Search Results (13)

Epigenetic and stress-response pathways play central roles in cancer progression and represent attractive therapeutic targets. In this study, a series of dipyridothiazine–1,2,3-triazole hybrids bearing p-fluorophenyl and p-trifluoromethylphenyl substituents was synthesized via efficient dipolar cycloaddition reactions. Structural characterization was performed using ¹H, ¹³C, and ¹⁹F NMR spectroscopy and high-resolution mass spectrometry. Anticancer activity was evaluated using WST-1 and MTT assays against human cancer cell lines SNB-19 (glioblastoma), C32 (amelanotic melanoma), A549 (lung carcinoma), and MDA-MB-231 and MCF-7 (breast cancer), as well as normal HFF-1 fibroblasts and HaCaT keratinocytes, with doxorubicin and cisplatin as reference drugs. The hybrids TDT2b and TDT3b containing a p-trifluoromethylphenyl moiety showed the highest cytotoxicity and cancer cell selectivity. RT-qPCR analysis of H3, TP53, CDKN1A, BCL-2, and BAX expression for the lead compound TDT2b revealed modulation of chromatin organization, p53-dependent stress responses, apoptosis, and cell cycle regulation. Molecular docking studies with human histone deacetylase 6 (HDAC6) demonstrated favorable binding of TDT2b and TDT3b, supporting their role as potential epigenetic anticancer agents. Full article

Heterocyclic compounds have enormous pharmacological potential and therefore play a key role in the design of new drugs. Dipyridothiazines, both heterocyclic compounds and phenothiazine derivatives, exhibit promising anticancer, immunostimulatory, and antioxidant activities. The aim of this study was to design, synthesize, and evaluate the cytotoxicity of new 10-heteroaryl dipyridothiazines based on 2,7- and 3,6-diazaphenothiazine cores. The structural characterization of the new compounds was confirmed by spectroscopic methods. Cytotoxicity analysis was performed using the MTT assay against human keratinocytes (HaCaT) and two types of cancer cell lines: breast cancer (MDA-MB-231), lung carcer (A-549). The reference drugs used in the study were doxorubicin and cisplatin. The group of derivatives studied included active compounds as well as inactive derivatives. In order to explain differences in an activity level, molecular modelling supported by molecular dynamics was performed on histone deacetylase 6 (HDAC6), a known therapeutic target associated with oncogenic transformation and cancer metastasis. Molecular docking indicated that the derivative formed on the 2,7-diazaphenothiazine core is a more potent HDAC6 inhibitor, characterized by more stable binding and more favourable complex energy, despite minimal structural differences compared to the compound formed on the 3,6-diazaphenothiazine core. A preliminary SAR analysis was performed. Full article

Pyridine derivatives are widely distributed in nature and have valuable pharmacological properties. The pyridine core can be found in drugs such as sorafenib, zapiclone or prothipendyl. Dipyridothiazines are derivatives of phenothiazines that exhibit valuable anticancer, antioxidant and immunomodulatory activities. In this study, we present the synthesis and preliminary in vitro analysis of anticancer activity towards melanotic (COLO829, G361) and amelanotic (A375, C32) melanoma cells and normal human fibroblasts (HDF) of a series of new tricyclic diazaphenothiazines containing a pyridine scaffold in their structure. The structures of these new molecules was confirmed using spectral techniques, including ¹H NMR, ¹³C NMR, 2D NMR and HRMS. An in vitro panel of experiments was assessed using the WST-1 assay and cytometric techniques. The two most promising compounds were analyzed for their effect on intracellular GSH levels, mitochondrial membrane potential and their ability to initiate DNA fragmentation to determine the potential mechanism of both cytotoxic and proapoptotic activity. The conducted studies confirmed the ability of the new 3-methyl-1,6-diazaphenothiazines to induce apoptosis in cancer cells, especially in terms of inducing initial as well as late-phase apoptosis. Moreover, the studied compounds were found to induce redox imbalance (evidenced by GSH depletion) in the analyzed melanoma cells, which may be an important factor that directs melanoma cells towards cell death signaling pathways. Full article

Lipophilicity is an essential parameter of a compound that determines the solubility and pharmacokinetic properties that determine the transport of the drug to the molecular target. Dimers of dipyridothiazines are diazaphenothiazine derivatives exhibiting diverse anticancer potential in vitro, which is related to their affinity for histone deacetylase. In this study, the lipophilicity of 16 isomeric dipyridothiazine dimers was investigated theoretically and experimentally by reversed-phase thin-layer chromatography (RP-TLC) in an acetone–TRIS buffer (pH = 7.4). The relative lipophilicity parameter R_M0 and specific hydrophobic surface area b were significantly intercorrelated, showing congeneric classes of dimers. The parameter R_M0 was transformed into parameter logP_TLC by use of the calibration curve. Molecular descriptors, ADMET parameters and probable molecular targets were determined in silico for analysis of the pharmacokinetic profile of the tested compounds showing anticancer activity. The analyzed compounds were tested in the context of Lipinski’s rule of five, Ghose’s rule and Veber’s rule, confirming their bioavailability. Full article

Dimers of dipyridothiazines with an m-xylene moiety are presented in terms of a comparative analysis with anticancer active structural analogs containing a lutidine system. The synthesis of new isomeric dimers was described, the structure of which was confirmed by ¹H, ¹³C and 2D NMR, and HR MS spectroscopic methods. The preliminary prediction of the pharmacological profile using the Way2Drug server indicated the anticancer potential of the tested derivatives. In vitro biological activity tests were performed on a normal skin cell line (HaCaT) and five cancer cell lines, including human primary colon cancer (SW480), human metastatic colon cancer (SW620), human breast adenocarcinoma (MDA-MB-231), human lung carcinoma (A-549), and human glioblastoma (LN-229), which indicated low cytotoxic activity. In order to explain the surprisingly low activity, a comparative structural analysis of the tested analogs compared to the dimers with the lutidine system was performed using quantum mechanics and molecular docking in relation to histone deacetylase. Molecular docking indicated the different binding sites of the analyzed dimers, which explained the differences in the activity. Full article

Many new isomeric dipyridothiazine dimers have been presented as molecules with anticancer potential. These compounds were obtained in efficient syntheses of 1,6-, 1,8-, 2,7- and 3,6-diazaphenothiazines with selected alkylaromatic linkers. The structures of these compounds has been proven with two-dimensional spectroscopic techniques (COSY, NOESY, HSQC and HMBC) and high-resolution mass spectrometry (HRMS). In silico analyses of probable molecular targets were performed using the Way2Drug server. All new dimers were tested for anticancer activity against breast cancer line MCF7 and colon cancer line SW480. Cytotoxicity was assessed on normal L6 muscle cells. The tested dimers had high anticancer potential expressed as IC₅₀ and the selectivity index SI. The most active derivative, 4c, showed an IC₅₀ activity of less than 1 µM and an SI selectivity index higher than 100. Moreover, the compounds were characterized by low toxicity towards normal cells, simultaneously indicating a high cytostatic potential. Full article

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. Full article

The lipophilicity parameters (logP_calcd, R_M0 and logP_TLC) of 10 new active anticancer dipirydothiazines with a 1,2,3-triazole ring were determined theoretically using computational methods and experimentally by reversed-phase TLC. Experimental lipophilicity was assessed using mobile phases (a mixture of TRIS buffer and acetone) using a linear correlation between the R_M retention parameter and the volume of acetone. The R_M0 parameter was correlated with the specific hydrophobic surface b, revealing two congenerative subgroups: 1,2,3-triazole-1,6-diazaphenothiazines and 1,2,3-triazole-1,8-diazaphenothiazines hybrids. The R_M0 parameter was converted into the logP_TLC lipophilicity parameter using a calibration curve. The investigated compounds appeared to be moderately lipophilic. Lipophilicity has been compared with molecular descriptors and ADME properties. The new derivatives followed Lipinski’s, Ghose’s and Veber’s rules. Full article

Azaphenothiazines are the largest and most perspective group of modified phenothiazines, and they exhibit variety of biological activities. The review sums up the current knowledge on the anticancer activity of isomeric pyridobenzothiazines and dipyridothiazines, which are modified azaphenothiazines with one and two pyridine rings, respectively, against 10 types of cancer cell lines. Some 10-substituted dipyridothiazines and even 10-unsubstituted parent compounds, such as 10H-1,9-diazaphenothiazine and 10H-3,6-diazaphenothiazine, exhibited very potent action with the IC₅₀ values less than 1 µg/mL and 1 µM against selected cancer cell lines. The strength of the anticancer action depends both on the tricyclic ring scaffolds and the substituents at the thiazine nitrogen atom. The review discusses the kind of the substituents, nature of tricyclic ring scaffolds with the location of the azine nitrogen atoms, the types of the cancer cell lines, and the mechanism of action. Full article

Two new anticancer-active 1,2,3-triazole-dipyridothiazine hybrids were evaluated for their lipophilicity using thin-layer chromatography (TLC) and computational methods. The experimental lipophilicity was evaluated with mobile phases (mixtures of TRIS buffer and acetone), exploiting a linear correlation between the retention parameter (R_M) and the volume of acetone. The relative lipophilicity parameter (R_M0) was obtained by extrapolation to 0% acetone concentration. This parameter was intercorrelated with a specific hydrophobic surface area (b) revealing two congeneric subgroups: hybrids of 1,2,3-triazole-2,7-diazaphenothiazines and 1,2,3-triazole-3,6-diazaphenothiazines. The parameter R_M0 was converted into the absolute lipophilicity parameter logP_TLC using a calibration curve prepared on the basis of compounds of known logP values. Triazole–dipyridothiazine hybrids turned out to be medium lipophilic with logP_TLC values of 1.232–2.979. The chromatographically established parameter logP_TLC was compared to the calculated lipophilic parameter logP_calcd obtained with various algorithms. The lipophilicity was correlated with molecular descriptors and ADME properties. The new triazole–dipyridothiazine hybrids followed Lipinski’s rule of five. The lipophilicity of these hybrids was dependent on the substituents attached to the triazole ring and the location of the azine nitrogen atoms. Full article

The inverse correlation observed between Alzheimer’s disease (AD) and cancer has prompted us to look for cholinesterase-inhibiting activity in phenothiazine derivatives that possess anticancer properties. With the use of in silico and in vitro screening methods, our study found a new biological activity in anticancer polycyclic, tricyclic, and tetracyclic compounds. The virtual screening of a library of 120 ligands, which are the derivatives of azaphenothiazine, led to the identification of 25 compounds that can act as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Biological assays revealed the presence of selective inhibitors of eeAChE (electric eel AChE) or eqBuChE (equine serum BuChE) and nonselective inhibitors of both enzymes among the tested compounds. Their potencies against eeAChE were in a submicromolar-to-micromolar range with IC₅₀ values from 0.78 to 19.32 μM, while their IC₅₀ values against eqBuChE ranged from 0.46 to 10.38 μM. The most potent among the compounds tested was the tetracyclic derivative, 6-(4-diethylaminobut-2-ynyl)-9-methylthioquinobenzothiazine 24, which was capable of inhibiting both enzymes. 9-Fluoro-6-(1-piperidylethyl)quinobenzothiazine 23 was found to act as a selective inhibitor of eqBuChE with an IC₅₀ value of 0.46 μM. Compounds with such a dual antitumor and cholinesterase-inhibitory activity can be considered as a valuable combination for the treatment of both cancer and AD prevention. The results presented in this study might open new directions of research on the group of tricyclic phenothiazine derivatives. Full article

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. Full article