplatin. For those two compounds, the expression of H3, TP53, CDKN1A, BCL-2 and 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). Graphical Abstract: