New Derivatives of 1-(3-Methyl-1-Benzofuran-2-yl)Ethan-1-one: Synthesis and Preliminary Studies of Biological Activity.

A set of nine derivatives, including five brominated compounds, was synthesized and the structures of these novel compounds were confirmed using 1H and 13C NMR as well as ESI MS spectra. These compounds were tested on four different cancer cell lines, chronic myelogenous leukemia (K562), prostate cancer (PC3), colon cancer (SW620), human kidney cancer (Caki 1), and on healthy human keratocytes (HaCaT). MTT results reveal that two newly developed derivatives (6 and 8) exhibit selective action towards K562 cells and no toxic effect in HaCat cells. The biological activity of these two most promising compounds was evaluated by trypan blue assay, reactive oxygen species generation, and IL-6 secretion. To investigate the proapoptotic activity of selected compounds, the two following types of tests were performed: Annexin V Apoptosis Detection Kit I and Caspase-Glo 3/7 assay. The studies of the mechanism showed that both compounds have pro-oxidative effects and increase reactive oxygen species in cancer cells, especially at 12 h incubation. Through the Caspase-Glo 3/7 assay, the proapoptotic properties of both compounds were confirmed. The Annexin V-FITC test revealed that compounds 6 and 8 induce apoptosis in K562 cells. Both compounds inhibit the release of proinflammatory interleukin 6 (IL-6) in K562 cells. Additionally, all compounds were screened for their antibacterial activities using standard and clinical strains. Within the studied group, compound 7 showed moderate activity towards Gram-positive strains in antimicrobial studies, with MIC values ranging from 16 to 64 µg/mL.

New aryl-/heteroarylpiperazine derivatives of 1,7-dimethyl-8,9-diphenyl-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5,10-trione: Synthesis and preliminary studies of biological activities.

Compounds containing dicarboximide skeleton such as succinimides, maleimides, glutarimides, and phthalimides possess broad biological properties including anti-fungal, antibacterial, antidepressant, or analgesic activities. The piperazine ring is found in a wide range of molecules that have demonstrated a variety of biological functions such as anticancer action and 5-HT receptors agonist/antagonist activity. In the present study, we combined both structures to develop new antitumor agents, a series of piperazine derivatives of 1,7-dimethyl-8,9-diphenyl-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5,10-trione and evaluated their biological activity. The structures of all tested compounds were confirmed by 1H and 13C NMR and by ESI MS spectral analysis. Their cytotoxicity was assessed in vitro against eight human cancer cell lines, namely prostate (PC3), colon (HCT116, SW480, SW620), leukemia (K562), liver (HepG2), lung (A549) and breast (MDA-Mb-231) in contrast to normal HMEC-1 cell line, by using MTT and Trypan blue method. The tested compounds showed significant activity toward cancer cells. The most pronounced cytotoxic effect was observed in K562 and HCT116 with IC50 values below 10 µM for all studied compounds. Importantly, the most promising derivatives for each cancer cell line (IC50 < 10 µM) exerted a weaker cytotoxic effect toward normal HMEC-1 cells than cancer cells. The evaluation of proapoptotic and inhibitory effects on IL-6 release showed that K562 and HCT116 cells were more sensitive to studied compounds than other cancer cell lines. Furthermore, for all piperazine derivatives, the functional activities at the 5-HT1A, D2 receptors as well as their binding affinities at the 5-HT2A, H1 and M receptors, were determined. The current investigation was able to successfully design compounds with both serotoninergic and anticancer properties. It serves as a good starting point for a multimodal approach for the management of cancer and cancer-related symptoms.

Proapoptotic effects of halogenated bis-phenylthiourea derivatives in cancer cells.

New halogenated thiourea derivatives were synthesized via the reaction of substituted phenylisothiocyanates with aromatic amines. Their cytotoxic activity was examined in in vitro studies against solid tumors (SW480, SW620, PC3), a hematological malignance (K-562), and normal keratinocytes (HaCaT). Most of the compounds were more effective against SW480 (1a, 3a, 3b, 5j), K-562 (2b, 3a, 4a), or PC3 (5d) cells than cisplatin, with favorable selectivity. Their anticancer mechanisms were studied by Annexin V-fluorescein-5-isothiocyanate apoptosis, caspase-3/caspase-7 assessment, cell cycle analysis, interleukin-6 (IL-6) release inhibition, and reactive oxygen species (ROS) generation assay. Thioureas 1a, 2b, 3a, and 4a were the most potent activators of early apoptosis in K-562 cells, and substances 1a, 3b, 5j triggered late-apoptosis or necrosis in SW480 cells. This proapoptotic effect was proved by the significant increase of caspase-3/caspase-7 activation. Cell cycle analysis revealed that derivatives 1a, 3a, 5j increased the number of SW480 and K-562 cells in the sub-G1 and/or G0/G1 phases, and one evoked cycle arrest at the G2 phase. The most potent thioureas inhibited IL-6 cytokine secretion from PC3 cells and both colon cancer cell lines. Apoptosis-inducing compounds also increased ROS production in all tumor cell cultures, which may enhance their anticancer properties.

Anticancer activity and metabolic alteration in colon and prostate cancer cells by novel moxifloxacin conjugates with fatty acids.

The positive and pro-economic trend in the management of cancer treatment is the search for the antineoplastic potential of known, widely used and safe drugs with a different clinical purpose. A good candidate seems to be moxifloxacin with broad-spectrum antibacterial activity, which as the member of the fourth generation fluoroquinolone is known to affect not only bacterial but also eukaryotic DNA topoisomerases, however at high concentration. Due to the fact that the modification of parent drug with lipid component can improve anticancer potential by increasing of bioavailability, selectivity, and cytotoxic efficiency, we evaluated the mechanisms of cytotoxic activity of novel moxifloxacin conjugates with fatty acids and verified metabolic profile in SW480, SW620 and PC3 cell lines. Our study revealed that cytotoxic potential of moxifloxacin conjugates was stronger than free moxifloxacin, moreover, they remained non-toxic to normal HaCaT cells. PC3 were more sensitive to MXF conjugates than colon cancer cells. The most promising cytotoxic activity exhibited conjugate 4m and 16m with oleic and stearic acid reducing viability of PC3 and SW620 cells. Tested conjugates activated caspases 3/7 and induced late-apoptosis, mainly in PC3 and SW620 cells. However, the most pronounced inhibition of NF-κB activation and IL-6 secretion was observed in SW480. Metabolomic analysis indicated influence of the moxifloxacin conjugates on intensity of lipid derivatives with the most successful metabolite profile in PC3. Our findings suggested the cytotoxic potential of moxifloxacin conjugates, especially with oleic and stearic acid can be beneficial in oncological therapy, including their possible anti-inflammatory and known antibacterial effect.