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.

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).

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.

Evaluation of Physicochemical Properties of Amphiphilic 1,4-Dihydropyridines and Preparation of Magnetoliposomes.

This study was focused on the estimation of the targeted modification of 1,4-DHP core with (1) different alkyl chain lengths at 3,5-ester moieties of 1,4-DHP (C12, C14 and C16); (2) N-substituent at position 1 of 1,4-DHP (N-H or N-CH3); (3) substituents of pyridinium moieties at positions 2 and 6 of 1,4-DHP (H, 4-CN and 3-Ph); (4) substituent at position 4 of 1,4-DHP (phenyl and napthyl) on physicochemical properties of the entire molecules and on the characteristics of the obtained magnetoliposomes formed by them. It was shown that thermal behavior of the tested 1,4-DHP amphiphiles was related to the alkyl chains length, the elongation of which decreased their transition temperatures. The properties of 1,4-DHP amphiphile monolayers and their polar head areas were determined. The packing parameters of amphiphiles were in the 0.43-0.55 range. It was demonstrated that the structure of 1,4-DHPs affected the physicochemical properties of compounds. "Empty" liposomes and magnetoliposomes were prepared from selected 1,4-DHP amphiphiles. It was shown that the variation of alkyl chains length or the change of substituents at positions 4 of 1,4-DHP did not show a significant influence on properties of liposomes.

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.

Contribution of Molecular Structure to Self-Assembling and Biological Properties of Bifunctional Lipid-Like 4-(N-Alkylpyridinium)-1,4-Dihydropyridines.

The design of nanoparticle delivery materials possessing biological activities is an attractive strategy for the development of various therapies. In this study, 11 cationic amphiphilic 4-(N-alkylpyridinium)-1,4-dihydropyridine (1,4-DHP) derivatives differing in alkyl chain length and propargyl moiety/ties number and position were selected for the study of their self-assembling properties, evaluation of their cytotoxicity in vitro and toxicity on microorganisms, and the characterisation of their interaction with phospholipids. These lipid-like 1,4-DHPs have been earlier proposed as promising nanocarriers for DNA delivery. We have revealed that the mean diameter of freshly prepared nanoparticles varied from 58 to 513 nm, depending upon the 4-(N-alkylpyridinium)-1,4-DHP structure. Additionally, we have confirmed that only nanoparticles formed by 4-(N-dodecylpyridinium)-1,4-DHP derivatives 3 and 6, and by 4-(N-hexadecylpyridinium)-1,4-DHP derivatives 10 and 11 were stable after two weeks of storage. The nanoparticles of these compounds were found to be homogenous in size distribution, ranging from 124 to 221 nm. The polydispersity index (PDI) values of 1,4-DHPs samples 3, 6, 10, and 11 were in the range of 0.10 to 0.37. We also demonstrated that the nanoparticles formed by 4-(N-dodecylpyridinium)-1,4-DHP derivatives 3, 6, and 9, and 4-(N-hexadecylpyridinium)-1,4-DHP derivatives 10 and 11 had zeta-potentials from +26.07 mV (compound 6) to +62.80 mV (compound 11), indicating a strongly positive surface charge and confirming the relative electrostatic stability of these nanoparticle solutions. Transmission electron microscopy (TEM) images of nanoaggregates formed by 1,4-DHPs 3 and 11 confirmed liposome-like structures with diameters around 70 to 170 nm. The critical aggregation concentration (CAC) value interval for 4-(N-alkylpyridinium)-1,4-DHP was from 7.6 µM (compound 11) to 43.3 µM (compound 6). The tested 4-(N-alkylpyridinium)-1,4-DHP derivatives were able to quench the fluorescence of the binary 1,6-diphenyl-1,3,5-hexatriene (DPH)-1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) system, demonstrating hydrophobic interactions of 1,4-DHPs with phospholipids. Thus, 4-(N-dodecylpyridinium)-1,4-DHP derivative 3 quenched the fluorescence of the DPH⁻DPPC system more efficiently than the other 4-(N-alkylpyridinium)-1,4-DHP derivatives. Likewise the compound 3, also 4-(N-dodecylpyridinium)-1,4-DHP derivative 9 interacted with the phospholipids. Moreover, we have established that increasing the length of the alkyl chain at the quaternised nitrogen of the 4-(N-alkylpyridinium)-1,4-DHP molecule or the introduction of propargyl moieties in the 1,4-DHP molecule significantly influences the cytotoxicity on HT-1080 (human fibrosarcoma) and MH-22A (mouse hepatocarcinoma) cell lines, as well as the estimated basal cytotoxicity. Additionally, it was demonstrated that the toxicity of the 4-(N-alkylpyridinium)-1,4-DHP derivatives on the Gram-positive and Gram-negative bacteria species and eukaryotic microorganism depended on the presence of the alkyl chain length at the N-alkyl pyridinium moiety, as well as the number of propargyl groups. These lipid-like compounds may be proposed for the further development of drug formulations to be used in cancer treatment.