Morak-Młodawska Beata, Pluta Krystian, Latocha Małgorzata, Jeleń Małgorzata, Kuśmierz Dariusz
a School of Pharmacy with the Division of Laboratory Medicine, Department of Organic Chemistry, The Medical University of Silesia , Sosnowiec , Poland and.
b School of Pharmacy with the Division of Laboratory Medicine, Department of Cell Biology, The Medical University of Silesia , Sosnowiec , Poland.
J Enzyme Inhib Med Chem. 2016 Dec;31(6):1132-8. doi: 10.3109/14756366.2015.1101092. Epub 2015 Nov 2.
New derivatives of two isomeric types of azaphenothiazines, 1,8- and 2,7-diazaphenothiazine, containing the triple bond substituents and additionally tertiary cyclic and acyclic amine groups, were synthesized and tested for their anticancer activity. The compounds exhibited differential inhibitory activities. Better results were obtained when the acetylenic group was transformed via the Mannich reaction to the dialkylaminobutynyl groups. The most active was 2,7-diazaphenothiazine with the N-methylpiperazine-2-butynyl substituent against the human ductal breast epithelial tumor cell line T47D, more potent than cisplatin. The 2,7-diazaphenothiazine system turned out to be more active than isomeric 1,8-diaza one. For the most active compound, the expression of TP53, CDKN1A, BCL-2 and BAX genes was detected by the RT-QPCR method. The gene expression ratio BACL-2/BAX suggests the mitochondrial apoptosis in T47D cells. The synthesis makes possible to obtain many new bioactive phenothiazines with the dialkylaminoalkynyl substituents inserting various tertiary cyclic and acyclic amine moieties to the substituents.
合成了两种异构类型的氮杂吩噻嗪（1,8 - 和2,7 - 二氮杂吩噻嗪）的新衍生物，它们含有三键取代基以及叔环胺和无环胺基团，并对其抗癌活性进行了测试。这些化合物表现出不同的抑制活性。当炔基通过曼尼希反应转化为二烷基氨基丁炔基时，获得了更好的结果。最具活性的是带有N - 甲基哌嗪 - 2 - 丁炔基取代基的2,7 - 二氮杂吩噻嗪，对人乳腺导管上皮肿瘤细胞系T47D的活性比顺铂更强。结果表明，2,7 - 二氮杂吩噻嗪体系比异构的1,8 - 二氮杂体系更具活性。对于最具活性的化合物，通过RT - QPCR方法检测了TP53、CDKN1A、BCL - 2和BAX基因的表达。基因表达比BAX/BCL - 2表明T47D细胞中存在线粒体凋亡。该合成方法使得能够获得许多带有二烷基氨基炔基取代基的新型生物活性吩噻嗪，这些取代基中插入了各种叔环胺和无环胺部分。
