Aromatic systems with two and three pyridine-2,6-dicarbazolyl-3,5-dicarbonitrile fragments as electron-transporting organic semiconductors exhibiting long-lived emissions.

The pyridine-3,5-dicarbonitrile moiety has gained significant attention in the field of materials chemistry, particularly in the development of heavy-metal-free pure organic light-emitting diodes (OLEDs). Extensive research on organic compounds exhibiting thermally activated delayed fluorescence (TADF) has led to numerous patents and research articles. This study focuses on the synthesis and investigation of the semiconducting properties of polyaromatic π-systems containing two and three fragments of pyridine-2,6-dicarbazolyl-3,5-dicarbonitrile. The compounds are synthesized by Sonogashira coupling reactions and characterized by steady-state and time-resolved luminescence spectroscopy. The compounds show efficient intramolecular charge transfer (ICT) from the donor to the acceptor. The photoluminescence (PL) spectra of the solutions of the compounds showed non-structured emission peaks in the visible region, which are attributed to ICT emission. The PL intensities of the solutions of the compounds are enhanced after deoxygenation, which is indicative of TADF. The photoluminescence quantum yields and TADF properties of the compounds are sensitive to the medium. Cyclic voltammetry measurements indicate good hole-blocking and electron-injecting properties due to their high ionization potentials. Photoelectron spectroscopy and time-of-flight measurements reveal good electron-transporting properties for one of the compounds. In general, polyaromatic π-systems with pyridine-3,5-dicarbonitrile fragments demonstrate promising potential for use in organic electronic devices, such as OLEDs.

Development of isoselenazolium chlorides as selective pyruvate kinase isoform M2 inhibitors.

Alterations in cancer metabolic pathways open up an opportunity for targeted and effective elimination of tumor cells. Pyruvate kinase M2 (PKM2) is predominantly expressed in proliferating cells and plays an essential role in directing glucose metabolism in cancer. Here, we report the design of novel class of selective PKM2 inhibitors as anti-cancer agents and their mechanism of action. Compound 5c being the most active with IC50 = 0.35 ± 0.07 µM, also downregulates PKM2 mRNA expression, modulates mitochondrial functionality, induces oxidative burst and is cytotoxic for various cancer types. Isoselenazolium chlorides have an unusual mechanism of PKM2 inhibition, inducing a functionally deficient tetrameric assembly, while exhibiting a competitive inhibitor character. The discovery of robust PKM2 inhibitors not only offers candidates for anticancer therapy but is also crucial for studying the role of PKM2 in cancer.

Olaparib Conjugates with Selenopheno[3,2-c]quinolinone Inhibit PARP1 and Reverse ABCB1-Related Multidrug Resistance.

The restoration of the efficacy of antitumor medicines is a cornerstone in the combat with multidrug resistant (MDR) cancers. The overexpression of the ABCB1 transporter is a major obstacle to conventional doxorubicin therapy. The synergy of ABCB1 suppression and PARP1 activity inhibition that hampers malignant cell DNA repair could be a powerful tool in anticancer therapy. Herein, we report the design and synthesis of three novel olaparib conjugates with selenophenoquinolinones, their ability to reverse doxorubicin resistance in uterus sarcoma cells as well as their mechanism of action. It was found that the most potent chemosensitizer among studied compounds preserves PARP1 inhibitory activity and attenuates cells' resistance to doxorubicin by inhibiting ABCB1 transporter activity. These results demonstrate that the conjugation of PARP inhibitors with selenophenoquinolinones is a prospective direction for the development of agents for the treatment of MDR cancers.

Binding versus Enzymatic Processing of ε-Trimethyllysine Dioxygenase Substrate Analogues.

ε-Trimethyllysine dioxygenase (TMLD) is a non-heme Fe(II) and α-ketoglutarate dependent oxygenase that catalyzes the stereospecific hydroxylation of ε-trimethyl-l-lysine (TML) to ß-hydroxy-TML during the first step of l-carnitine biosynthesis. Targeting TMLD with inhibitors is a viable strategy for the treatment of cardiovascular diseases. Herein, we report a methodology for isothermal titration calorimetry analysis of TMLD substrate analogue binding to the enzyme. Despite the high structural similarity of the tested compounds, two different binding mechanisms (enthalpy- and entropy-driven) were observed, giving insight into the ligand (substrate) selectivity of TMLD. We demonstrate that the method allows distinguishing a natural substrate-like binding mode, which correlates with the ability of the compounds to serve as substrates in the TMLD catalytic reaction.

Nonyl Acridine Orange as a Prospective Photocatalyst in Chalcogenylation of Coumarins and Quinolinones.

A mild and efficient method for preparation of 3-sulfenyl and 3-selenyl coumarins and quinolinones mediated by artificial light or sunlight is presented. The elaborated protocol highlights the use of nonyl acridine orange as a photocatalyst to generate a sulfenyl radical from thiols that is further trapped by a heterocycle. The utility of the protocol is justified by a diverse scope of thiols, including short cysteine-containing peptides. The same reaction conditions can be applied for preparation of 3-selenyl coumarins and quinolinones. Various protected and unprotected selenocysteine-containing peptides were successfully utilized demonstrating high tolerance for amino acids with sensitive groups (Arg, Lys, Trp, His, and Tyr).

Fused isoselenazolium salts suppress breast cancer cell growth by dramatic increase in pyruvate-dependent mitochondrial ROS production.

The development of targeted drugs for the treatment of cancer remains an unmet medical need. This study was designed to investigate the mechanism underlying breast cancer cell growth suppression caused by fused isoselenazolium salts. The ability to suppress the proliferation of malignant and normal cells in vitro as well as the effect on NAD homeostasis (NAD+, NADH, and NMN levels), NAMPT inhibition and mitochondrial functionality were studied. The interactions of positively charged isoselenazolium salts with the negatively charged mitochondrial membrane model were assessed. Depending on the molecular structure, fused isoselenazolium salts display nanomolar to high micromolar cytotoxicities against MCF-7 and 4T1 breast tumor cell lines. The studied compounds altered NMN, NAD+, and NADH levels and the NAD+/NADH ratio. Mitochondrial functionality experiments showed that fused isoselenazolium salts inhibit pyruvate-dependent respiration but do not directly affect complex I of the electron transfer system. Moreover, the tested compounds induce an immediate dramatic increase in the production of reactive oxygen species. In addition, the isoselenazolothiazolium derivative selectively binds to cardiolipin in a liposomal model. Isoselenazolium salts may be a promising platform for the development of potent drug candidates for anticancer therapy that impact mitochondrial pyruvate-dependent metabolism in breast cancer cells.

Inhibition of CPT2 exacerbates cardiac dysfunction and inflammation in experimental endotoxaemia.

The suppression of energy metabolism is one of cornerstones of cardiac dysfunction in sepsis/endotoxaemia. To investigate the role of fatty acid oxidation (FAO) in the progression of inflammation-induced cardiac dysfunction, we compared the effects of FAO-targeting compounds on mitochondrial and cardiac function in an experimental model of lipopolysaccharide (LPS)-induced endotoxaemia. In LPS-treated mice, endotoxaemia-induced inflammation significantly decreased cardiac FAO and increased pyruvate metabolism, while cardiac mechanical function was decreased. AMP-activated protein kinase activation by A769662 improved mitochondrial FAO without affecting cardiac function and inflammation-related gene expression during endotoxaemia. Fatty acid synthase inhibition by C75 restored both cardiac and mitochondrial FAO; however, no effects on inflammation-related gene expression and cardiac function were observed. In addition, the inhibition of carnitine palmitoyltransferase 2 (CPT2)-dependent FAO by aminocarnitine resulted in the accumulation of FAO intermediates, long-chain acylcarnitines, in the heart. As a result, cardiac pyruvate metabolism was inhibited, which further exacerbated inflammation-induced cardiac dysfunction. In conclusion, although inhibition of CPT2-dependent FAO is detrimental to cardiac function during endotoxaemia, present findings show that the restoration of cardiac FAO alone is not sufficient to recover cardiac function. Rescue of cardiac FAO should be combined with anti-inflammatory therapy to ameliorate cardiac dysfunction in endotoxaemia.

Benzoselenophenylpyridine platinum complexes: green versus red phosphorescence towards hybrid OLEDs.

The first examples of phosphorescent platinum complexes bearing 2- and 3-(2-pyridyl)benzo[b]selenophenes (PyBSe) were synthesized and fully characterized. Almost identical ionization potential values (5.6 and 5.58 eV) of the solid samples of the Pt complexes were obtained by electron photoemission spectroscopy. Having slightly different molecular design, the solid solutions of the complexes emitted efficient green and red phosphorescence with absolute quantum yields of 52% (for green) and 11.6% (for red). It is demonstrated that the platinum complexes synthesized can be used as phosphorescent dopants for hybrid solution-processable OLEDs.

Synthesis and Performance in OLEDs of Selenium-Containing Phosphorescent Emitters with Red Emission Color Deeper Than the Corresponding NTSC Standard.

The synthesis of new iridium(III) complexes containing a 2-(benzo[b]selenophen-2-yl)pyridine ligand is reported along with their photophysical, thermal, electrochemical and electroluminescent properties. These complexes are characterized by deep red phosphorescence with photoluminescence quantum yields exceeding 31% in the solid state. Solid layers of the complexes were characterized by ionization potentials of 5.17-5.27 eV and electron affinities of 2.87-2.95 eV. Their thermal and electrochemical stabilities were proved by cyclic voltammetry and thermogravimetric analysis. Deep red selenium-based iridium phosphorescent emitters were used in red electroluminescent devices which were characterized by a deep red color with Commission Internationale de l'Eclairage (CIE 1931) chromaticity coordinates (x, y) of (0.69, 0.31). This color is deeper than that defined by the red color standard (0.67, 0.33) of the National Television System Committee (NTSC) or CIE 1931 of (0.68, 0.32) of the widely known red phosphorescent emitter bis(1-phenylisoquinoline)(acetylacetonate)iridium(III) (Ir(piq)2(acac)). Using newly developed deep red iridium complexes, white hybrid wet-processable light-emitting devices were fabricated, the electroluminescence of which was characterized by a white color with a color rendering index (CRI) reaching 85. White hybrid OLEDs were obtained by mixing blue fluorescence, green thermally activated delayed fluorescence, and red phosphorescence. They showed a maximum brightness exceeding 10000 cd/m2 and a high external quantum efficiency of 6.3% as for solution-processed white devices.

Synthesis of Linear and V-Shaped Carbazolyl-Substituted Pyridine-3,5-dicarbonitriles Exhibiting Efficient Bipolar Charge Transport and E-Type Fluorescence.

With the aim of developing all-organic bipolar semiconductors with high charge mobility and efficient E-type fluorescence (so-called TADF) as environmentally friendly light-emitting materials for optoelectronic applications, four noble metals-free dyes with linear and V-shapes were designed using accepting pyridine-3,5-dicarbonitrile and donating carbazole units. By exploiting a donor-acceptor design strategy and using moieties with different donating and accepting abilities, TADF emitters with a wide variety of molecular weights were synthesized to achieve the optimum combination of charge-transporting and fluorescent properties in one TADF molecule. Depending on molecule structures, different TADF emitters capable of emitting in the range from 453 to 550 nm with photoluminescence quantum yields up to 98 % for the solutions in oxygen-free toluene were obtained. All compounds showed bipolar charge-transport. Hole mobility of 2.8×10-3  cm2 /Vs at 7×105  V cm-1 was observed for the compound containing two di-tert-butyl-substituted carbazole moieties. The compounds were tested in both non-doped and doped organic light-emitting diodes using different hosts. It was shown that the developed TADF emitters are suitable for different color devices with electroluminescence ranging from blue to yellow and with brightness, maximum current and external quantum efficiencies exceeding 10 000 cd m-2 , 15 cd/A, and 7 %, respectively.

Resveratrol-Inspired Benzo[b]selenophenes Act as Anti-Oxidants in Yeast.

Resveratrol is a natural (poly)phenol primarily found in plants protecting them against pathogens, as well as harmful effects of physical and chemical agents. In higher eukaryotic cells and organisms, this compound displays a remarkable range of biological activities, such as anti-oxidant, anti-inflammatory, anti-cancer, anti-aging, cardio- and neuro-protective properties. Here, biological activities of synthetic selenium-containing derivatives of resveratrol-benzo[b]selenophenes-have been studied in lower eukaryotes Saccharomyces cerevisiae. Their toxicity, as well as DNA damaging and reactive oxygen species (ROS) inducing potencies, manifested through their ability to act as redox active anti-microbial agents, have been examined. We show that some benzo[b]selenophenes can kill yeast cells and that the killing effects are not mediated by DNA damage types that can be detected as DNA double-strand breaks. These benzo[b]selenophenes could potentially be used as anti-fungal agents, although their concentrations relevant to application in humans need to be further evaluated. In addition, most of the studied benzo[b]selenophenes display redox-modulating/anti-oxidant activity (comparable or even higher than that of resveratrol or Trolox) causing a decrease in the intracellular ROS levels in yeast cells. Therefore, after careful re-evaluation in other biological systems these observations might be transferred to humans, where resveratrol-inspired benzo[b]selenophenes could be used as supra-anti-oxidant supplements.

Selenopheno quinolinones and coumarins promote cancer cell apoptosis by ROS depletion and caspase-7 activation.

AIM: This study was designed to investigate the mechanism underlying cancer cell apoptosis caused by selenophenoquinolinones and coumarins. MATERIALS AND METHODS: Twelve derivatives were studied according to their ability to suppress the proliferation of cancer cells in vitro (i.e., HepG2, MH-22A, MCF-7), induce cell apoptosis, modulate cellular antioxidant enzyme system activities (i.e., SOD, GPx, TrxR), influence the level of ROS, and modulate caspase activity. RESULTS: A plausible mechanism of apoptosis is presented. The lack of change in the activity of caspase-8 demonstrates that these compounds affect the intrinsic rather than the extrinsic pathway; moreover, the absence of caspase-9 activation suggests that the studied compounds are involved in the intrinsic pathway of apoptosis in a non-canonical manner. Provisionally, the increase in Smac/Diablo released from the mitochondria removes the inhibitory effect and activates caspase-7, leading to apoptosis. Additionally, the activation of caspase-1 activates effector caspase-7, thereby increasing the amount of cytochrome c and Smac/Diablo released from the mitochondria and ultimately leading to apoptosis. CONCLUSION: This present study provides scientific evidence that selenopheno quinolinones and coumarins promote cancer cell apoptosis by ROS depletion and caspase-7 activation in malignant cells.

Selenazolinium Salts as "Small Molecule Catalysts" with High Potency against ESKAPE Bacterial Pathogens.

In view of the pressing need to identify new antibacterial agents able to combat multidrug-resistant bacteria, we investigated a series of fused selenazolinium derivatives (1-8) regarding their in vitro antimicrobial activities against 25 ESKAPE-pathogen strains. Ebselen was used as reference compound. Most of the selenocompounds demonstrated an excellent in vitro activity against all S. aureus strains, with activities comparable to or even exceeding the one of ebselen. In contrast to ebselen, some selenazolinium derivatives (1, 3, and 7) even displayed significant actions against all Gram-negative pathogens tested. The 3-bromo-2-(1-hydroxy-1-methylethyl)[1,2]selenazolo[2,3-a]pyridinium chloride (1) was particularly active (minimum inhibitory concentrations, MICs: 0.31-1.24 µg/mL for MRSA, and 0.31-2.48 µg/mL for Gram-negative bacteria) and devoid of any significant mutagenicity in the Ames assay. Our preliminary mechanistic studies in cell culture indicated that their mode of action is likely to be associated with an alteration of intracellular levels of glutathione and cysteine thiols of different proteins in the bacterial cells, hence supporting the idea that such compounds interact with the intracellular thiolstat. This alteration of pivotal cysteine residues is most likely the result of a direct or catalytic oxidative modification of such residues by the highly reactive selenium species (RSeS) employed.

Natural-Antioxidant-Inspired Benzo[b]selenophenes: Synthesis, Redox Properties, and Antiproliferative Activity.

The cyclization of arylalkynes under selenobromination conditions, combined with an acid-induced 3,2-aryl shift, was elaborated as a general synthetic pathway for the preparation of polyhydroxy-2- and -3-arylbenzo[b]selenophenes from the same starting materials. The redox properties, free-radical-scavenging ability, and cytotoxicity against malignant cell lines (MCF-7, MDA-MB-231, HepG2, and 4T1) of the synthesized compounds were explored, and the obtained results were used to consider the structure-activity relationships (SARs) in these compounds. Consequently, the structural features that were responsible for the highly potent peroxyl-radical-scavenging activity were established.

1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC) increases Carmofur stability and in vitro antiproliferative effect.

Addition of DMPC considerably inhibits the degradation of Carmofur in neutral phosphate buffer solutions and this drug becomes less influenced by pH. Carmofur stabilization at neutral pH caused by DMPC addition for in vitro studies was characterized and monitored by 1H NMR. Antiproliferative activity studies on various tumor cell lines showed considerable increase of Carmofur ability to prevent tumor cell growth, when it is added as a mixture with DMPC. This technique opens a way for Carmofur drug delivery in neutral and basic media.

Selenium analogues of raloxifene as promising antiproliferative agents in treatment of breast cancer.

Synthetic protocols for the preparation of selenium analogues of raloxifene were elaborated. General aim of the current research is to improve the positive impact of selenium atom introduction in drug design. Antiproliferative activity on CCL-8 (mouse sarcoma), MDA-MB-435s (human melanoma), MES-SA (human uterus sarcoma), MCF-7 (human breast adenocarcinoma), HT-1080 (human fibrosarcoma), MG-22A (mouse hepatoma) tumor cell lines, and normal cell line NIH 3T3 (mouse fibroblasts) was studied. Influence of aminoethoxy "tail" and benzoyl group position on SAR was discussed. Results of in vivo studies on BALB/c female mice with 4T1 cell induced breast cancer model showed that selenium analogue of raloxifene is able to suppress estrogen-depending tumor growth.

Synthesis, structure and cytotoxicity of 3-C, N, S, Se substituted benzo[b]selenophene derivatives.

Synthesis, molecular structure and cytotoxic activity of a series of 3-C, N, S, Se substituted benzo[b]selenophene derivatives on human fibrosarcoma HT-1080, mouse hepatoma MG-22A, and mouse fibroblasts 3T3 cell lines are described. The correlation between compound LD(50) 3T3 fibroblast cell line and HT-1080 morphology was shown.

4-Methyl-1,2,3-selenadiazole-5-carboxylic acid amides: antitumor action and cytotoxic effect correlation.

Synthesis and cytotoxic activity of a series of 4-methyl-1,2,3-selenadiazole-5-carboxylic acid amides on human fibrosarcoma HT-1080, mouse hepatoma MG-22A, and mouse fibroblasts 3T3 cell lines are described. The correlation between compound LD(50) and 3T3 fibroblast cell line morphology was shown. In vivo evaluation of amides on mouse sarcoma S-180 confirms high antitumor activity (58-85%).

Organoammonium hydroselenites: antitumor action through radical balance regulation.

Organoammonium hydroselenites were synthesized and investigated as potential selective, anticancer prodrugs. These compounds were studied in vitro on human fibrosarcoma (HT-1080), hamster kidney endothelial (BHK 21) and normal mouse embryonic fibroblasts (NIH 3T3). Most of them were very active against HT-1080 (0.6-5.3 g/ml). Amino acid hydroselenites readily increased the nitric oxide (NO) concentration in the culture medium of HT-1080 cells (up to TG(100)=1500%); however, 4-amidohydroximinomethylpyridinium hydroselenite (TG(100)=24%) and o-phenanthrolinium hydroselenite (TG(100)=50%) were free radical inhibitors. All compounds were glutathione peroxidase inhibitors; some of them could also prevent hydrogen peroxide degradation by inhibition of catalase. The influence of the investigated ammonium hydroselenites on tumor cell (HT-1080) morphology was examined. The substances studied were also active in vivo against sarcoma S-180. The role of organoammonium hydroselenites as free radical regulators and their therapeutic antitumor are discussed.

Synthesis and cytotoxicity of silicon and germanium containing pyridine oxime O-ethers.

Silicon and germanium containing pyridine aldoxime, ketoxime and amidoxime O-ethers have been prepared using phase transfer catalytic systems oxime alkyl halide solid KOH 18-crown-6 benzene and oxime alkyl halide solid K(2)CO(3) or Cs(2)CO(3) 18-crown-6 toluene. Cytotoxic activity of silicon and germanium containing pyridine oxime O-ethers was tested in vitro on two monolayer tumor cell lines: MG- 22A (mouse hepatoma) and HT-1080 (human fibrosarcoma). O-[3-Yriethylsilylpropyl]- and O-[3-(1-methyl- 1-silacyclopentyl)propyl] oximes of pyridine aldehydes and ketones exhibit high cytotoxicity. Presence of methyl group in the pyridine ring considerably decreased activity of amidoxime O-ethers. Oxime ethers containing two elements are essentially inactive. For 2-acetylpyridine oxime ethers the activity increases in order of alkyl substituents: Et(3)GeCH(2)CH(2)SiMe(2)CH(2) < Et(3)SiCH(2)CH(2)CH(2) < (CH(2))(4)SiCH(2)CH(2)CH(2). Cytotoxicity of ketoxime O-ethers is considerably lower in comparison with aldoxime O-ethers.