Intrinsic drug potential of oxazolo[5,4-d]pyrimidines and oxazolo[4,5-d]pyrimidines.

The oxazole and pyrimidine rings are widely displayed in natural products and synthetic molecules. They are known as the prime skeletons for drug discovery. On the account of structural and chemical diversity, oxazole and pyrimidine-based molecules, as central scaffolds, not only provide different types of interactions with various receptors and enzymes, showing broad biological activities, but also occupy a core position in medicinal chemistry, showing their importance for development and discovery of newer potential therapeutic agents (Curr Top Med Chem, 16, 2016, 3133; Int J Pharm Pharm Sci, 8, 2016, 8; BMC Chem, 13, 2019, 44). For a long time, relatively little attention has been paid to their fused rings that are oxazolopyrimidines, whose chemical structure is similar to that of natural purines because probably none of these compounds were found in natural products or their biological activities turned out to be unexpressed (Bull Chem Soc Jpn, 43, 1970, 187). Recently, however, a significant number of studies have been published on the biological properties of oxazolo[5,4-d]pyrimidines, showing their significant activity as agonists and antagonists of signaling pathways involved in the regulation of the cell life cycle, whereas oxazolo[4,5-d]pyrimidines, on the contrary, represent a poorly studied class of compounds. Limited access to this scaffold has resulted in a corresponding lack of biological research (Eur J Organ Chem, 18, 2018, 2148). Actually, oxazolo[5,4-d]pyrimidine is a versatile scaffold used for the design of bioactive ligands against enzymes and receptors. This review focuses on biological targets and associated pathogenetic mechanisms, as well as pathological disorders that can be modified by well-known oxazolopyrimidines that have been proven to date. Many molecular details of these processes are omitted here, which the interested reader will find in the cited literature. This work also does not cover the methods for the synthesis of the oxazolopyrimidines, which are exhaustively described by De Coen et al. (Eur J Organ Chem, 18, 2018, 2148). The review as well does not discuss the structure-activity relationship, which is described in detail in the original works and deliberately, whenever possible, cites not primary sources, but mostly relevant review articles, so that the reader who wants to delve into a particular problem will immediately receive more complete information. It is expected that the information presented in this review will help readers better understand the purpose of the development of oxazolopyrimidines and the possibility of their development as drugs for the treatment of a wide range of diseases.

The osmotic resistance, and zeta potential responses of human erythrocytes to transmembrane modification of Ca2+ fluxes in the presence of the imposed low rate radiation field of 90Sr.

PURPOSE: To investigate the effects of the imposed low dose rate ionizing field on membrane stability of human erythrocytes under modulation of transmembrane exchange of Ca(2+). MATERIALS AND METHODS: Osmotic resistance of human erythrocytes was determined by a measure of haemoglobin released from erythrocytes when placed in a medium containing serial dilutions of Krebs isotonic buffer. The zeta potential as indicator of surface membrane potential was calculated from value of the cellular electrophoretic mobility. The irradiation of erythrocyte suspensions carried out by applying suitable aliquots of (90)Sr in incubation media. RESULTS: Irradiation of human erythrocytes by (90)Sr (1.5-15.0 µGy·h(-1)) induced a reversible increase of hyposmotic hemolysis and negative charge value on the outer membrane surface as well as changed responses these parameters to modification of Ca(2+) fluxes with calcimycin and nitrendipine. CONCLUSIONS: Findings indicate that the low dose rate radionuclides ((90)Sr) field modifies both Ca(2+)-mediated, and Ca(2+)-independent cellular signalling regulating mechanical stability of erythrocyte membrane. A direction of that modification presumably depends on the initial structure of membranes, and it is determined by the quality and quantitative parameters of changes in membrane structure caused by concrete operable factors.

Scaling limits of resistive memories.

This paper is intended to provide an expository, physics-based, framework for the estimation of the performance potential and physical scaling limits of resistive memory. The approach taken seeks to provide physical insights into those parameters and physical effects that define device performance and scaling properties. The mechanisms of resistive switching are based on atomic rearrangements in a material. The three model cases are: (1) formation of a continuous conductive path between two electrodes within an insulating matrix, (2) formation of a discontinuous path of conductive atoms between two electrodes within an insulating matrix and (3) rearrangement of charged defects/impurities near the interface between the semiconductor matrix and an electrode, resulting in contact resistance changes. The authors argue that these three model mechanisms or their combinations are representative of the operation of all known resistive memories. The central question addressed in this paper is: what is the smallest volume of matter needed for resistive memory? The two related tasks explored in this paper are: (i) resistance changes due to addition or removal of a few atoms and (ii) stability of a few-atom system.

The effects of ultra-low dose beta-radiation on the physical properties of human erythrocyte membranes.

PURPOSE: To determine the effects of ultra-low dose beta-radiation (ULDBR) on the physical properties of human erythrocyte membranes. MATERIALS AND METHODS: To study the structural changes induced by beta-radiation in erythrocyte ghosts, the interactions of fluorescent probes (1-anilino-8-naphthalene sulfonate, pyrene) with the erythrocyte membranes were investigated. The fluorescent responses to the ULDBR were registered after the addition of (14)C-leucine (37-3700 kBq(l(-1)) in the cellular suspension. RESULTS: The ULDBR induced essential rearrangements of the membrane structure that appear in alterations of membrane spatial organisation, conformation of membrane proteins (structural flexibility, folding-unfolding), modification of surface and deep zones of membranes, lipid-protein interactions, and fluidity of annular lipids. CONCLUSIONS: These findings are evidence that, as previously discovered by us, the reversible effect of ULDBR on the zeta potential of human erythrocytes and the functional state of the membrane signal systems is most likely realised through local structural and dynamic rearrangements of macromolecules in cellular membranes.

Ultra-low dose beta-irradiation induces constriction of rabbit carotid arteries via the endothelium.

PURPOSE: To investigate the action of ultra-low dose beta-radiation (ULDBR) on isolated segments of blood vessels. MATERIALS AND METHODS: We used the pharmacological model of isolated rabbit carotid arteries with intact or mechanically removed endothelium. Specific vascular responses to beta-irradiation were registered after addition of (90)Sr in the concentration range between 12 and 96 microCi l(-1) to the organ bath containing physiological salt solution (PSS). RESULTS: Intact vascular rings, preconstricted with 20 mM K(+)-PSS, developed an additional constriction upon the addition of (90)Sr depending on the absorbed radiation dose (21.5, 42.9, 85.8, and 171.6 microGy) and the dose rate (51.5, 103.0, 206.0 and 412.0 microGy h(-1)). The vasoconstriction due to (90)Sr was absent in the endothelium-denuded vascular segments indicating the endothelium dependent action of ULDBR. Irradiation did not alter the endothelium dependent relaxation of rabbit carotid arteries induced by acetylcholine. The endothelium dependent responses to ULDBR were abolished after increasing the extra-cellular K(+) to 40 mM. CONCLUSIONS: ULDBR acts on rabbit carotid arteries as a pharmacological signalling agent because ULDBR effects were completely reversible. ULDBR-mediated contractile responses of the vessels are endothelium dependent. The resistance of acetylcholine endothelium-dependent relaxation of rabbit carotid arteries to ULDBR indicates that the polyphosphoinositide-nitric oxide (NO) signalling cascade is not impaired by ULDBR in endothelial cells.