Polyproline-Polyornithine Diblock Copolymers with Inherent Mitochondria Tropism.

Mitochondria play critical roles in regulating cell fate, with dysfunction correlating with the development of multiple diseases, emphasizing the need for engineered nanomedicines that cross biological barriers. Said nanomedicines often target fluctuating mitochondrial properties and/or present inefficient/insufficient cytosolic delivery (resulting in poor overall activity), while many require complex synthetic procedures involving targeting residues (hindering clinical translation). The synthesis/characterization of polypeptide-based cell penetrating diblock copolymers of poly-L-ornithine (PLO) and polyproline (PLP) (PLO-PLP, n:m ratio 1:3) are described as mitochondria-targeting nanocarriers.

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.

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.

Olaparib Conjugates with Selenopheno[3,2-]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.

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--lysine (TML) to β-hydroxy-TML during the first step of -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.

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.

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.

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.

A study of tetrapeptide enantiomeric separation on crown ether based chiral stationary phases.

The chiral separations of small peptides is an important challenge in the biological and medical sciences, because different stereoisomers of chiral drugs can often possess different pharmacological, pharmacokinetic, and/or toxicological activities. Commercially available crown ether chiral stationary phases based on S-(3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6 (CROWNPAK CR-I (+)) and (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid (ChiroSil RCA (+)) have been successfully used for separating enantiomers of various racemic compounds containing primary amino groups. In this investigation, enantioresolution of more complex model analyte - tetrapeptide Tyr-Arg-Phe-Lys-NH, has been reported on crown ether chiral stationary phases.

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.

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[]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.

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.

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[]selenophenes-have been studied in lower eukaryotes .

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 (-) 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 strains, with activities comparable to or even exceeding the one of ebselen.

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.

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 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 studies was characterized and monitored by H 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.

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.

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.

Silacyclic derivatives of heteroaromatic sulfides as selective cholesterol level lowering and vasodilating agents.

Silacyclic derivatives of heteroaromatic sulfides have been prepared by using phase transfer catalytic (PTC) system thiol / silacyclopropyl iodide / solid K(2)CO(3) / 18-crown-6 / toluene. The target sulfides were isolated in yields up to 70 %. The S-derivatives of N-methylimidazolyl, benzoxazolyl and 1,3,4-triazolyl thiols selectively lowered the low density lipoprotein (LDL) level in mice with the high cholesterol diet in nutrition.

Synthesis of silicon and germanium containing heteroaromatic sulfides as cholesterol level lowering and vasodilating agents.

Silicon and germanium containing heteroaromatic sulfides have been prepared using phase transfer catalytic (PTC) system thiol / Si or Ge containing alkyl halide / solid KOH / 18- crown-6 / toluene. The target sulfides were isolated in yields up to 92 %. It has been found that 2-{[dimethyl (beta-triethylgermylethyl)-silylmethyl]thio}-1-methylimidazole and 2-{[dimethyl(beta-triphenylsilylethyl) silyl-methyl]thio}benzothiazole are the most active cholesterol level lowering and vasodilating agents.

Cytotoxic Activity of Silyl- and Germyl-Substituted 4,4-Dioxo-3a,6a-Dihydrothieno[2,3-d]isoxazolines-2.

The [2+3] dipolar cycloaddition of nitrile oxides to the double C = C bonds of thiophene-1, 1-dioxides leads to formation of the fused isoxazolines-2 (1, 2). Tumor growth inhibition of these compounds strongly depends on the nature of group IV A element increasing from slightly active tert-butyl derivatives to silicon and germanium containing analogues. The products of benzonitrile oxide cycloaddition have greater cytotoxic effect than the compounds obtained from the cycloaddition reaction of 2, 5-disubstituted thiophene-1, 1-dioxides with acetonitrile oxide.

Synthesis and cytotoxicity of silicon containing pyridine and quinoline sulfides.

Silicon containing pyridine and quinoline sulfides have been prepared using phase transfer catalytic system thiol/alkyl halide / solid KOH/18-crown-6 / toluene. The target S-ethers were isolated in yields up to 81%. The cytotoxicity of the synthesized compounds was studied.

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.