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Structural modification of azolylacryloyl derivatives yields a novel class of covalent modifiers of hemoglobin as potential antisickling agents
The intracellular polymerization and the concomitant sickling processes, central to the pathology of sickle cell disease, can be mitigated by increasing the oxygen affinity of sickle hemoglobin (HbS). Attempts to develop azolylacryloyl derivatives to covalently interact with βCys93 and destabilize t...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Royal Society of Chemistry
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069400/ https://www.ncbi.nlm.nih.gov/pubmed/32206236 http://dx.doi.org/10.1039/c9md00291j |
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author | Omar, A. M. David, T. Pagare, P. P. Ghatge, M. S. Chen, Q. Mehta, A. Zhang, Y. Abdulmalik, O. Naghi, A. H. El-Araby, M. E. Safo, M. K. |
author_facet | Omar, A. M. David, T. Pagare, P. P. Ghatge, M. S. Chen, Q. Mehta, A. Zhang, Y. Abdulmalik, O. Naghi, A. H. El-Araby, M. E. Safo, M. K. |
author_sort | Omar, A. M. |
collection | PubMed |
description | The intracellular polymerization and the concomitant sickling processes, central to the pathology of sickle cell disease, can be mitigated by increasing the oxygen affinity of sickle hemoglobin (HbS). Attempts to develop azolylacryloyl derivatives to covalently interact with βCys93 and destabilize the low-O(2)-affinity T-state (deoxygenated) HbS to the polymer resistant high-O(2)-affinity R-state (liganded) HbS were only partially successful. This was likely due to the azolylacryloyls carboxylate moiety directing the compounds to also bind in the central water cavity of deoxygenated Hb and stabilizing the T-state. We now report a second generation of KAUS compounds (KAUS-28, KAUS-33, KAUS-38, and KAUS-39) without the carboxylate moiety designed to bind exclusively to βCys93. As expected, the compounds showed reactivity with both free amino acid l-Cys and the Hb βCys93. At 2 mM concentrations, the compounds demonstrated increased Hb affinity for oxygen (6% to 15%) in vitro, while the previously reported imidazolylacryloyl carboxylate derivative, KAUS-15 only showed 4.5% increase. The increased O(2) affinity effects were sustained through the experimental period of 12 h for KAUS-28, KAUS-33, and KAUS-38, suggesting conserved pharmacokinetic profiles. When incubated at 2 mM with red blood cells from patients with homozygous SS, the compounds inhibited erythrocyte sickling by 5% to 9%, respectively in correlation with the increase Hb-O(2) affinity. These values compare to 2% for KAUS-15. When tested with healthy mice, KAUS-38 showed very low toxicity. |
format | Online Article Text |
id | pubmed-7069400 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-70694002020-03-23 Structural modification of azolylacryloyl derivatives yields a novel class of covalent modifiers of hemoglobin as potential antisickling agents Omar, A. M. David, T. Pagare, P. P. Ghatge, M. S. Chen, Q. Mehta, A. Zhang, Y. Abdulmalik, O. Naghi, A. H. El-Araby, M. E. Safo, M. K. Medchemcomm Chemistry The intracellular polymerization and the concomitant sickling processes, central to the pathology of sickle cell disease, can be mitigated by increasing the oxygen affinity of sickle hemoglobin (HbS). Attempts to develop azolylacryloyl derivatives to covalently interact with βCys93 and destabilize the low-O(2)-affinity T-state (deoxygenated) HbS to the polymer resistant high-O(2)-affinity R-state (liganded) HbS were only partially successful. This was likely due to the azolylacryloyls carboxylate moiety directing the compounds to also bind in the central water cavity of deoxygenated Hb and stabilizing the T-state. We now report a second generation of KAUS compounds (KAUS-28, KAUS-33, KAUS-38, and KAUS-39) without the carboxylate moiety designed to bind exclusively to βCys93. As expected, the compounds showed reactivity with both free amino acid l-Cys and the Hb βCys93. At 2 mM concentrations, the compounds demonstrated increased Hb affinity for oxygen (6% to 15%) in vitro, while the previously reported imidazolylacryloyl carboxylate derivative, KAUS-15 only showed 4.5% increase. The increased O(2) affinity effects were sustained through the experimental period of 12 h for KAUS-28, KAUS-33, and KAUS-38, suggesting conserved pharmacokinetic profiles. When incubated at 2 mM with red blood cells from patients with homozygous SS, the compounds inhibited erythrocyte sickling by 5% to 9%, respectively in correlation with the increase Hb-O(2) affinity. These values compare to 2% for KAUS-15. When tested with healthy mice, KAUS-38 showed very low toxicity. Royal Society of Chemistry 2019-08-23 /pmc/articles/PMC7069400/ /pubmed/32206236 http://dx.doi.org/10.1039/c9md00291j Text en This journal is © The Royal Society of Chemistry 2019 http://creativecommons.org/licenses/by-nc/3.0/ This article is freely available. This article is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported Licence (CC BY-NC 3.0) |
spellingShingle | Chemistry Omar, A. M. David, T. Pagare, P. P. Ghatge, M. S. Chen, Q. Mehta, A. Zhang, Y. Abdulmalik, O. Naghi, A. H. El-Araby, M. E. Safo, M. K. Structural modification of azolylacryloyl derivatives yields a novel class of covalent modifiers of hemoglobin as potential antisickling agents |
title | Structural modification of azolylacryloyl derivatives yields a novel class of covalent modifiers of hemoglobin as potential antisickling agents |
title_full | Structural modification of azolylacryloyl derivatives yields a novel class of covalent modifiers of hemoglobin as potential antisickling agents |
title_fullStr | Structural modification of azolylacryloyl derivatives yields a novel class of covalent modifiers of hemoglobin as potential antisickling agents |
title_full_unstemmed | Structural modification of azolylacryloyl derivatives yields a novel class of covalent modifiers of hemoglobin as potential antisickling agents |
title_short | Structural modification of azolylacryloyl derivatives yields a novel class of covalent modifiers of hemoglobin as potential antisickling agents |
title_sort | structural modification of azolylacryloyl derivatives yields a novel class of covalent modifiers of hemoglobin as potential antisickling agents |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069400/ https://www.ncbi.nlm.nih.gov/pubmed/32206236 http://dx.doi.org/10.1039/c9md00291j |
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