Synthesis and Biological Investigation of Phenothiazine-Based Benzhydroxamic Acids as Selective Histone Deacetylase 6 Inhibitors
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The phenothiazine system was identified as a favorable cap group for potent and selective histone deacetylase 6 (HDAC6) inhibitors. Here, we report the preparation and systematic variation of phenothiazines and their analogues containing a benzhydroxamic acid moiety as the zinc-binding group. We evaluated their ability to selectively inhibit HDAC6 by a recombinant HDAC enzyme assay, by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines. Structure-activity relationship studies revealed that incorporation of a nitrogen atom into the phenothiazine framework results in increased potency and selectivity for HDAC6 (more than 500-fold selectivity relative to the inhibition of HDAC1, HDAC4, and HDAC8), as rationalized by molecular modeling and docking studies. The binding mode was confirmed by co-crystallization of the potent azaphenothiazine inhibitor with catalytic domain 2 from Danio rerio HDAC6.
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HDAC6 has two catalytic domains and a C-terminal zinc finger domain, interacts with tau and α-tubulin, and is involved in degradation of protein aggregates, mitochondrial transport, and cognitive memory, making it relevant to AD pathology.
“Among them, HDAC6 has two catalytic domains and a C-terminal zinc finger domain, interacts with tau and α-tubulin, and is involved in the degradation of protein aggregates, mitochondrial transport, and cognitive memory,506–509 making it relevant to AD pathology.”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [508]
The Introduction (page unavailable) describes HDAC6’s two catalytic domains, its action on α-tubulin, its role in transporting protein aggregates for processing, and its implication in Alzheimer’s disease. It does not describe the ubiquitin-binding domain as a C-terminal zinc finger or establish interactions with tau, mitochondrial transport, or a direct role in cognitive memory; it reports improved cognition in Alzheimer’s-model mice after HDAC6 inhibitor treatment. (LLM, conf=0.86)
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Zhang, J., Zhang, Y., Wang, J., Xia, Y., Zhang, J., & Chen, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01911-3 · Cited by 1,138 · see citing works
Development of Multifunctional Histone Deacetylase 6 Degraders with Potent Antimyeloma Activity
Wu, H., Yang, K., Zhang, Z., Leisten, E. D., Li, Z., Xie, H., Liu, J., Smith, K. A., Novakova, Z., Barinka, C., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00516 · Cited by 180 · see citing works
Strategies To Design Selective Histone Deacetylase Inhibitors
Melesina, J., Simoben, C. V., Praetorius, L., Bülbül, E. F., Robaa, D., & Sippl, W. (2021) · ChemMedChem · doi:10.1002/cmdc.202000934 · Cited by 118 · see citing works
Self-citationWang, X.-X., Xie, F., Jia, C.-C., Yan, N., Zeng, Y.-L., Wu, J.-D., & Liu, Z.-P. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113821 · Cited by 23 · see citing works
- Authors
- Vögerl, K., Ong, N., Senger, J., Herp, D., Schmidtkunz, K., Marek, M., Müller, M., Bartel, K., Shaik, T. B., Porter, N. J., Robaa, D., Christianson, D. W., Romier, C., Sippl, W., Jung, M., & Bracher, F.
- Affiliations
- Ludwig-Maximilians-Universität München (DE)
- Department of Pharmacy—Center for Drug Research, Ludwig-Maximilians University Munich, Butenandtstr. 5-13, 81377 Munich, Germany
- University of Freiburg (DE)
- Centre National de la Recherche Scientifique (FR)
- University of Pennsylvania (US)
- Martin Luther University Halle-Wittenberg (DE)
- Corresponding author
- Bracher, Franz
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-01-15
- Volume
- 62
- Issue
- 3
- Pages
- 1138-1166
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC6519732
- OpenAlex
- W2909709456
- Cited by
- 104
- References
- 85
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 15 · 2023: 11 · 2022: 10 · 2021: 17 · 2020: 23 · 2019: 12
- FWCI
- 6.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Université de Strasbourg
- Deutsche Forschungsgemeinschaft (Ju295/13-1, Si868/13-1)
- Centre National de la Recherche Scientifique
- National Institute of General Medical Sciences (GM49758)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phenothiazines and Benzothiazines Synthesis and Activities
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- phenothiazines, benzhydroxamic acid, HDAC6, HDAC6 inhibitors, structure-activity relationship, zinc-binding groups, protein acetylation, tubulin acetylation, histone acetylation, cancer cell lines, molecular docking, co-crystallization
- MeSH terms
- Histone Deacetylase 6, Acetylation, Animals, Cells, Cultured, Humans, Hydroxamic Acids, Microsomes, Liver, Phenothiazines, Structure-Activity Relationship, Zebrafish, Molecular Structure, Crystallography, X-Ray, HL-60 Cells, Catalytic Domain, Histone Deacetylase Inhibitors, Molecular Docking Simulation, In Vitro Techniques
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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