{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T13:18:30Z","timestamp":1787750310620,"version":"build-2784847793"},"reference-count":41,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Research Foundation (DFG)","award":["INST 163\/720-1 FUGG (HR EI\/CI-GCMS)"],"award-info":[{"award-number":["INST 163\/720-1 FUGG (HR EI\/CI-GCMS)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Aromatic ring systems appear ubiquitously in active pharmaceutical substances, such as FDA-approved histone deacetylase inhibitors. However, these rings reduce the water solubility of the molecules, which is a disadvantage during application. To address this problem, azaborine rings may be substituted for conventional aromatic ring systems. These are obtained by replacing two adjacent carbon atoms with boron and nitrogen. Incorporating B\u2013N analogs in place of aromatic rings not only enhances structural diversity but also provides a strategy to navigate around patent-protected scaffolds. We synthesized azaborines, which are isosteric to naphthalene and indole, and utilized them as capping units for HDAC inhibitors. These molecules were attached to various aliphatic and aromatic linkers with different zinc-binding units, used in established active compounds. Nearly half of the twenty-four molecules tested exhibited inhibitory activity against at least one of the enzymes HDAC1, HDAC4, or HDAC8, with three compounds displaying IC50 values in the nanomolar range. We have therefore demonstrated that azaborine building blocks can be successfully incorporated into HDACis, resulting in a highly active profile. Consequently, it should be feasible to develop active substances containing azaborine rings against other targets.<\/jats:p>","DOI":"10.3390\/molecules30194017","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T12:04:52Z","timestamp":1759925092000},"page":"4017","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Novel Azaborine-Based Inhibitors of Histone Deacetylases (HDACs)"],"prefix":"10.3390","volume":"30","author":[{"given":"Martin","family":"Behringer","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Haardtring 100, 64295 Darmstadt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Schweipert","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Haardtring 100, 64295 Darmstadt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enna E.","family":"Peters","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Haardtring 100, 64295 Darmstadt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Kopranovic","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Haardtring 100, 64295 Darmstadt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1001-3249","authenticated-orcid":false,"given":"Franz-Josef","family":"Meyer-Almes","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Haardtring 100, 64295 Darmstadt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1006\/excr.2001.5187","article-title":"Histone acetylation and chromatin remodeling","volume":"265","author":"Gregory","year":"2001","journal-title":"Exp. Cell Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"a026831","DOI":"10.1101\/cshperspect.a026831","article-title":"HDACs and HDAC Inhibitors in Cancer Development and Therapy","volume":"6","author":"Li","year":"2016","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Seto, E., and Yoshida, M. (2014). Erasers of histone acetylation: The histone deacetylase enzymes. Cold Spring Harb. Perspect. Biol., 6.","DOI":"10.1101\/cshperspect.a018713"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2173","DOI":"10.1007\/s00018-012-0921-9","article-title":"Multiple roles of class I HDACs in proliferation, differentiation, and development","volume":"69","author":"Reichert","year":"2012","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1139\/o01-032","article-title":"Class II histone deacetylases: Structure, function, and regulation","volume":"79","author":"Bertos","year":"2001","journal-title":"Biochem. Cell Biol."},{"key":"ref_6","first-page":"53","article-title":"Transcription Regulation by Class III Histone Deacetylases (HDACs)-Sirtuins","volume":"3","author":"Dai","year":"2008","journal-title":"Transl. Oncogenom."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"25748","DOI":"10.1074\/jbc.M111871200","article-title":"Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family","volume":"277","author":"Gao","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1634\/theoncologist.12-10-1247","article-title":"FDA approval summary: Vorinostat for treatment of advanced primary cutaneous T-cell lymphoma","volume":"12","author":"Mann","year":"2007","journal-title":"Oncologist"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5410","DOI":"10.1200\/JCO.2008.21.6150","article-title":"Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma","volume":"27","author":"Piekarz","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1586\/era.10.88","article-title":"Romidepsin: A new therapy for cutaneous T-cell lymphoma and a potential therapy for solid tumors","volume":"10","author":"Grant","year":"2010","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2666","DOI":"10.1158\/1078-0432.CCR-14-3119","article-title":"FDA Approval: Belinostat for the Treatment of Patients with Relapsed or Refractory Peripheral T-cell Lymphoma","volume":"21","author":"Lee","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_12","first-page":"7131802","article-title":"Efficacy of Panobinostat for the Treatment of Multiple Myeloma","volume":"2020","author":"Kanellias","year":"2020","journal-title":"J. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1007\/s40265-024-02052-1","article-title":"Givinostat: First Approval","volume":"84","author":"Lamb","year":"2024","journal-title":"Drugs"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Sun, Y., Hong, J.H., Ning, Z., Pan, D., Fu, X., Lu, X., and Tan, J. (2022). Therapeutic potential of tucidinostat, a subtype-selective HDAC inhibitor, in cancer treatment. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.932914"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1111\/j.2042-7158.2010.01030.x","article-title":"Pharmaceutical applications of cyclodextrins: Basic science and product development","volume":"62","author":"Loftsson","year":"2010","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5845","DOI":"10.1021\/jm4017625","article-title":"Rings in drugs","volume":"57","author":"Taylor","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6401","DOI":"10.1021\/acs.jmedchem.8b00077","article-title":"Lipophilic Efficiency as an Important Metric in Drug Design","volume":"61","author":"Johnson","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1080\/17425247.2016.1182485","article-title":"Polyethylene glycol (PEG): A versatile polymer for pharmaceutical applications","volume":"13","author":"Shegokar","year":"2016","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10279","DOI":"10.1021\/ja303595z","article-title":"UV-photoelectron spectroscopy of 1,2- and 1,3-azaborines: A combined experimental and computational electronic structure analysis","volume":"134","author":"Chrostowska","year":"2012","journal-title":"J. Am. Chem. Soc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1021\/jacs.7b09446","article-title":"The State of the Art in Azaborine Chemistry: New Synthetic Methods and Applications","volume":"140","author":"Giustra","year":"2018","journal-title":"J. Am. Chem. Soc."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2728","DOI":"10.1039\/jr9590002728","article-title":"546. New heteroaromatic compounds. Part III. 2,1-Borazaro-naphthalene (1,2-dihydro-1-aza-2-boranaphthalene)","volume":"3","author":"Dewar","year":"1959","journal-title":"J. Chem. Soc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"15414","DOI":"10.1021\/ja508813v","article-title":"Two BN Isosteres of Anthracene: Synthesis and Characterization","volume":"136","author":"Ishibashi","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9287","DOI":"10.1021\/acs.jmedchem.5b01088","article-title":"Benzazaborinines as Novel Bioisosteric Replacements of Naphthalene: Propranolol as an Example","volume":"58","author":"Rombouts","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"152667","DOI":"10.1016\/j.tetlet.2020.152667","article-title":"Synthesis and biological evaluation of an antibacterial azaborine retinoid isostere","volume":"62","author":"Haney","year":"2021","journal-title":"Tetrahedron Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11508","DOI":"10.1021\/ja205779b","article-title":"Boron in disguise: The parent \u201cfused\u201d BN indole","volume":"133","author":"Abbey","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1039\/c3ob27436e","article-title":"BN isosteres of indole","volume":"11","author":"Abbey","year":"2013","journal-title":"Org. Biomol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1039\/D3MD00677H","article-title":"Indole-containing pharmaceuticals: Targets, pharmacological activities, and SAR studies","volume":"15","author":"Zeng","year":"2024","journal-title":"RSC Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.ejmech.2018.10.018","article-title":"Naphthalene, a versatile platform in medicinal chemistry: Sky-high perspective","volume":"161","author":"Makar","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1002\/cmdc.201700047","article-title":"Medicinal Chemistry Profiling of Monocyclic 1,2-Azaborines","volume":"12","author":"Zhao","year":"2017","journal-title":"ChemMedChem"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4899","DOI":"10.1021\/ol036026n","article-title":"Enantioselective synthesis of cyclic secondary amines through Mo-catalyzed asymmetric ring-closing metathesis (ARCM)","volume":"5","author":"Dolman","year":"2003","journal-title":"Org. Lett."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5636","DOI":"10.1021\/ol502708z","article-title":"Accessing an azaborine building block: Synthesis and substitution reactions of 2-chloromethyl-2,1-borazaronaphthalene","volume":"16","author":"Molander","year":"2014","journal-title":"Org. Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3771","DOI":"10.1021\/acs.joc.6b00435","article-title":"Synthesis of Functionalized 1,3,2-Benzodiazaborole Cores Using Bench-Stable Components","volume":"81","author":"Davies","year":"2016","journal-title":"J. Org. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Suzuki, T., Kasuya, Y., Itoh, Y., Ota, Y., Zhan, P., Asamitsu, K., Nakagawa, H., Okamoto, T., and Miyata, N. (2013). Identification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assembly. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0068669"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/s00280-011-1766-x","article-title":"Chidamide (CS055\/HBI-8000): A new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicity","volume":"69","author":"Ning","year":"2012","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"147222","DOI":"10.1016\/j.brainres.2020.147222","article-title":"Entinostat improves acute neurological outcomes and attenuates hematoma volume after Intracerebral Hemorrhage","volume":"1752","author":"Bonsack","year":"2021","journal-title":"Brain Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1124\/jpet.103.055541","article-title":"Identification of novel isoform-selective inhibitors within class I histone deacetylases","volume":"307","author":"Hu","year":"2003","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.ejmech.2006.02.002","article-title":"Synthesis and cancer antiproliferative activity of new histone deacetylase inhibitors: Hydrophilic hydroxamates and 2-aminobenzamide-containing derivatives","volume":"41","author":"Nagaoka","year":"2006","journal-title":"Eur. J. Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e005871","DOI":"10.1136\/jitc-2022-005871","article-title":"Tacedinaline (CI-994), a class I HDAC inhibitor, targets intrinsic tumor growth and leptomeningeal dissemination in MYC-driven medulloblastoma while making them susceptible to anti-CD47-induced macrophage phagocytosis via NF-kB-TGM2 driven tumor inflammation","volume":"11","author":"Marquardt","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Rai, M., Soragni, E., Chou, C.J., Barnes, G., Jones, S., Rusche, J.R., Gottesfeld, J.M., and Pandolfo, M. (2010). Two new pimelic diphenylamide HDAC inhibitors induce sustained frataxin upregulation in cells from Friedreich\u2019s ataxia patients and in a mouse model. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0008825"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Schweipert, M., Nehls, T., Wurster, E., B\u00f6ltner, J., Anton, K., Lammer, P., Lermyte, F., and Meyer-Almes, F.-J. (2024). The pivotal role of histidine 976 in human histone deacetylase 4 for enzyme function and ligand recognition. Bioorg. Chem., 153.","DOI":"10.1016\/j.bioorg.2024.107883"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"13249","DOI":"10.1002\/chem.202001712","article-title":"Switching the Switch: Ligand Induced Disulfide Formation in HDAC8","volume":"26","author":"Sugiarto","year":"2020","journal-title":"Chemistry"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/19\/4017\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T04:33:02Z","timestamp":1760070782000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/19\/4017"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,8]]},"references-count":41,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["molecules30194017"],"URL":"https:\/\/doi.org\/10.3390\/molecules30194017","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,8]]}}}