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Design, Synthesis, and Antisickling Investigation of a Thiazolidine Prodrug of TD-7 That Prolongs the Duration of Action of Antisickling Aromatic Aldehyde

The synthetic allosteric effector of hemoglobin, TD-7 has been investigated as a potential therapeutic agent for the treatment of sickle cell disease. The pharmacologic activity of TD-7 is due to formation of a Schiff-base interaction between its aldehyde group and the two N-terminal αVal1 amines of...

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Autores principales: Alhashimi, Rana T., Ahmed, Tarek A., Alghanem, Lamya, Pagare, Piyusha P., Huang, Boshi, Ghatge, Mohini S., Omar, Abdelsattar M., Abdulmalik, Osheiza, Zhang, Yan, Safo, Martin K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10675597/
https://www.ncbi.nlm.nih.gov/pubmed/38004527
http://dx.doi.org/10.3390/pharmaceutics15112547
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author Alhashimi, Rana T.
Ahmed, Tarek A.
Alghanem, Lamya
Pagare, Piyusha P.
Huang, Boshi
Ghatge, Mohini S.
Omar, Abdelsattar M.
Abdulmalik, Osheiza
Zhang, Yan
Safo, Martin K.
author_facet Alhashimi, Rana T.
Ahmed, Tarek A.
Alghanem, Lamya
Pagare, Piyusha P.
Huang, Boshi
Ghatge, Mohini S.
Omar, Abdelsattar M.
Abdulmalik, Osheiza
Zhang, Yan
Safo, Martin K.
author_sort Alhashimi, Rana T.
collection PubMed
description The synthetic allosteric effector of hemoglobin, TD-7 has been investigated as a potential therapeutic agent for the treatment of sickle cell disease. The pharmacologic activity of TD-7 is due to formation of a Schiff-base interaction between its aldehyde group and the two N-terminal αVal1 amines of hemoglobin, effectively inhibiting sickling of red blood cells. However, TD-7 faces a challenge in terms of poor oral bioavailability due to rapid in-vivo oxidative metabolism of its aldehyde functional group. To address this shortcoming, researches have explored the use of a L-cysteine ethyl ester group to cap the aldehyde group to form a thiazolidine aromatic aldehyde prodrug complex, resulting in the improvement of the metabolic stability of this class of compounds. This report details the synthesis of a thiazolidine prodrug of TD-7, referred to as Pro-7, along with a comprehensive investigation of Pro-7 functional and biological properties. In an in-vitro Hb modification and Hb oxygen affinity studies using normal whole blood, as well as erythrocyte sickling inhibition using sickle whole blood, Pro-7 exhibited a gradual onset but progressive increase in all activities. Additionally, in-vivo pharmacokinetic studies conducted with Sprague Dawley rats demonstrated that Pro-7 can undergo hydrolysis to release TD-7. However, the blood concentration of TD-7 did not reach the desired therapeutic level. These findings suggest that the incorporation of the L-cysteine ethyl ester group to TD-7 represents a promising strategy to enhance the metabolic stability of aromatic aldehydes that could lead to the development of a more effective drug for the treatment of sickle cell disease.
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spelling pubmed-106755972023-10-28 Design, Synthesis, and Antisickling Investigation of a Thiazolidine Prodrug of TD-7 That Prolongs the Duration of Action of Antisickling Aromatic Aldehyde Alhashimi, Rana T. Ahmed, Tarek A. Alghanem, Lamya Pagare, Piyusha P. Huang, Boshi Ghatge, Mohini S. Omar, Abdelsattar M. Abdulmalik, Osheiza Zhang, Yan Safo, Martin K. Pharmaceutics Article The synthetic allosteric effector of hemoglobin, TD-7 has been investigated as a potential therapeutic agent for the treatment of sickle cell disease. The pharmacologic activity of TD-7 is due to formation of a Schiff-base interaction between its aldehyde group and the two N-terminal αVal1 amines of hemoglobin, effectively inhibiting sickling of red blood cells. However, TD-7 faces a challenge in terms of poor oral bioavailability due to rapid in-vivo oxidative metabolism of its aldehyde functional group. To address this shortcoming, researches have explored the use of a L-cysteine ethyl ester group to cap the aldehyde group to form a thiazolidine aromatic aldehyde prodrug complex, resulting in the improvement of the metabolic stability of this class of compounds. This report details the synthesis of a thiazolidine prodrug of TD-7, referred to as Pro-7, along with a comprehensive investigation of Pro-7 functional and biological properties. In an in-vitro Hb modification and Hb oxygen affinity studies using normal whole blood, as well as erythrocyte sickling inhibition using sickle whole blood, Pro-7 exhibited a gradual onset but progressive increase in all activities. Additionally, in-vivo pharmacokinetic studies conducted with Sprague Dawley rats demonstrated that Pro-7 can undergo hydrolysis to release TD-7. However, the blood concentration of TD-7 did not reach the desired therapeutic level. These findings suggest that the incorporation of the L-cysteine ethyl ester group to TD-7 represents a promising strategy to enhance the metabolic stability of aromatic aldehydes that could lead to the development of a more effective drug for the treatment of sickle cell disease. MDPI 2023-10-28 /pmc/articles/PMC10675597/ /pubmed/38004527 http://dx.doi.org/10.3390/pharmaceutics15112547 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Alhashimi, Rana T.
Ahmed, Tarek A.
Alghanem, Lamya
Pagare, Piyusha P.
Huang, Boshi
Ghatge, Mohini S.
Omar, Abdelsattar M.
Abdulmalik, Osheiza
Zhang, Yan
Safo, Martin K.
Design, Synthesis, and Antisickling Investigation of a Thiazolidine Prodrug of TD-7 That Prolongs the Duration of Action of Antisickling Aromatic Aldehyde
title Design, Synthesis, and Antisickling Investigation of a Thiazolidine Prodrug of TD-7 That Prolongs the Duration of Action of Antisickling Aromatic Aldehyde
title_full Design, Synthesis, and Antisickling Investigation of a Thiazolidine Prodrug of TD-7 That Prolongs the Duration of Action of Antisickling Aromatic Aldehyde
title_fullStr Design, Synthesis, and Antisickling Investigation of a Thiazolidine Prodrug of TD-7 That Prolongs the Duration of Action of Antisickling Aromatic Aldehyde
title_full_unstemmed Design, Synthesis, and Antisickling Investigation of a Thiazolidine Prodrug of TD-7 That Prolongs the Duration of Action of Antisickling Aromatic Aldehyde
title_short Design, Synthesis, and Antisickling Investigation of a Thiazolidine Prodrug of TD-7 That Prolongs the Duration of Action of Antisickling Aromatic Aldehyde
title_sort design, synthesis, and antisickling investigation of a thiazolidine prodrug of td-7 that prolongs the duration of action of antisickling aromatic aldehyde
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10675597/
https://www.ncbi.nlm.nih.gov/pubmed/38004527
http://dx.doi.org/10.3390/pharmaceutics15112547
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