Morak-Młodawska Beata, Pluta Krystian, Latocha Małgorzata, Suwińska Kinga, Jeleń Małgorzata, Kuśmierz Dariusz
a Department of Organic Chemistry, School of Pharmacy with the Division of Laboratory Medicine , The Medical University of Silesia , Sosnowiec , Poland .
b Department of Cell Biology, School of Pharmacy with the Division of Laboratory Medicine , The Medical University of Silesia , Sosnowiec , Poland , and.
J Enzyme Inhib Med Chem. 2016 Dec;31(6):1512-9. doi: 10.3109/14756366.2016.1151014. Epub 2016 Mar 7.
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 μg/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.
3,6-二氮杂吩噻嗪是通过3-氨基-3'-硝基-2,4'-二吡啶基硫醚的环化反应，以及3-氨基-2-吡啶硫醇钠与4-氯-3-硝基吡啶反应，随后进行烷基化和杂芳基化反应得到的。噻嗪环的形成是通过斯迈尔斯重排反应进行的。结构解析基于N-甲基化产物的二维核磁共振和X射线分析。使用胶质母细胞瘤SNB-19、黑色素瘤C-32和乳腺癌MCF-7细胞对3,6-二氮杂吩噻嗪的抗肿瘤活性进行了研究。10H-3,6-二氮杂吩噻嗪的活性比顺铂高10倍（半数抑制浓度<0.72μg/mL）。两种带有2-嘧啶基和二甲基氨基丙基取代基的二氮杂吩噻嗪对MCF-7和C-32细胞具有选择性活性。通过逆转录定量聚合酶链反应（RT-QPCR）方法检测了H3（增殖标志物）、TP53、CDKN1A（细胞周期调节因子）、BAX和BCL-2（促凋亡和抗凋亡基因）的表达。表达分析表明MCF-7和SNB-19细胞中存在细胞周期阻滞和线粒体凋亡途径激活。
