An Investigation of Structure-Activity Relationships of Azolylacryloyl Derivatives Yielded Potent and Long-Acting Hemoglobin Modulators for Reversing Erythrocyte Sickling
Aromatic aldehydes that bind to sickle hemoglobin (HbS) to increase the protein oxygen affinity and/or directly inhibit HbS polymer formation to prevent the pathological hypoxia-induced HbS polymerization and the subsequent erythrocyte sickling have for several years been studied for the treatment o...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-11-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/10/11/1508 |
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| author | Abdelsattar M. Omar Osheiza Abdulmalik Mohini S. Ghatge Yosra A. Muhammad Steven D. Paredes Moustafa E. El-Araby Martin K. Safo |
| author_facet | Abdelsattar M. Omar Osheiza Abdulmalik Mohini S. Ghatge Yosra A. Muhammad Steven D. Paredes Moustafa E. El-Araby Martin K. Safo |
| author_sort | Abdelsattar M. Omar |
| collection | DOAJ |
| description | Aromatic aldehydes that bind to sickle hemoglobin (HbS) to increase the protein oxygen affinity and/or directly inhibit HbS polymer formation to prevent the pathological hypoxia-induced HbS polymerization and the subsequent erythrocyte sickling have for several years been studied for the treatment of sickle cell disease (SCD). With the exception of Voxelotor, which was recently approved by the U.S. Food and Drug Administration (FDA) to treat the disease, several other promising antisickling aromatic aldehydes have not fared well in the clinic because of metabolic instability of the aldehyde moiety, which is critical for the pharmacologic activity of these compounds. Over the years, our group has rationally developed analogs of aromatic aldehydes that incorporate a stable Michael addition reactive center that we hypothesized would form covalent interactions with Hb to increase the protein affinity for oxygen and prevent erythrocyte sickling. Although, these compounds have proven to be metabolically stable, unfortunately they showed weak to no antisickling activity. In this study, through additional targeted modifications of our lead Michael addition compounds, we have discovered other novel antisickling agents. These compounds, designated MMA, bind to the α-globin and/or β-globin to increase Hb affinity for oxygen and concomitantly inhibit erythrocyte sickling with significantly enhanced and sustained pharmacologic activities in vitro. |
| first_indexed | 2024-03-10T15:08:21Z |
| format | Article |
| id | doaj.art-b3322b5bdc3b4c949d8736deafb25c05 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T15:08:21Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-b3322b5bdc3b4c949d8736deafb25c052023-11-20T19:34:10ZengMDPI AGBiomolecules2218-273X2020-11-011011150810.3390/biom10111508An Investigation of Structure-Activity Relationships of Azolylacryloyl Derivatives Yielded Potent and Long-Acting Hemoglobin Modulators for Reversing Erythrocyte SicklingAbdelsattar M. Omar0Osheiza Abdulmalik1Mohini S. Ghatge2Yosra A. Muhammad3Steven D. Paredes4Moustafa E. El-Araby5Martin K. Safo6Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi ArabiaDivision of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USADepartment of Medicinal Chemistry, School of Pharmacy and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA 23219, USADepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi ArabiaDepartment of Medicinal Chemistry, School of Pharmacy and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA 23219, USADepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Alsulaymanyah, Jeddah 21589, Saudi ArabiaDepartment of Medicinal Chemistry, School of Pharmacy and Institute for Structural Biology, Drug Discovery and Development, Virginia Commonwealth University, Richmond, VA 23219, USAAromatic aldehydes that bind to sickle hemoglobin (HbS) to increase the protein oxygen affinity and/or directly inhibit HbS polymer formation to prevent the pathological hypoxia-induced HbS polymerization and the subsequent erythrocyte sickling have for several years been studied for the treatment of sickle cell disease (SCD). With the exception of Voxelotor, which was recently approved by the U.S. Food and Drug Administration (FDA) to treat the disease, several other promising antisickling aromatic aldehydes have not fared well in the clinic because of metabolic instability of the aldehyde moiety, which is critical for the pharmacologic activity of these compounds. Over the years, our group has rationally developed analogs of aromatic aldehydes that incorporate a stable Michael addition reactive center that we hypothesized would form covalent interactions with Hb to increase the protein affinity for oxygen and prevent erythrocyte sickling. Although, these compounds have proven to be metabolically stable, unfortunately they showed weak to no antisickling activity. In this study, through additional targeted modifications of our lead Michael addition compounds, we have discovered other novel antisickling agents. These compounds, designated MMA, bind to the α-globin and/or β-globin to increase Hb affinity for oxygen and concomitantly inhibit erythrocyte sickling with significantly enhanced and sustained pharmacologic activities in vitro.https://www.mdpi.com/2218-273X/10/11/1508hemoglobinsickle cell diseaseMichael additionantisicklingoxygen equilibrium |
| spellingShingle | Abdelsattar M. Omar Osheiza Abdulmalik Mohini S. Ghatge Yosra A. Muhammad Steven D. Paredes Moustafa E. El-Araby Martin K. Safo An Investigation of Structure-Activity Relationships of Azolylacryloyl Derivatives Yielded Potent and Long-Acting Hemoglobin Modulators for Reversing Erythrocyte Sickling Biomolecules hemoglobin sickle cell disease Michael addition antisickling oxygen equilibrium |
| title | An Investigation of Structure-Activity Relationships of Azolylacryloyl Derivatives Yielded Potent and Long-Acting Hemoglobin Modulators for Reversing Erythrocyte Sickling |
| title_full | An Investigation of Structure-Activity Relationships of Azolylacryloyl Derivatives Yielded Potent and Long-Acting Hemoglobin Modulators for Reversing Erythrocyte Sickling |
| title_fullStr | An Investigation of Structure-Activity Relationships of Azolylacryloyl Derivatives Yielded Potent and Long-Acting Hemoglobin Modulators for Reversing Erythrocyte Sickling |
| title_full_unstemmed | An Investigation of Structure-Activity Relationships of Azolylacryloyl Derivatives Yielded Potent and Long-Acting Hemoglobin Modulators for Reversing Erythrocyte Sickling |
| title_short | An Investigation of Structure-Activity Relationships of Azolylacryloyl Derivatives Yielded Potent and Long-Acting Hemoglobin Modulators for Reversing Erythrocyte Sickling |
| title_sort | investigation of structure activity relationships of azolylacryloyl derivatives yielded potent and long acting hemoglobin modulators for reversing erythrocyte sickling |
| topic | hemoglobin sickle cell disease Michael addition antisickling oxygen equilibrium |
| url | https://www.mdpi.com/2218-273X/10/11/1508 |
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