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

Abstract

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.

New Polyether Macrocycles as Promising Antitumor Agents─Targeted Synthesis and Induction of Mitochondrial Apoptosis

“…Since 1967, when Pedersen reported the synthesis and study of properties of a new class of polyether macrocyclic compounds, , called crown ethers, the research interest in this class of macrocycles has been steadily growing. Today, these polyether macrocycles represent groups of compounds that, apart from their high versatility and broad use in chemistry and industry, could also find biomedical applications as modern effective antibacterial and antitumor agents. − …”

Synthesis of novel macrocyclic di‐ and tetralactams and their corresponding C‐pivot lariat derivatives

“…[8] The biological properties of aza-and diaza-crown ethers, which can be altered by adding different substituents to their nitrogen atoms, are also of particular interest. [9] Aza-and diaza-crown ethers have been shown to exhibit antiproliferative, [10,11] antitumor, [12,13] antibacterial, [14][15][16] hematopoietic and colony-stimulating activity, [17] as well as other biological effects. The ligand framework of the crown ether is modified structurally by adding a flexible side arm bearing extra soft donor coordination sites, leading to the creation of a new class of complexing agents known as lariat macrocyclic ethers.…”

“…This includes the synthesis of aza‐crown ethers in which one or more nitrogen atoms have been added to the macrocyclic ring in an attempt to modify its ligating properties [8] . The biological properties of aza‐ and diaza‐crown ethers, which can be altered by adding different substituents to their nitrogen atoms, are also of particular interest [9] . Aza‐ and diaza‐crown ethers have been shown to exhibit antiproliferative, [10,11] antitumor, [12,13] antibacterial, [14–16] hematopoietic and colony‐stimulating activity, [17] as well as other biological effects.…”