Synthesis, Biological Evaluation, and Molecular Modeling of Aza-Crown Ethers.

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.

Two new "onium" fluorosilicates, the products of interaction of fluorosilicic acid with 12-membered macrocycles: structures and spectroscopic properties.

Two novel compounds, (L(1)H)(2)[SiF(6)] x 2H(2)O (1) and (L(2)H)(2)[SiF(5)(H(2)O)](2) x 3H(2)O (2), resulting from the reactions of H(2)SiF(6) with 4'-aminobenzo-12-crown-4 (L(1)) and monoaza-12-crown-4 (L(2)), respectively, were studied by X-ray diffraction and characterised by IR and (19)F NMR spectroscopic methods. Both complexes have ionic structures due to the proton transfer from the fluorosilicic acid to the primary amine group in L(1) and secondary amine group incorporated into the macrocycle L(2). The structure of 1 is composed of [SiF(6)](2-) centrosymmetric anions, N-protonated cations (L(1)H)(+), and two water molecules, all components being bound in the layer through a system of NH[...]F, NH[...]O and OH[...]F hydrogen bonds. The [SiF(6)](2-) anions and water molecules are assembled into inorganic negatively-charged layers via OH[dot dot dot]F hydrogen bonds. The structure of 2 is a rare example of stabilisation of the complex anion [SiF(5)(H(2)O)](-), the labile product of hydrolytic transformations of the [SiF(6)](2-) anion in an aqueous solution. The components of 2, i.e., [SiF(5)(H(2)O)](-), (L(2)H)(+), and water molecules, are linked by a system of NH[...]F, NH[...]O, OH[...]F, OH[dot dot dot]O hydrogen bonds. In a way similar to 1, the [SiF(5)(H(2)O)](-) anions and water molecules in 2 are combined into an inorganic negatively-charged layer through OH[...]F and OH[...]O interactions.

Hierarchy of hydrogen bonding in bis(1,4,7-trioxa-10-azoniacyclododecane) bis(4-aminobenzoate) trihydrate.

In the title compound, 2C8H18NO3+.2C7H6NO2-.3H2O, proton transfer occurs from the carboxylic acid group of the 4-aminobenzoic acid (PABA) molecule to the amine group of the macrocycle, resulting in the formation of a salt-like adduct. The anions are combined into helical chains which are further bound by the water molecules into sheets. The macrocyclic cations are situated between these layers and are bound to the anions both directly and via bridging water molecules. The structure exhibits a diverse system of hydrogen bonding.

A new phase of 7,16-dibenzyl-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane, and 7,16-dibenzyl-1,4,10,13-tetraoxa-7,16-diazoniacyclooctadecane bis(tetrafluoroborate) monohydrate, both determined at 123 K.

7,16-Dibenzyl-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane, C26H38N2O4, (I), crystallizes in space group P2(1)/c, with two independent molecules adopting different conformations. The 'free' crowns adopt a typical 'arallelogram' shape, in which two methylene groups are turned inward toward the center of the ring and the benzyl groups splay out from the ring. In 7,16-dibenzyl-1,4,10,13-tetraoxa-7,16-diazoniacyclooctadecane bis(tetrafluoroborate) monohydrate, C26H40N2O4(2+).2BF4-.H2O, (II), the macrocycle is centrosymmetric, and the protonated N atoms adopt an endo-endo orientation that is stabilized by a bifurcated N-H...O hydrogen bond, where the O atoms of the macrocycle act as hydrogen-bond acceptors. The phenyl groups of the benzyl side arms are turned above and below the macrocycle; C-H...pi interactions between the phenyl substituents and two macrocyclic methylene H atoms govern the overall conformation of the macrocycle. Bridging tetrafluoroborate anions link the macrocyclic cations via weak C-H...F hydrogen bonds into channels running along [100], which are filled by the weakly hydrogen-bonded water molecules.