Synthesis, Characterization, In Vitro Anticancer Evaluation, ADMET Properties, and Molecular Docking of Novel 5-Sulfanyl Substituted (Thiazol-4-yl)-Phosphonium Salts.

Seven TPP+ new 5-sulfanyl substituted (thiazol-4-yl) phosphonium salts functionalized with different substituents were designed, synthesized, and studied against the NCI-60 human cancer cell lines. Compounds 1-4 show the total average parameters GI50=0.7-2.7 µM, TGI=7.0-14.6 µM, and LC50=25.2-41.8 µM, and compounds 5-7 show GI50=0.3-0.5 µM, TGI=1.3-3.1 µM, and LC50=3.6-4.0 µM. The most active compound 7 demonstrated the best anticancer results against leukemia (K-562, GI50=0.141 µM; RPMI-8226, GI50=0.143 µM), ovarian cancer (NCI/ADR-RES, GI50=0.142 µM), breast cancer (HS578T, GI50=0.175 µM; MDA-MB-468, GI50=0.101 µM), melanoma (SK-MEL-5, GI50=0.155 µM), and colon cancer (COLO 205, GI50=0.163 µM). All compounds showed low cytotoxicity against the leukemia subpanel (LC50>100 µM). The SAR analysis reveals the critical role of the substitutes at the thiazole C2 and C5 positions. Adding the phenyl, p-tolyl, or 4-chlorophenyl group to the C2 position in compounds 5-7 increases anticancer effectiveness. According to the NCI COMPARE analysis, compounds 2-3 showed a very high (r=0.92, 0.81) correlation with morpholino-doxorubicin. Molecular docking-analyzing the antitumor mechanism of compounds 1-4 action demonstrated that the DNA chain is a probable biotarget. The ADMET analysis acknowledges the favorable prognosis using compounds as potential anticancer agents.

Synthesis, characterization of novel N-(4-cyano-1,3-oxazol-5-yl)sulfonamide derivatives and in†vitro screening their activity against NCI-60 cancer cell lines.

A novel series of N-(4-cyano-1,3-oxazol-5-yl)sulfonamides have been synthesized and characterized by IR, 1 H NMR, 13 C NMR spectroscopy, elemental analysis and chromato-mass-spectrometry. The anticancer activities of all newly synthesized compounds were evaluated via a single high-dose assay (10 µM) against 60 cancer cell lines by the National Cancer Institute (USA) according to its screening protocol. Among them, compounds 2 and 10 exhibited the highest activity against the 60 cancer cell lines panel in the one-dose assay. Compounds 2 and 10 showed inhibitory activity within the GI50 parameter and in five dose analyses. However, their cytostatic activity was only observed against some cancer cell lines, and cytotoxic concentration was outside the maximum used, i. e., >100 µM. The COMPARE analysis showed that the average graphs of the tested compounds have a moderate positive correlation with compounds with the L-cysteine analog and vinblastine (GI50 ) as well as paclitaxel (TGI), which target microtubules. Therefore, disruption of microtubule formation may be one of the mechanisms of the anticancer activity of the tested compounds, especially since among tubulin inhibitors with antitumor activity, compounds with an oxazole motif are widely represented. Therefore, N-(4-cyano-1,3-oxazol-5-yl)sulfonamides may be promising for further functionalization to obtain more active compounds.

Synthesis, Characterization and in†vitro Anticancer Evaluation of 5-Sulfinyl(sulfonyl)-4-arylsulfonyl-Substituted 1,3-Oxazoles.

A novel series of 5-sulfinyl(sulfonyl)-4-arylsulfonyl-substituted 1,3-oxazoles has been synthesized, characterized and subjected to NCI in vitro assessment. Cancer cell lines of all subpanels were most sensitive to 2-{[4-[(4-fluorophenyl)sulfonyl]-2-(2-furyl)-1,3-oxazol-5-yl]sulfinyl}acetamide (3 l). Its antiproliferative and cytotoxic activity averaged over each subpanel was manifested in a very narrow range of concentrations (GI50 : 1.64-1.86 µM, TGI: 3.16-3.81 µM and LC50 : 5.53-7.27 µM), i. e. practically did not depend on the origin of the cancer cell line. The COMPARE matrix using TGI vector showed a high positive correlation of 3 l (r=0.88) with the intercalating agent aclarubicin, which inhibits topoisomerases. The absence in the database of standard agents that have a high correlation with the cytotoxicity of this compound suggests that it may have a unique mechanism of action. According to the results of the docking analysis, the most promising anticancer target for compound 3 l is DNA topoisomerase IIß. The obtained results indicate the anticancer activity of 5-sulfinyl(sulfonyl)-4-arylsulfonyl-substituted 1,3-oxazoles, which may be useful for the development of new anticancer drugs. 2-{[4-[(4-Fluorophenyl)sulfonyl]-2-(2-furyl)-1,3-oxazol-5-yl]sulfinyl}acetamide (3 l), as the most active, can be recommended for further in-depth studies.

Design, synthesis and evaluation of the anti-breast cancer activity of 1,3-oxazolo[4,5-d]pyrimidine and 1,3-oxazolo[5,4-d]pyrimidine derivatives.

A series of 1,3-oxazolo[4,5-d]pyrimidine and 1,3-oxazolo[5,4-d]pyrimidine derivatives were synthesized and functionalized in this study. The obtained compounds were tested against breast cancer cell lines of the NCI subpanel, followed by further analysis using the COMPARE algorithm from the Therapeutics Development Program, NCI. All synthesized derivatives displayed activity against most cell lines in the range of micromolar concentrations in terms of all parameters studied. Oxazolopyrimidine 5 exhibited the highest antitumor activity. A standard COMPARE analysis of the compounds showed that the vectors of the cytotoxic activity of derivatives 10 and 11 displayed a close to very high correlation with tamoxifen, and oxazolopyrimidine 13 displayed a very high correlation with the same drug. Five derivatives (2, 4, 6, 11 and 13) showed a high correlation with aclacinomycin A in the TGI vector. At the same time, compound 1 effectively suppressed ADK in cultured MDA-MB 231 cell lines, indicating that ADK is one of its targets through which it exerts anticancer properties. Based on molecular docking results, the possible binding mode of oxazolopyrimidine 1 to ADK has been suggested.

Evaluation of Anticancer Activity of 1,3-Oxazol-4-ylphosphonium Salts in Vitro.

A novel series of 1,3-oxazol-4-yltriphenylphosphonium salts has been synthesized and functionalized. Oxazole derivatives were subjected to NCI in vitro assessment. Seven most active derivatives have been selected for five-dose assay. Among them, compounds 9 ([2-(4-methylphenyl)-5-[(4-methylphenyl)sulfanyl]-1,3-oxazol-4-yl]triphenylphosphonium perchlorate), 1 ([5-(4-methylphenyl)amino]-2-phenyl-1,3-oxazol-4-yl]triphenylphosphonium perchlorate) and 4 ([5-phenyl-2-[(4-methylphenyl)amino]-1,3-oxazol-4-yl]triphenylphosphonium perchlorate) were the most active against all tested cancer subpanels. Statistical analysis of the total panel data showed average values of parameters of anticancer activity in the range of 0.3-1.1 µM (GI50 ), 1.2-2.5 µM (TGI) and 5-6 µM (LC50 ). It was found that the presence of phenyl or 4-methylphenyl groups at C(2) and C(5) in the oxazole ring is of critical importance for the manifestation of the anticancer activity. Matrix COMPARE analysis using LC50 vector showed a high positive correlation of compound 9 with standard anticancer agents that can directly disrupt mitochondrial function, causing programmed death of cancer cells. The obtained results indicate the anticancer activity of 1,3-oxazol-4-ylphosphonium salts, which could be useful for developing new anticancer drugs. The most active of them can be recommended for further in-depth studies and synthesis of new derivatives with antitumor activity on their basis.

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.

New 2-Oxoimidazolidine Derivatives: Design, Synthesis and Evaluation of Anti-BK Virus Activities in Vitro.

A series of novel 2-oxoimidazolidine derivatives were synthesized and their antiviral activities against BK human polyomavirus type 1 (BKPyV) were evaluated in vitro. Bioassays showed that the synthesized compounds 1-{[(4E)-5-(dichloromethylidene)-2-oxoimidazolidin-4-ylidene]sulfamoyl}piperidine-4-carboxylic acid (5) and N-Cyclobutyl-N'-[(4E)-5-(dichloromethylidene)-2-oxoimidazolidin-4-ylidene]sulfuric diamide (4) exhibited moderate activities against BKPyV (EC50 =5.4 and 5.5 µm, respectively) that are comparable to the standard drug Cidofovir. Compound 5 exhibited the same cytotoxicity in HFF cells and selectivity index (SI50 ) as Cidofovir. The selectivity index of compound 4 is three times less than that of Cidofovir due to the higher toxicity of this compound. Hence, these compounds may be taken as lead compound for further development of novel ant-BKPyV agents.

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.