3,6-Diazaphenothiazines as potential lead molecules - synthesis, characterization and anticancer activity

作者：Morak Mlodawska Beata; Pluta Krystian^*; Latocha Malgorzata; Suwinska Kinga; Jelen Malgorzata; Kusmierz Dariusz

来源：Journal of Enzyme Inhibition and Medicinal Chemistry, 2016, 31(6): 1512-1519.

DOI：10.3109/14756366.2016.1151014

• 2D NMR spectra
• anticancer activity
• gene expressions
• phenothiazines
• the Smiles rearrangement
• X-ray analysis

3,6-Diazaphenothiazines were obtained in cyclization of 3-amino-3'-nitro-2,4'-dipyridinyl sulfide and the reaction of sodium 3-amino-2-pyridinethiolate with 4-chloro-3-nitropyridine followed by alkylation and heteroarylation. The thiazine ring formation ran via the Smiles rearrangement. The structure elucidation was based on 2D NMR and X-ray analysis of N-methylated product. 3,6-Diazaphenothiazines were investigated for antitumor activity using glioblastoma SNB-19, melanoma C-32 and breast cancer MCF-7 cells. 10H-3,6-diazaphenothiazine was 10 times more active (IC50 < 0.72 mu g/mL) than cisplatin. Two diazaphenothiazines with the 2-pyrimidinyl and dimethylaminopropyl substituents were selectively active against MCF-7 and C-32 cells. The expressions of H3 (proliferation marker), TP53, CDKN1A (cell cycle regulators), BAX and BCL-2 (proapoptopic and antiapoptopic genes) were detected by RT-QPCR method. The expression analysis suggests the cell cycle arrest and the mitochondrial apoptosis pathway activation in MCF-7 and SNB-19 cells.

• 出版日期2016