Synthesis, Biological Evaluation, and Molecular Modeling of Aza-Crown Ethers; Molecules; Vol. 26, iss. 8
| Parent link: | Molecules Vol. 26, iss. 8.— 2021.— [2225, 26 p.] |
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| Corporate Authors: | , |
| Andre forfattere: | , , , , , , , , , |
| Summary: | Title screen 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 e-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. |
| Sprog: | engelsk |
| Udgivet: |
2021
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| Fag: | |
| Online adgang: | https://doi.org/10.3390/molecules26082225 |
| Format: | Electronisk Book Chapter |
| KOHA link: | https://koha.lib.tpu.ru/cgi-bin/koha/opac-detail.pl?biblionumber=664967 |
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| 200 | 1 | |a Synthesis, Biological Evaluation, and Molecular Modeling of Aza-Crown Ethers |f S. S. Basok, I. A. Schepetkin (Shchepyotkin), A. I. Khlebnikov [et al.] | |
| 203 | |a Text |c electronic | ||
| 300 | |a Title screen | ||
| 320 | |a [References: 60 tit.] | ||
| 330 | |a 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 e-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. | ||
| 461 | |t Molecules | ||
| 463 | |t Vol. 26, iss. 8 |v [2225, 26 p.] |d 2021 | ||
| 610 | 1 | |a труды учёных ТПУ | |
| 610 | 1 | |a электронный ресурс | |
| 610 | 1 | |a aza-crown ether | |
| 610 | 1 | |a neutrophil | |
| 610 | 1 | |a ionophore | |
| 610 | 1 | |a density-functional theory (DFT) | |
| 610 | 1 | |a quantitative structure-activity relationship (QSAR) modeling | |
| 701 | 1 | |a Basok |b S. S. |g Stepan | |
| 701 | 1 | |a Schepetkin (Shchepyotkin) |b I. A. |c doctor-biophysicist |c leading researcher of Tomsk Polytechnic University, candidate of medical science |f 1962- |g Igor Aleksandrovich |3 (RuTPU)RU\TPU\pers\37358 | |
| 701 | 1 | |a Khlebnikov |b A. I. |c Chemist |c Professor of Tomsk Polytechnic University |f 1963- |g Andrey Ivanovich |3 (RuTPU)RU\TPU\pers\33927 |9 17500 | |
| 701 | 1 | |a Lutsyuk |b A. F. |g Anatoly Fedorovich | |
| 701 | 1 | |a Kirichenko |b T. I. |g Tatjyana Ivanovna | |
| 701 | 1 | |a Kirpotina |b L. N. |g Liliya Nikolaevna | |
| 701 | 1 | |a Pavlovsky |b V. I. |c chemist |c Professor of Tomsk Polytechnic University, Doctor of chemical sciences |f 1958- |g Viktor Ivanovich |3 (RuTPU)RU\TPU\pers\46884 | |
| 701 | 1 | |a Leonov |b K. A. |g Klim Andreevich | |
| 701 | 1 | |a Vishenkova |b D. A. |c chemist |c engineer of Tomsk Polytechnic University |f 1989- |g Dariya Aleksandrovna |3 (RuTPU)RU\TPU\pers\33918 | |
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