{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T21:07:33Z","timestamp":1775855253702,"version":"3.50.1"},"reference-count":27,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,2,21]],"date-time":"2019-02-21T00:00:00Z","timestamp":1550707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"MIUR","doi-asserted-by":"publisher","award":["FFABRA2017_MICALE_NICOLA_RI"],"award-info":[{"award-number":["FFABRA2017_MICALE_NICOLA_RI"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Genetic abnormalities have been conventionally considered as hallmarks of cancer. However, recent studies have demonstrated that epigenetic mechanisms are also implicated in the insurgence and development of cancer. Patterns of the epigenetic component include DNA methylation and histone modifications. Acetylation of histones is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Imbalance of these two enzymatic systems is known to be a key factor in tumor progression. Because HDACs have been found to function incorrectly in cancer, various HDAC inhibitors (HDACIs) are being investigated to act as cancer chemotherapeutics. Herein, we report the synthesis, docking studies and biological activity of a series of hydroxamic acid-based HDACIs bearing an N1-aryl or N1-H pyrazole nucleus as surface recognition motif and a cinnamoyl group as a linker to the hydroxamic acid zinc-binding group (ZBG). Some of the tested compounds exhibited inhibitory properties towards HDACs and antiproliferative activity against neuroblastoma SH-SY5Y tumor cell line both at micromolar concentrations.<\/jats:p>","DOI":"10.3390\/ijms20040945","type":"journal-article","created":{"date-parts":[[2019,2,22]],"date-time":"2019-02-22T03:49:44Z","timestamp":1550807384000},"page":"945","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Hydroxamic Acid-Based Histone Deacetylase (HDAC) Inhibitors Bearing a Pyrazole Scaffold and a Cinnamoyl Linker"],"prefix":"10.3390","volume":"20","author":[{"given":"Chiara","family":"Zagni","sequence":"first","affiliation":[{"name":"Department of Drug Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5881-7142","authenticated-orcid":false,"given":"Andrea","family":"Citarella","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale F. Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahjoub","family":"Oussama","sequence":"additional","affiliation":[{"name":"Higher Institute of Applied Sciences and Technology of Mahdia, University of Monastir, Sidi Massa-oud, Hiboun Mahdia Tunisian 5100, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5039-2151","authenticated-orcid":false,"given":"Antonio","family":"Rescifina","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy"},{"name":"Consorzio Interuniversitario Nazionale di ricerca in Metodologie e Processi Innovativi di Sintesi (C.I.N.M.P.S.), Via E. Orabona, 4, 70125 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8670-3123","authenticated-orcid":false,"given":"Alessandro","family":"Maugeri","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale F. Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6492-7820","authenticated-orcid":false,"given":"Michele","family":"Navarra","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale F. Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2171-9033","authenticated-orcid":false,"given":"Angela","family":"Scala","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale F. Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6004-5196","authenticated-orcid":false,"given":"Anna","family":"Piperno","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale F. Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9294-6033","authenticated-orcid":false,"given":"Nicola","family":"Micale","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale F. Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,2,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/cr.2011.22","article-title":"Regulation of chromatin by histone modifications","volume":"21","author":"Bannister","year":"2011","journal-title":"Cell Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"505","DOI":"10.4155\/fmc.12.3","article-title":"Targeted cancer therapy: Giving histone deacetylase inhibitors all they need to succeed","volume":"4","author":"Gryder","year":"2012","journal-title":"Future Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"757","DOI":"10.7150\/ijbs.9067","article-title":"Targeting histone deacetylases for cancer therapy: From molecular mechanisms to clinical implications","volume":"10","author":"Li","year":"2014","journal-title":"Int. J. Biol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1002\/med.21437","article-title":"The search for potent, small-molecule HDACIs in cancer treatment: A decade after vorinostat","volume":"37","author":"Zagni","year":"2017","journal-title":"Med. Res. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Eckschlager, T., Plch, J., Stiborova, M., and Hrabeta, J. (2017). Histone deacetylase inhibitors as anticancer drugs. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071414"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2642","DOI":"10.2174\/09298673113209990191","article-title":"A structural insight into hydroxamic acid based histone deacetylase inhibitors for the presence of anticancer activity","volume":"21","author":"Rajak","year":"2014","journal-title":"Curr. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1021\/jm020377a","article-title":"Development of potential antitumor agents. Synthesis and biological evaluation of a new set of sulfonamide derivatives as histone deacetylase inhibitors","volume":"46","author":"Bouchain","year":"2003","journal-title":"J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3344","DOI":"10.1021\/jm049002a","article-title":"Class II (IIa)-selective histone deacetylase inhibitors. 1. Synthesis and biological evaluation of novel (aryloxopropenyl) pyrrolyl hydroxyamides","volume":"48","author":"Mai","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5950","DOI":"10.1016\/j.bmc.2010.06.081","article-title":"Dual inhibitors of inosine monophosphate dehydrogenase and histone deacetylase based on a cinnamic hydroxamic acid core structure","volume":"18","author":"Chen","year":"2010","journal-title":"Bioorg. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1002\/cmdc.201000535","article-title":"Novel cinnamyl hydroxyamides and 2-aminoanilides as histone deacetylase inhibitors: Apoptotic induction and cytodifferentiation activity","volume":"6","author":"Valente","year":"2011","journal-title":"ChemMedChem"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4728","DOI":"10.1016\/j.bmc.2015.05.048","article-title":"Design, synthesis and preliminary biological evaluation of indoline-2,3-dione derivatives as novel HDAC inhibitors","volume":"23","author":"Jin","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7245","DOI":"10.1021\/acs.jmedchem.8b00664","article-title":"Small molecules simultaneously inhibiting p53-murine double minute 2 (MDM2) interaction and histone deacetylases (HDACs): Discovery of novel multitargeting antitumor agents","volume":"61","author":"He","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.bmcl.2015.12.007","article-title":"Novel thiol-based histone deacetylase inhibitors bearing 3-phenyl-1H-pyrazole-5-carboxamide scaffold as surface recognition motif: Design, synthesis and SAR study","volume":"26","author":"Wen","year":"2016","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1016\/j.bmc.2017.08.029","article-title":"Design, synthesis and biological evaluation of novel hydroxamic acid based histone deacetylase 6 selective inhibitors bearing phenylpyrazol scaffold as surface recognition motif","volume":"26","author":"Yang","year":"2018","journal-title":"Bioorg. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6195","DOI":"10.1021\/jm0407761","article-title":"New COX-2\/5-LOX inhibitors: Apoptosis-inducing agents potentially useful in prostate cancer chemotherapy","volume":"47","author":"Pommery","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.ejmech.2012.12.058","article-title":"Arylsulfonamide inhibitors of aggrecanases as potential therapeutic agents for osteoarthritis: Synthesis and biological evaluation","volume":"62","author":"Nuti","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3945","DOI":"10.1021\/jm030888c","article-title":"Pyrazole derivatives as partial Agonists for the nicotinic acid receptor","volume":"46","author":"Brussee","year":"2003","journal-title":"J. Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nchembio.313","article-title":"Chemical phylogenetics of histone deacetylases","volume":"6","author":"Bradner","year":"2010","journal-title":"Nat. Chem. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1111\/jphp.12403","article-title":"Effects of bergamot essential oil and its extractive fractions on SH-SY5Y human neuroblastoma cell growth","volume":"67","author":"Navarra","year":"2015","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.lfs.2015.12.040","article-title":"NF-kappa B mediates the antiproliferative and proapoptotic effects of bergamot juice in HepG2 cells","volume":"146","author":"Ferlazzo","year":"2016","journal-title":"Life Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1002\/jcb.20179","article-title":"Regulation of histone deacetylase activities","volume":"93","author":"Sengupta","year":"2004","journal-title":"J. Cell. Biochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1023\/B:JCAM.0000035186.90683.f2","article-title":"VEGA\u2014An open platform to develop chemo-bio-informatics applications, using plug-in architecture and script programming","volume":"18","author":"Pedretti","year":"2004","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1021\/ci500209e","article-title":"AutoDock4(Zn): An improved AutoDock force field for small-molecule docking to zinc metalloproteins","volume":"54","author":"Forli","year":"2014","journal-title":"J. Chem. Inf. Model."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/pro.3235","article-title":"UCSF ChimeraX: Meeting modern challenges in visualization and analysis","volume":"27","author":"Goddard","year":"2018","journal-title":"Protein Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1021\/ci200227u","article-title":"LigPlot+: Multiple ligand-protein interaction diagrams for drug discovery","volume":"51","author":"Laskowski","year":"2011","journal-title":"J. Chem. Inf. 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