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

dc.contributor.authorBasok, Stepan S.
dc.contributor.authorSchepetkin, Igor A.
dc.contributor.authorKhlebnikov, Andrei I.
dc.contributor.authorLutsyuk, Anatoliy F.
dc.contributor.authorKirichenko, Tatiana I.
dc.contributor.authorKirpotina, Liliya N.
dc.contributor.authorPavlovsky, Victor I.
dc.contributor.authorLeonov, Klim A.
dc.contributor.authorVishenkova, Darya A.
dc.contributor.authorQuinn, Mark T.
dc.date.accessioned2022-08-30T17:12:49Z
dc.date.available2022-08-30T17:12:49Z
dc.date.issued2021-04
dc.description.abstractSynthetic 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.en_US
dc.identifier.citationBasok, S. S., Schepetkin, I. A., Khlebnikov, A. I., Lutsyuk, A. F., Kirichenko, T. I., Kirpotina, L. N., ... & Quinn, M. T. (2021). Synthesis, biological evaluation, and molecular modeling of aza-crown ethers. Molecules, 26(8), 2225.en_US
dc.identifier.issn1420-3049
dc.identifier.urihttps://scholarworks.montana.edu/handle/1/17023
dc.language.isoen_USen_US
dc.publisherMDPI AGen_US
dc.rightscc-byen_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.subjectaza crownen_US
dc.titleSynthesis, Biological Evaluation, and Molecular Modeling of Aza-Crown Ethersen_US
dc.typeArticleen_US
mus.citation.extentfirstpage1en_US
mus.citation.extentlastpage26en_US
mus.citation.issue8en_US
mus.citation.journaltitleMoleculesen_US
mus.citation.volume26en_US
mus.data.thumbpage14en_US
mus.identifier.doi10.3390/molecules26082225en_US
mus.relation.collegeCollege of Agricultureen_US
mus.relation.departmentMicrobiology & Cell Biology.en_US
mus.relation.universityMontana State University - Bozemanen_US

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