Synthesis and anticancer and lipophilic properties of 10-dialkylaminobutynyl derivatives of 1,8- and 2,7-diazaphenothiazines.
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.
a School of Pharmacy with the Division of Laboratory Medicine, Department of Organic Chemistry, The Medical University of Silesia , Sosnowiec , Poland and.
Beata
B
Morak-Młodawska
a School of Pharmacy with the Division of Laboratory Medicine, Department of Organic Chemistry, The Medical University of Silesia , Sosnowiec , Poland and.
Krystian
K
Pluta
b School of Pharmacy with the Division of Laboratory Medicine, Department of Cell Biology, The Medical University of Silesia , Sosnowiec , Poland.
Małgorzata
M
Latocha
a School of Pharmacy with the Division of Laboratory Medicine, Department of Organic Chemistry, The Medical University of Silesia , Sosnowiec , Poland and.
Małgorzata
M
Jeleń
b School of Pharmacy with the Division of Laboratory Medicine, Department of Cell Biology, The Medical University of Silesia , Sosnowiec , Poland.
Dariusz
D
Kuśmierz
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D010640:Phenothiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D066244:Proton Magnetic Resonance Spectroscopy; D016339:Spectrometry, Mass, Fast Atom Bombardment
D000970:Antineoplastic Agents; D010640:Phenothiazines; C031637:phenothiazine
Antiproliferative activity; BACL-2/BAX ratio; dialkylaminoalkynyl substituents; dipyridothiazines; phenothiazines