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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royal Society of Chemistry 2019
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.
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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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