Metal‐Cation Recognition in Water by a Tetrapyrazinoporphyrazine‐Based Tweezer Receptor

A series of zinc azaphthalocyanines with two azacrowns in a rigid tweezer arrangement were prepared and the fluorescence sensing properties were investigated. The size‐driven recognition of alkali and alkaline earth metal cations was significantly enhanced by the close cooperation of the two azacrown units, in which both donor nitrogen atoms need to be involved in analyte binding to switch the sensor on. The mono‐ or biphasic character of the binding isotherms, together with the binding stoichiometry and magnitude of association constants (KA), indicated specific complexation of particular analytes. Water solvation was shown to play an important role and resulted in a strong quenching of sensor fluorescence in the ON state. The lead compound was embedded into silica nanoparticles and advantageous sensing properties towards K+ were demonstrated in water (λF=671 nm, apparent KA=82 m−1, increase of 17×), even in the presence of (supra)physiological concentrations of Na+ and Ca2+.In a pinch: Close cooperation of azacrowns in fluorescence sensors derived from tetrapyrazinoporphyrazines is responsible for high sensitivity and selectivity towards particular cations. Water solvation, however, quenches the fluorescence strongly. Interestingly, embedding the sensor into silica nanoparticles overcomes this problem and result in an excellent red‐emitting fluorescence sensor (see figure).Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137532/1/chem201504268.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137532/2/chem201504268-sup-0001-misc_information.pd

Synthesis of 5-substituted tetrazoles and their derivatives

Katedra anorganické a organické chemieDepartment of Inorganic And Organic ChemistryFarmaceutická fakulta v Hradci KrálovéFaculty of Pharmacy in Hradec Králov

Synthesis and Functionalization of 5-Substituted Tetrazoles

In the last decades, the chemistry of tetrazoles underwent a great expansion, which was closely connected with their usage as an isosteric replacement of carboxylic acid moiety in the molecules of potential or clinically used drugs. In this work, existing methods of the preparation of 5-substituted tetrazoles were modified by utilising microwave irradiation and by changing the reaction conditions and the reaction medium. First, Sharpless synthesis, consisting in the conversion of nitriles into 5-substituted tetrazoles via the reaction of sodium azide and zinc halide in boiling water, was modified. The application of the microwave irradiation decreased reaction time while maintaining high yields of products. Furthermore, a new method for the preparation of 5-substituted tetrazoles was developed, based on the reaction of nitrile with sodium azide and triethylammonium chloride in the polar aromatic solvents under microwave irradiation. By this method, 5-substituted tetrazoles were prepared in high yields in short reaction times from nitriles, including those that react poorly using common methods. Based on the results of several selected methods of the preparation of 5-substituted tetrazoles, carried out under either conventional or microwave heating at the same reaction temperatures, the non-thermal..

Synthesis And Analysis Of Novel Analogues Of Dexrazoxane And Its Open-Ring Hydrolysis Product For Protection Against Anthracycline Cardiotoxicity In Vitro And In Vivo

Cardiotoxicity is a serious drawback of anthracycline anti-cancer drugs and dexrazoxane is the only cardioprotective agent with clinically established efficacy. Iron-mediated oxidative stress is traditionally believed to be the primary cause of anthracycline cardiotoxicity, and dexrazoxane-induced cardioprotection is attributed to iron chelating properties of its open ring metabolite, ADR-925, which may inhibit the oxidative injury. However, dexrazoxane is also a catalytic inhibitor of topoisomerase II (TOP2), and the role of oxidative stress in clinically relevant forms of cardiotoxicity has increasingly been questioned. In this study, novel analogues of dexrazoxane (MK-15, ES-5) and ADR-925 (KH-TA4, JR-159) were synthesized, and evaluated in vitro and in vivo. When examined in the leukemic cell line, HL-60, these novel analogues did not interfere with the anti-proliferative action of daunorubicin. In contrast to dexrazoxane, they had no anti-cancer effect on their own and the changes in the chemical structure resulted in a loss of TOP2 inhibitory activity. Although some of the novel compounds showed significant anti-oxidant and iron chelating properties in vitro, they did not protect isolated cardiomyocytes and rabbits from daunorubicin-induced cardiotoxicity and heart failure. Importantly, dexrazoxane has been found to be a relatively weak intracellular iron chelator and it failed to protect the isolated cardiomyocytes from model oxidative injury induced by hydrogen peroxide. However, in contrast to all novel analogues, dexrazoxane induced depletion of the TOP2 beta isoform. This isoform is typical for terminally differentiated cells and its genetic deletion has been reported to overcome anthracycline-induced cardiotoxicity. Hence, TOP2 beta, rather than (or along with) iron chelation, may be a promising target for effective cardioprotection induced by bisdioxopiperazine agents

Pyrimidine derivatives with antitubercular activity

Small molecules with antitubercular activity containing the pyrimidine motif in their structure have gained more attention after three drugs, namely GSK 2556286 (GSK-286), TBA-7371 and SPR720, have entered clinical trials. This review provides an overview of recent advances in the hit-to-lead drug discovery studies of antitubercular pyrimidine-containing compounds with the aim to highlight their structural diversity. In the first part, the review discusses the pyrimidine compounds according to their targets, pinpointing the structure-activity relationships of each pyrimidine family. The second part of this review is concentrated on antitubercular pyrimidine derivatives with a yet unexplored or speculative target, dividing the compounds according to their structural types

Scalable Synthesis of Human Ultralong Chain Ceramides

Ceramides with ultralong chains (≥30 carbons), also known as acylceramides, play a critical role in the survival of mammals on dry land. An efficient and scalable synthesis of four major classes of ultralong human skin ceramides is reported. The key approach involves the use of a succinimidyl ester that acts as a protective group, helps overcome the extremely low solubility, and simultaneously activates the fatty acid for its clean and high-yielding attachment to a sphingoid base

In Vitro Characterization of the Pharmacological Properties of the Anti-Cancer Chelator, Bp4eT, and Its Phase I Metabolites.

Cancer cells have a high iron requirement and many experimental studies, as well as clinical trials, have demonstrated that iron chelators are potential anti-cancer agents. The ligand, 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT), demonstrates both potent anti-neoplastic and anti-retroviral properties. In this study, Bp4eT and its recently identified amidrazone and semicarbazone metabolites were examined and compared with respect to their anti-proliferative activity towards cancer cells (HL-60 human promyelocytic leukemia, MCF-7 human breast adenocarcinoma, HCT116 human colon carcinoma and A549 human lung adenocarcinoma), non-cancerous cells (H9c2 neonatal rat-derived cardiomyoblasts and 3T3 mouse embryo fibroblasts) and their interaction with intracellular iron pools. Bp4eT was demonstrated to be a highly potent and selective anti-neoplastic agent that induces S phase cell cycle arrest, mitochondrial depolarization and apoptosis in MCF-7 cells. Both semicarbazone and amidrazone metabolites showed at least a 300-fold decrease in cytotoxic activity than Bp4eT towards both cancer and normal cell lines. The metabolites also lost the ability to: (1) promote the redox cycling of iron; (2) bind and mobilize iron from labile intracellular pools; and (3) prevent 59Fe uptake from 59Fe-labeled transferrin by MCF-7 cells. Hence, this study demonstrates that the highly active ligand, Bp4eT, is metabolized to non-toxic and pharmacologically inactive analogs, which most likely contribute to its favorable pharmacological profile. These findings are important for the further development of this drug candidate and contribute to the understanding of the structure-activity relationships of these agents