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 (, -, and ) increased intracellular calcium ([Ca]) in human neutrophils, with the most potent being compound (,'-[2-(1-adamantyl)acetyl]-4,10-diaza-15-crown-5), suggesting that these compounds could alter normal neutrophil [Ca] flux. Indeed, a number of these compounds (i.e., , -, and ) inhibited [Ca] flux in human neutrophils activated by -formyl peptide (MLF). Some of these compounds also inhibited chemotactic peptide-induced [Ca] 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 MLF, as both of these processes are highly dependent on regulated [Ca] flux. Quantum chemical calculations were performed on five structure-related diaza-crown ethers and their complexes with Ca, 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, Ca ions were more effectively bound by these compounds versus Na and K. The DFT-optimized structures of the ligand-Ca complexes and quantitative structure-activity relationship (QSAR) analysis showed that the carbonyl oxygen atoms of the ,'-diacylated diaza-crown ethers participated in cation binding and could play an important role in Ca 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.