Synthesis and biological evaluation of ortho-phenyl phenylhydroxamic acids containing phenothiazine with improved selectivity for class IIa histone deacetylases
Class IIa histone deacetylases (HDACs) have been linked to tumorigenesis in various cancers. Previously, we designed phenylhydroxamic acid LH4f as a potent class IIa HDAC inhibitor. However, it also unselectively inhibited class I and class IIb HDACs. To enhance the compound’s selectivity towards cl...
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Taylor & Francis Group
2024-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2024.2406025 |
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| author | Kai-Cheng Hsu Yun-Yi Huang Jung-Chun Chu Yu-Wen Huang Jing-Lan Hu Tony Eight Lin Shih-Chung Yen Jing-Ru Weng Wei-Jan Huang |
| author_facet | Kai-Cheng Hsu Yun-Yi Huang Jung-Chun Chu Yu-Wen Huang Jing-Lan Hu Tony Eight Lin Shih-Chung Yen Jing-Ru Weng Wei-Jan Huang |
| author_sort | Kai-Cheng Hsu |
| collection | DOAJ |
| description | Class IIa histone deacetylases (HDACs) have been linked to tumorigenesis in various cancers. Previously, we designed phenylhydroxamic acid LH4f as a potent class IIa HDAC inhibitor. However, it also unselectively inhibited class I and class IIb HDACs. To enhance the compound’s selectivity towards class IIa HDACs, the ortho-phenyl group from the selective HDAC7 inhibitor 1 is incorporated into ortho position of the phenylhydroxamic acid in LH4f. Compared to LH4f, most resulting compounds displayed substantially improved selectivity towards the class IIa HDACs. Notably, compound 7 g exhibited the strongest HDAC9 inhibition with an IC50 value of 40 nM. Molecular modelling further identified the key interactions of compound 7 g bound to HDAC9. Compound 7 g significantly inhibited several human cancer cells, induced apoptosis, modulated caspase-related proteins as well as p38, and caused DNA damage. These findings suggest the potential of class IIa HDAC inhibitors as lead compounds for the development of cancer therapeutics. |
| format | Article |
| id | doaj-art-2d0d3d594369440e9a61c2c583b064c2 |
| institution | OA Journals |
| issn | 1475-6366 1475-6374 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj-art-2d0d3d594369440e9a61c2c583b064c22025-08-20T02:35:33ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742024-12-0139110.1080/14756366.2024.2406025Synthesis and biological evaluation of ortho-phenyl phenylhydroxamic acids containing phenothiazine with improved selectivity for class IIa histone deacetylasesKai-Cheng Hsu0Yun-Yi Huang1Jung-Chun Chu2Yu-Wen Huang3Jing-Lan Hu4Tony Eight Lin5Shih-Chung Yen6Jing-Ru Weng7Wei-Jan Huang8Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, TaiwanPh.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, TaiwanPh.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, TaiwanGraduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei, TaiwanDepartment of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, TaiwanGraduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, TaiwanWarshel Institute for Computational Biology, The Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong, ChinaDepartment of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, TaiwanPh.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, TaiwanClass IIa histone deacetylases (HDACs) have been linked to tumorigenesis in various cancers. Previously, we designed phenylhydroxamic acid LH4f as a potent class IIa HDAC inhibitor. However, it also unselectively inhibited class I and class IIb HDACs. To enhance the compound’s selectivity towards class IIa HDACs, the ortho-phenyl group from the selective HDAC7 inhibitor 1 is incorporated into ortho position of the phenylhydroxamic acid in LH4f. Compared to LH4f, most resulting compounds displayed substantially improved selectivity towards the class IIa HDACs. Notably, compound 7 g exhibited the strongest HDAC9 inhibition with an IC50 value of 40 nM. Molecular modelling further identified the key interactions of compound 7 g bound to HDAC9. Compound 7 g significantly inhibited several human cancer cells, induced apoptosis, modulated caspase-related proteins as well as p38, and caused DNA damage. These findings suggest the potential of class IIa HDAC inhibitors as lead compounds for the development of cancer therapeutics.https://www.tandfonline.com/doi/10.1080/14756366.2024.2406025Class IIa histone deacetylases (HDACs)structure-activity relationship (SAR)molecular modellingcancer cells |
| spellingShingle | Kai-Cheng Hsu Yun-Yi Huang Jung-Chun Chu Yu-Wen Huang Jing-Lan Hu Tony Eight Lin Shih-Chung Yen Jing-Ru Weng Wei-Jan Huang Synthesis and biological evaluation of ortho-phenyl phenylhydroxamic acids containing phenothiazine with improved selectivity for class IIa histone deacetylases Journal of Enzyme Inhibition and Medicinal Chemistry Class IIa histone deacetylases (HDACs) structure-activity relationship (SAR) molecular modelling cancer cells |
| title | Synthesis and biological evaluation of ortho-phenyl phenylhydroxamic acids containing phenothiazine with improved selectivity for class IIa histone deacetylases |
| title_full | Synthesis and biological evaluation of ortho-phenyl phenylhydroxamic acids containing phenothiazine with improved selectivity for class IIa histone deacetylases |
| title_fullStr | Synthesis and biological evaluation of ortho-phenyl phenylhydroxamic acids containing phenothiazine with improved selectivity for class IIa histone deacetylases |
| title_full_unstemmed | Synthesis and biological evaluation of ortho-phenyl phenylhydroxamic acids containing phenothiazine with improved selectivity for class IIa histone deacetylases |
| title_short | Synthesis and biological evaluation of ortho-phenyl phenylhydroxamic acids containing phenothiazine with improved selectivity for class IIa histone deacetylases |
| title_sort | synthesis and biological evaluation of ortho phenyl phenylhydroxamic acids containing phenothiazine with improved selectivity for class iia histone deacetylases |
| topic | Class IIa histone deacetylases (HDACs) structure-activity relationship (SAR) molecular modelling cancer cells |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2024.2406025 |
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