Tri- and Pentacyclic Azaphenothiazine as Pro-Apoptotic Agents in Lung Carcinoma with a Protective Potential to Healthy Cell Lines

Abstract

The phenothiazine derivatives, tricyclic 10H-3,6-diazaphenothiazine (DPT-1) and pentacyclic 7-(3′-dimethylaminopropyl)diquinothiazine (DPT-2), have recently been shown to exhibit promising anticancer activities in vitro. In this report, we demonstrated that DPT-1 and DPT-2 could be pro-apoptotic agents in lung carcinoma, the human lung carcinoma A549 and non-small lung carcinoma H1299, in the range of IC50 = 1.52–12.89 µM, with a protective potential to healthy cell lines BEAS-2B and NHDF. The compounds showed higher activity in the range of the tested concentrations and low cytotoxicity in relation to normal healthy cells than doxorubicin, used as the reference drug. The cytostatic potential of DPT-1 and DPT-2 was demonstrated with the use of MTT assay. Cell cycle analysis via flow cytometry using Annexin-V assay showed the pro-apoptotic and pro-necrotic role of the studied diazaphenothiazines in the cell cycle. DPT-1 and DPT-2 initiated a biological response in the investigated cancer models with a different mechanism and at a different rate. Based on these findings, it can be concluded that DPT-1 and DPT-2 have potential as chemotherapeutic agents.

Substituted 1‐Azaphenothiazines and Their 10‐(2′‐Morpholinylethyl) Derivatives: Synthesis, Characterization and Anticancer Evaluation

“…Also, azaphenothiazine substituted with dialkylaminoalkyl or cyclicaminoalkyl as a pharmacophoric group containing a ChemistrySelect www.chemistryselect.org lipophilic chain has shown good cytotoxic potential toward various cancer cell lines such as T98G (malignant brain cancer), H460 (lung cancer), SNU80 (thyroid cancer), T47D (ductal carcinoma) and A549 (lung cancer). [36][37][38] Encouraged by these findings and as part of our research work on exploring anticancer activity of novel heterocyclic compounds, [39][40] we have synthesized 1-azaphenothiazine and its 10-(2'-morpholinylethyl) derivatives substituted at 3-and 8-positions with different groups (Cl, Br, CF 3 , and Me) and examined their anticancer activities toward various cancer cell lines such as colon cancer cells (CaCO2), lung cancer cells (A549), pancreatic cancer cells (SW1990, SW48), and human breast cancer cells (MDA-MB-231, MCF-7).…”

New Isomeric Dipyridothiazine Dimers — Synthesis, Structural Characterization and Cytotoxicity Screening

“…Such a group of 2 modified phenothiazines includes dipyridothiazines having two pyridine rings in their structure instead of benzene rings [21]. Dipyridothiazines show valuable anticancer activities involving induction of apoptosis via mitochondrial activation of it as well as partial DNA intercalation [25][26][27]. Dipyridothiazines also showed significant immunosuppressive and anti-inflammatory activity by inhibiting TNF alpha and interleukin 6 levels [28].…”

Study of the Lipophilicity and ADMET Parameters of New Anticancer Diquinothiazines with Pharmacophore Substituents

“…The weak lethal effect observed in NHDF or BEAS-2B cells at IC 50 doses against A549 or H1299 cells confirms promising cancer selectivity. The cell cycle revealed that substance 2 activated the necrosis phase [ 25 ].…”