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Synthesis, Anticancer Activity, and Apoptosis Induction of Novel 3,6-Diazaphenothiazines

1
Department of Organic Chemistry, School of Pharmacy with the Division of Laboratory Medicine, The Medical University of Silesia, Jagiellońska 4, 41-200 Sosnowiec, Poland
2
Department of Cell Biology, School of Pharmacy with the Division of Laboratory Medicine, The Medical University of Silesia, Jedności 8, 41-200 Sosnowiec, Poland
*
Author to whom correspondence should be addressed.
Part CLIII in the series of Azinyl Sulfides.
Academic Editors: David Díez and María Ángeles Castro
Molecules 2019, 24(2), 267; https://doi.org/10.3390/molecules24020267
Received: 30 November 2018 / Revised: 9 January 2019 / Accepted: 9 January 2019 / Published: 12 January 2019
(This article belongs to the Special Issue Application of Organic Synthesis to Bioactive Compounds)
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Abstract

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. View Full-Text
Keywords: phenothiazines; dipyridothiazines; antiproliferative activity; dialkylaminoalkynyl substituents; apoptosis; H3; TP53; CDKN1A; BAX/BCL-2 ratio phenothiazines; dipyridothiazines; antiproliferative activity; dialkylaminoalkynyl substituents; apoptosis; H3; TP53; CDKN1A; BAX/BCL-2 ratio
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Morak-Młodawska, B.; Pluta, K.; Latocha, M.; Jeleń, M.; Kuśmierz, D. Synthesis, Anticancer Activity, and Apoptosis Induction of Novel 3,6-Diazaphenothiazines. Molecules 2019, 24, 267.

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