Synthetic and natural ionophores have been developed to catalyze ion transport and have been shown to exhibit a variety of biological effects. We synthesized 24 aza- and diaza-crown ethers containing adamantyl, adamantylalkyl, aminomethylbenzoyl, and ε-aminocaproyl substituents and analyzed their biological effects in vitro. Ten of the compounds (8, 10–17, and 21) increased intracellular calcium ([Ca2+]i) in human neutrophils, with the most potent being compound 15 (N,N’-bis[2-(1-adamantyl)acetyl]-4,10-diaza-15-crown-5), suggesting that these compounds could alter normal neutrophil [Ca2+]i flux. Indeed, a number of these compounds (i.e., 8, 10–17, and 21) inhibited [Ca2+]i flux in human neutrophils activated by N-formyl peptide (fMLF). Some of these compounds also inhibited chemotactic peptide-induced [Ca2+]i flux in HL60 cells transfected with N-formyl peptide receptor 1 or 2 (FPR1 or FPR2). In addition, several of the active compounds inhibited neutrophil reactive oxygen species production induced by phorbol 12-myristate 13-acetate (PMA) and neutrophil chemotaxis toward fMLF, as both of these processes are highly dependent on regulated [Ca2+]i flux. Quantum chemical calculations were performed on five structure-related diaza-crown ethers and their complexes with Ca2+, Na+, and K+ to obtain a set of molecular electronic properties and to correlate these properties with biological activity. According to density-functional theory (DFT) modeling, Ca2+ ions were more effectively bound by these compounds versus Na+ and K+. The DFT-optimized structures of the ligand-Ca2+ complexes and quantitative structure–activity relationship (QSAR) analysis showed that the carbonyl oxygen atoms of the N,N’-diacylated diaza-crown ethers participated in cation binding and could play an important role in Ca2+ transfer. Thus, our modeling experiments provide a molecular basis to explain at least part of the ionophore mechanism of biological action of aza-crown ethers.

Розроблено ефективні методи синтезу потенційних антивірусних препаратівадамантановмісних похідних азакраун-етерів амідного типу та їх відновлення до відповідних адамантаналкілазакраун-етерів. Встановлено, що найбільш ефективним методом синтезу макроциклічних похідних, в яких замісник приєднується до азакраун-етеру за допомогою амідного фрагменту, є хлорангідридний метод. Відновлення макроциклічних амідів з фрагментами адамантану за допомогою диборану в тетрагідрофурані призводить до макроциклічних амінів з виходами 92-97 %. Комбінування розроблених методів ацилування і відновлення дозволяє підвищити сумарні виходи адамантаналкіловмісних азакраун-етерів до 87-92 %. Синтезовані сполуки передані для лабораторних досліджень їх антивірусної активності.Ключові слова: антивірусна активність, азакраун-етери, адамантан, відновлення.

Among the most important properties governing wide spectrum of biological activities of crown ethers are their high lipophilicity, selectivity of the complex formation as well as ability of transporting ions and some neutral molecules across the biological membranes, similarly to the natural ionophores. Modification of diazacrown ethers by introducing fragments of known antiviral agents into their structure can be assumed to yield new products with high antiviral activity. The compounds of a class of protease inhibitors, 4-aminomethylbenzoic and 6-aminocaproic acids are of interest in respect of this. We have synthesized derivatives with free amino and carboxyl groups containing fragments of known antiviral drugs, 4-aminomethylbenzoic and 6-aminocaproic acids, based on the macrocyclic diaza-18-crown-6 platform. The cytotoxicity and antiviral activity of synthesized compounds against of human influenza strains А/Hong Kong/1/68 (H3N2) and А/Puerto Rico/8/34 (H1N1) have been studied. Synthesis of compounds with free amino group (1,10-bis(6-aminohexanoyl)-diaza-18-crown-6 and 1,10-bis(4-aminomethylbenzoyl)-diaza-18-crown-6) have been carried out by interaction of diaza-18-crown-6 with Boc-protected derivatives of 6-aminocaproic and 4-aminomethylbenzoic acids in the presence of DCC and HOBT followed by removal of the Boc-protective group in the intermediate compounds by the action of trifluoroacetic acid. It should be noted that using HOBT allowed us to avoid the formation of collateral bis-N-acylureas, simplify the purification, and increase the total yields of final products to 90-92 %. Acylation of benzyl esters of studied N,N'-dicarboxymethyldiaza-18-crown-6 amino acids was investigated to obtain the compounds with the free carboxyl group, 6,6'-{(7,16-diaza-18-crown-6)-7,16-diylbis[(1-oxoethane-2,1-diyl)imino]} dihexanoic acid and 4,4'-{(7,16-diaza-18-crown-6)-7,16-diylbis[(1-oxoethane-2,1-diyl)iminomethylene]} dibenzoic acid. In this case, using DCC as a condensing agent has resulted the main reaction product to be macrocyclic bis-N-acylureas, and the desired compounds have not been obtained. Therefore, another method of peptide chemistry was used for the acylation of esters of the studied acids-mixed anhydride method with ethyl chloroformate. By this method the benzyl esters of dipeptides with yields of 85-87 % were obtained. Subsequent removal of the benzyl protecting group in these compounds by catalytic hydrogenolysis resulted in desired products with yields of 92-94 %. The toxicity level for all the synthesized compounds was studied on a model using Colpoda steinii infusoria culture and the chorionallantoic membrane cells of chick embryos, and antiviral activity against human influenza strains A/ Hong Kong/1/68 (H3N2) and А/Puerto Rico/8/34 (H1N1) in culture of the chorionallantoic membrane cells of chick embryos. Synthesized compounds showed significantly higher level of antiviral activity compared to that of 4-aminomethylbenzoic and 6-aminocaproic acids on both strains of the influenza virus with no cytoto...

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