72912-01-7Relevant academic research and scientific papers
Synthesis, biological evaluation, and molecular modeling of aza-crown ethers
Basok, Stepan S.,Schepetkin, Igor A.,Khlebnikov, Andrei I.,Lutsyuk, Anatoliy F.,Kirichenko, Tatiana I.,Kirpotina, Liliya N.,Pavlovsky, Victor I.,Leonov, Klim A.,Vishenkova, Darya A.,Quinn, Mark T.
, (2021/05/28)
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 (f MLF). 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 f MLF, 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.
Syntheses of Calcium-Selective, Substituted Diaza-Crown Ethers: A Novel, One-Step Formation of Bibracchial Lariat Ethers (BiBLEs)
Gatto, Vincent J.,Gokel, George W.
, p. 8240 - 8244 (2007/10/02)
Ten N,N-disubstituted derivatives of 4,13-diaza-18-crown-6 (7) have been prepared, three of which exhibit Ca2+, over either Na+ or K+, selectivity.This selectivity has been achieved by utilizing polar, yet uncharged, donor groups such as carbethoxymethyl.Several of these compunds have been prepared by a novel, one-step reaction of aliphatic primary amines with triethylene glycol diiodide.The compounds prepared by this method include examples having the following substituents on nitrogen: benzyl, 2-methoxybenzyl, 2-hydroxyethyl, allyl, 2-furylmethyl, and 2-pyridylmethyl.Isolated yields of pure product for the one-step reaction were in the range 26 +/- 4percent.The corresponding derivatives of 7 having 2-methoxyethyl, carbethoxymethyl, carboxymethyl, and 2-hydroxybenzyl sidearms were also prepared so that cation selectivity as a function of structure could be assessed.Homogeneous stability constants (Ks) for the association between the various ligands and Na+, K+, and Ca2+ were determined and are reported.Significant Ca2+ selectivity is achieved for the first time in these systems which should retain a high degree of binding dynamics since the donor groups of primary interest in this study are non-ionizable.
