Synthesis, Anticancer Activity, and Apoptosis Induction of Novel 3,6-Diazaphenothiazines
Beata Morak-Młodawska,
Krystian Pluta,
Małgorzata Latocha,
Małgorzata Jeleń,
Dariusz Kuśmierz
Affiliations
Beata Morak-Młodawska
Department of Organic Chemistry, School of Pharmacy with the Division of Laboratory Medicine, The Medical University of Silesia, Jagiellońska 4, 41-200 Sosnowiec, Poland
Krystian Pluta
Department of Organic Chemistry, School of Pharmacy with the Division of Laboratory Medicine, The Medical University of Silesia, Jagiellońska 4, 41-200 Sosnowiec, Poland
Małgorzata Latocha
Department of Cell Biology, School of Pharmacy with the Division of Laboratory Medicine, The Medical University of Silesia, Jedności 8, 41-200 Sosnowiec, Poland
Małgorzata Jeleń
Department of Organic Chemistry, School of Pharmacy with the Division of Laboratory Medicine, The Medical University of Silesia, Jagiellońska 4, 41-200 Sosnowiec, Poland
Dariusz Kuśmierz
Department of Cell Biology, School of Pharmacy with the Division of Laboratory Medicine, The Medical University of Silesia, Jedności 8, 41-200 Sosnowiec, Poland
New 10-substituted derivatives of 3,6-diazaphenothiazine, containing the triple bond linker terminated with tertiary cyclic and acyclic amine groups, were synthesized and screened for their anticancer action. The compounds exhibited varied anticancer activities against human glioblastoma SNB-19, melanoma C-32, and breast cancer MDA-MB231 cell lines, depending on the nature of the substituents. The most active 3,6-diazaphenothiazine, 4, was the derivative with the N,N-diethylamino-2-butynyl substituent against glioblastoma SNB-19, and was ten times more potent than cisplatin. For this compound, the expression of H3, TP53, CDKN1A, BCL-2, and BAX genes was detected by the RT-qPCR method. The gene expression ratio BAX/BCL-2 indicated the induction of mitochondrial apoptosis in cancer cell lines. The transformation of the propynyl substituent into amino-2-butynyl can be a method applicable to the search for more anticancer-active azaphenothiazines.
