Design, synthesis, and biological evaluation of histone deacetylase inhibitor with novel salicylamide zinc binding group
Abstract. Introduction:. Histone deacetylases (HDACs) have emerged as important therapeutic targets for various diseases, such as cancer and neurological disorders. Although a majority of HDAC inhibitors use hydroxamic acids as zinc binding groups, hydroxamic acid zinc-binding groups suffer from poo...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wolters Kluwer
2022-04-01
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| Series: | Medicine |
| Online Access: | http://journals.lww.com/10.1097/MD.0000000000029049 |
| _version_ | 1828747613810196480 |
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| author | Ji Hyun Kim, MS Khan Hashim Ali, MS Yong Jin Oh, PhD Young Ho Seo, PhD Chang Chen. |
| author_facet | Ji Hyun Kim, MS Khan Hashim Ali, MS Yong Jin Oh, PhD Young Ho Seo, PhD Chang Chen. |
| author_sort | Ji Hyun Kim, MS |
| collection | DOAJ |
| description | Abstract. Introduction:. Histone deacetylases (HDACs) have emerged as important therapeutic targets for various diseases, such as cancer and neurological disorders. Although a majority of HDAC inhibitors use hydroxamic acids as zinc binding groups, hydroxamic acid zinc-binding groups suffer from poor bioavailability and nonspecific metal-binding properties, necessitating a new zinc-binding group. Salicylic acid and its derivatives, well-known for their therapeutic value, have also been reported to chelate zinc ions in a bidentate fashion. This drew our attention towards replacing hydroxamic acid with salicylamide as a zinc-binding group.
Methods:. In this study, for the first time, compound 5 possessing a novel salicylamide zinc-binding group was synthesized and evaluated biologically for its ability to inhibit various HDAC isoforms and induce acetylation upon α-tubulin and histone H3 among MDA-MB-231 cells.
Results:. Compound 5 exhibits selective inhibition against class I HDAC isoforms (HDAC1, 2, and 3) over class II and IV HDAC isoforms (HDAC4, 6, and 11). The exposure of MDA-MB-231 cells to compound 5 efficiently induced the acetylation of more histone H3 than α-tubulin, suggesting that compound 5 is a class I selective HDAC inhibitor. Moreover, the molecular docking study indicated that the salicylamide zinc-binding group of compound 5 coordinates the active zinc ion of class I HDAC2 in a bidentate fashion.
Conclusion:. Overall, salicylamide represents a novel zinc-binding group for the development of class I selective HDAC inhibitors.
Graphical abstract:. |
| first_indexed | 2024-04-14T04:44:34Z |
| format | Article |
| id | doaj.art-77200d712f1f430f913e54d5b43484a3 |
| institution | Directory Open Access Journal |
| issn | 0025-7974 1536-5964 |
| language | English |
| last_indexed | 2024-04-14T04:44:34Z |
| publishDate | 2022-04-01 |
| publisher | Wolters Kluwer |
| record_format | Article |
| series | Medicine |
| spelling | doaj.art-77200d712f1f430f913e54d5b43484a32022-12-22T02:11:29ZengWolters KluwerMedicine0025-79741536-59642022-04-0110117e2904910.1097/MD.0000000000029049202204290-00018Design, synthesis, and biological evaluation of histone deacetylase inhibitor with novel salicylamide zinc binding groupJi Hyun Kim, MS0Khan Hashim Ali, MS1Yong Jin Oh, PhD2Young Ho Seo, PhD3Chang Chen.4College of Pharmacy, Keimyung University, Daegu, Republic of Korea.College of Pharmacy, Keimyung University, Daegu, Republic of Korea.College of Pharmacy, Keimyung University, Daegu, Republic of Korea.College of Pharmacy, Keimyung University, Daegu, Republic of Korea.College of Pharmacy, Keimyung University, Daegu, Republic of Korea.Abstract. Introduction:. Histone deacetylases (HDACs) have emerged as important therapeutic targets for various diseases, such as cancer and neurological disorders. Although a majority of HDAC inhibitors use hydroxamic acids as zinc binding groups, hydroxamic acid zinc-binding groups suffer from poor bioavailability and nonspecific metal-binding properties, necessitating a new zinc-binding group. Salicylic acid and its derivatives, well-known for their therapeutic value, have also been reported to chelate zinc ions in a bidentate fashion. This drew our attention towards replacing hydroxamic acid with salicylamide as a zinc-binding group. Methods:. In this study, for the first time, compound 5 possessing a novel salicylamide zinc-binding group was synthesized and evaluated biologically for its ability to inhibit various HDAC isoforms and induce acetylation upon α-tubulin and histone H3 among MDA-MB-231 cells. Results:. Compound 5 exhibits selective inhibition against class I HDAC isoforms (HDAC1, 2, and 3) over class II and IV HDAC isoforms (HDAC4, 6, and 11). The exposure of MDA-MB-231 cells to compound 5 efficiently induced the acetylation of more histone H3 than α-tubulin, suggesting that compound 5 is a class I selective HDAC inhibitor. Moreover, the molecular docking study indicated that the salicylamide zinc-binding group of compound 5 coordinates the active zinc ion of class I HDAC2 in a bidentate fashion. Conclusion:. Overall, salicylamide represents a novel zinc-binding group for the development of class I selective HDAC inhibitors. Graphical abstract:.http://journals.lww.com/10.1097/MD.0000000000029049 |
| spellingShingle | Ji Hyun Kim, MS Khan Hashim Ali, MS Yong Jin Oh, PhD Young Ho Seo, PhD Chang Chen. Design, synthesis, and biological evaluation of histone deacetylase inhibitor with novel salicylamide zinc binding group Medicine |
| title | Design, synthesis, and biological evaluation of histone deacetylase inhibitor with novel salicylamide zinc binding group |
| title_full | Design, synthesis, and biological evaluation of histone deacetylase inhibitor with novel salicylamide zinc binding group |
| title_fullStr | Design, synthesis, and biological evaluation of histone deacetylase inhibitor with novel salicylamide zinc binding group |
| title_full_unstemmed | Design, synthesis, and biological evaluation of histone deacetylase inhibitor with novel salicylamide zinc binding group |
| title_short | Design, synthesis, and biological evaluation of histone deacetylase inhibitor with novel salicylamide zinc binding group |
| title_sort | design synthesis and biological evaluation of histone deacetylase inhibitor with novel salicylamide zinc binding group |
| url | http://journals.lww.com/10.1097/MD.0000000000029049 |
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