{"doi":"10.3390/molecules26082225","title":"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.","journal":"Molecules","year":2021,"id":175336,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9515,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":317901,"name":"Igor A. Schepetkin","orcid":"0000-0003-2139-8110","position":1,"is_corresponding":false},{"id":320910,"name":"Аndrei I. Khlebnikov","orcid":"0000-0002-3022-4510","position":2,"is_corresponding":false},{"id":715892,"name":"Anatoliy F. Lutsyuk","orcid":"0000-0002-8822-6551","position":3,"is_corresponding":false},{"id":716381,"name":"Tatiana I. Kirichenko","orcid":null,"position":4,"is_corresponding":false},{"id":322086,"name":"Liliya N. Kirpotina","orcid":null,"position":5,"is_corresponding":false},{"id":715893,"name":"V. І. Pavlovsky","orcid":"0000-0002-4583-6245","position":6,"is_corresponding":false},{"id":715894,"name":"Klim A. Leonov","orcid":"0000-0003-4268-1724","position":7,"is_corresponding":false},{"id":715895,"name":"Darya A. Vishenkova","orcid":"0000-0002-1793-5991","position":8,"is_corresponding":false},{"id":317900,"name":"Mark T. Quinn","orcid":"0000-0001-8114-5073","position":9,"is_corresponding":false},{"id":715891,"name":"S.S. Basok","orcid":"0000-0001-6389-5081","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-18T23:47:11.249697Z","pmid":"33921479","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}