title: 3,6-Diazaphenothiazines as potential lead molecules - synthesis, characterization and anticancer activity.
abstract: 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.
authors.affiliation: a Department of Organic Chemistry, School of Pharmacy with the Division of Laboratory Medicine , The Medical University of Silesia , Sosnowiec , Poland .
authors.forename: Beata
authors.initials: B
authors.lastname: Morak-Młodawska
authors.affiliation: a Department of Organic Chemistry, School of Pharmacy with the Division of Laboratory Medicine , The Medical University of Silesia , Sosnowiec , Poland .
authors.forename: Krystian
authors.initials: K
authors.lastname: Pluta
authors.affiliation: b Department of Cell Biology, School of Pharmacy with the Division of Laboratory Medicine , The Medical University of Silesia , Sosnowiec , Poland , and.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Latocha
authors.affiliation: c Faculty of Mathematics and Natural Sciences , Cardinal Stefan Wyszyński University , Warszawa , Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Suwińska
authors.affiliation: a Department of Organic Chemistry, School of Pharmacy with the Division of Laboratory Medicine , The Medical University of Silesia , Sosnowiec , Poland .
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Jeleń
authors.affiliation: b Department of Cell Biology, School of Pharmacy with the Division of Laboratory Medicine , The Medical University of Silesia , Sosnowiec , Poland , and.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Kuśmierz
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D010640:Phenothiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D066244:Proton Magnetic Resonance Spectroscopy
chemical_list: D000970:Antineoplastic Agents; D010640:Phenothiazines; C031637:phenothiazine
keywords: 2D NMR spectra; X-ray analysis; anticancer activity; gene expressions; phenothiazines; the Smiles rearrangement