{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T20:34:08Z","timestamp":1790282048209,"version":"4.1.0"},"reference-count":136,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T00:00:00Z","timestamp":1599091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Peptidyl fluoromethyl ketones occupy a pivotal role in the current scenario of synthetic chemistry, thanks to their numerous applications as inhibitors of hydrolytic enzymes. The insertion of one or more fluorine atoms adjacent to a C-terminal ketone moiety greatly modifies the physicochemical properties of the overall substrate, especially by increasing the reactivity of this functionalized carbonyl group toward nucleophiles. The main application of these peptidyl \u03b1-fluorinated ketones in medicinal chemistry relies in their ability to strongly and selectively inhibit serine and cysteine proteases. These compounds can be used as probes to study the proteolytic activity of the aforementioned proteases and to elucidate their role in the insurgence and progress on several diseases. Likewise, if the fluorinated methyl ketone moiety is suitably connected to a peptidic backbone, it may confer to the resulting structure an excellent substrate peculiarity and the possibility of being recognized by a specific subclass of human or pathogenic proteases. Therefore, peptidyl fluoromethyl ketones are also currently highly exploited for the target-based design of compounds for the treatment of topical diseases such as various types of cancer and viral infections.<\/jats:p>","DOI":"10.3390\/molecules25174031","type":"journal-article","created":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T11:22:43Z","timestamp":1599132163000},"page":"4031","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Peptidyl Fluoromethyl Ketones and Their Applications in Medicinal Chemistry"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5881-7142","authenticated-orcid":false,"given":"Andrea","family":"Citarella","sequence":"first","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D\u2019Alcontres 31, I-98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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 Ferdinando Stagno D\u2019Alcontres 31, I-98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"855","DOI":"10.2174\/1568026614666140202204242","article-title":"Fluorinated compounds in medicinal chemistry: Recent applications, synthetic advances and matched-pair analyses","volume":"14","author":"Beck","year":"2014","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/S0731-7085(97)00102-7","article-title":"Isolation and quantification of fluoroacetate in rat tissues, following dosing of Z-Phe-Ala-CH2-F, a peptidyl fluoromethyl ketone protease inhibitor","volume":"16","author":"Eichhold","year":"1997","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/nchembio707","article-title":"Activity-based probes that target diverse cysteine protease families","volume":"1","author":"Kato","year":"2005","journal-title":"Nat. Chem. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4639","DOI":"10.1021\/cr010182v","article-title":"Irreversible inhibitors of serine, cysteine, and threonine proteases","volume":"102","author":"Powers","year":"2002","journal-title":"Chem. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1007\/s00894-010-0807-4","article-title":"Reactivity versus steric effects in fluorinated ketones as esterase inhibitors: A quantum mechanical and molecular dynamics study","volume":"16","author":"Rayo","year":"2010","journal-title":"J. Mol. Model."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7353","DOI":"10.1021\/acs.jpcb.6b04089","article-title":"Serine Protease Catalysis: A Computational Study of Tetrahedral Intermediates and Inhibitory Adducts","volume":"120","author":"Ngo","year":"2016","journal-title":"J. Phys. Chem. B"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/0003-2697(85)90598-6","article-title":"Synthesis of peptide fluoromethyl ketones and the inhibition of human cathepsin B","volume":"149","author":"Rasnick","year":"1985","journal-title":"Anal. Biochem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.3389\/fimmu.2019.02037","article-title":"Cysteine Cathepsins in Tumor-Associated Immune Cells","volume":"10","author":"Jakos","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_9","first-page":"1525","article-title":"Cysteine proteinase activity in arthritic rat knee joints and the effects of a selective systemic inhibitor, Z-Phe-AlaCH2F","volume":"15","author":"Smith","year":"1988","journal-title":"J. Rheumatol."},{"key":"ref_10","first-page":"1176","article-title":"The effects of fluoromethyl ketone inhibitors of cathepsin B on adjuvant induced arthritis","volume":"20","author":"Esser","year":"1993","journal-title":"J. Rheumatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"91","DOI":"10.4331\/wjbc.v4.i4.91","article-title":"Cathepsins mediate tumor metastasis","volume":"4","author":"Tan","year":"2013","journal-title":"World J. Biol. Chem."},{"key":"ref_12","first-page":"3553","article-title":"Suppression by cathepsin L inhibitors of the invasion of amnion membranes by murine cancer cells","volume":"49","author":"Yagel","year":"1989","journal-title":"Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1042\/bj2390633","article-title":"The Synthesis of Peptidylfluoromethanes and Their Properties as Inhibitors of Serine Proteinases and Cysteine Proteinases","volume":"239","author":"Rauber","year":"1986","journal-title":"Biochem. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1042\/bj2410871","article-title":"The Synthesis of Lysylfluoromethanes and Their Properties as Inhibitors of Trypsin, Plasmin and Cathepsin-B","volume":"241","author":"Angliker","year":"1987","journal-title":"Biochem. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1042\/bj2560481","article-title":"Synthesis and properties of peptidyl derivatives of arginylfluoromethanes","volume":"256","author":"Angliker","year":"1988","journal-title":"Biochem. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1016\/0006-2952(92)90385-V","article-title":"Peptidyl fluoromethyl ketones as inhibitors of cathepsin B","volume":"44","author":"Ahmed","year":"1992","journal-title":"Biochem. Pharm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1006\/bbrc.2001.4787","article-title":"Significance of cathepsin B accumulation in synovial fluid of rheumatoid arthritis","volume":"283","author":"Hashimoto","year":"2001","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3827","DOI":"10.4049\/jimmunol.177.6.3827","article-title":"The cathepsin B inhibitor, z-FA-FMK, inhibits human T cell proliferation in vitro and modulates host response to pneumococcal infection in vivo","volume":"177","author":"Lawrence","year":"2006","journal-title":"J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.abb.2004.04.011","article-title":"Design and evaluation of inhibitors for dipeptidyl peptidase I (Cathepsin C)","volume":"427","author":"Kam","year":"2004","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6570","DOI":"10.1093\/emboj\/20.23.6570","article-title":"Structure of human dipeptidyl peptidase I (cathepsin C): Exclusion domain added to an endopeptidase framework creates the machine for activation of granular serine proteases","volume":"20","author":"Turk","year":"2001","journal-title":"EMBO J."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Rudzinska, M., Parodi, A., Maslova, V.D., Efremov, Y.M., Gorokhovets, N.V., Makarov, V.A., Popkov, V.A., Golovin, A.V., Zernii, E.Y., and Zamyatnin, A.A. (2020). Cysteine Cathepsins Inhibition Affects Their Expression and Human Renal Cancer Cell Phenotype. Cancers, 12.","DOI":"10.3390\/cancers12051310"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Gorokhovets, N.V., Makarov, V.A., Petushkova, A.I., Prokopets, O.S., Rubtsov, M.A., Savvateeva, L.V., Zernii, E.Y., and Zamyatnin, A.A. (2017). Rational Design of Recombinant Papain-Like Cysteine Protease: Optimal Domain Structure and Expression Conditions for Wheat-Derived Enzyme Triticain-alpha. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18071395"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"114","DOI":"10.3389\/fcell.2017.00114","article-title":"The Multifaceted Role of the Lysosomal Protease Cathepsins in Kidney Disease","volume":"5","author":"Cocchiaro","year":"2017","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"McIlwain, D.R., Berger, T., and Mak, T.W. (2015). Caspase functions in cell death and disease. Cold Spring Harb. Perspect. Biol., 7.","DOI":"10.1101\/cshperspect.a026716"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj3260001","article-title":"Caspases: The executioners of apoptosis","volume":"326","author":"Cohen","year":"1997","journal-title":"Biochem. J."},{"key":"ref_26","first-page":"568","article-title":"The potential for caspases in drug discovery","volume":"13","author":"MacKenzie","year":"2010","journal-title":"Curr. Opin. Drug Discov. Dev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1992","DOI":"10.1172\/JCI2169","article-title":"Caspase inhibitor affords neuroprotection with delayed administration in a rat model of neonatal hypoxic-ischemic brain injury","volume":"101","author":"Cheng","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1096\/fasebj.13.13.1875","article-title":"Combined mechanical trauma and metabolic impairment in vitro induces NMDA receptor-dependent neuronal cell death and caspase-3-dependent apoptosis","volume":"13","author":"Allen","year":"1999","journal-title":"FASEB J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1006\/exnr.1999.7241","article-title":"Reversible physiological alterations in sympathetic neurons deprived of NGF but protected from apoptosis by caspase inhibition or Bax deletion","volume":"161","author":"Werth","year":"2000","journal-title":"Exp. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1097\/00001756-200103050-00022","article-title":"Caspase inhibitors promote the survival of avulsed spinal motoneurons in neonatal rats","volume":"12","author":"Chan","year":"2001","journal-title":"Neuroreport"},{"key":"ref_31","first-page":"869","article-title":"Caspase inhibitor BD-fmk distinguishes transforming growth factor beta-induced apoptosis from growth inhibition","volume":"9","author":"Brown","year":"1998","journal-title":"Cell Growth Differ."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"32608","DOI":"10.1074\/jbc.273.49.32608","article-title":"Inhibition of human caspases by peptide-based and macromolecular inhibitors","volume":"273","author":"Peterson","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2970","DOI":"10.1182\/blood-2004-07-2870","article-title":"z-VAD-fmk augmentation of TNF alpha-stimulated neutrophil apoptosis is compound specific and does not involve the generation of reactive oxygen species","volume":"105","author":"Cowburn","year":"2005","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/sj.jcbfm.9600338","article-title":"boc-Aspartyl(OMe)-fluoromethylketone attenuates mitochondrial release of cytochrome c and delays brain tissue loss after traumatic brain injury in rats","volume":"27","author":"Clark","year":"2007","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1016\/j.bmcl.2003.12.065","article-title":"Dipeptidyl aspartyl fluoromethylketones as potent caspase-3 inhibitors: SAR of the P2 amino acid","volume":"14","author":"Wang","year":"2004","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/sj.bjp.0705450","article-title":"MX1013, a dipeptide caspase inhibitor with potent in vivo antiapoptotic activity","volume":"140","author":"Yang","year":"2003","journal-title":"Br. J. Pharm."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6539","DOI":"10.1074\/jbc.272.10.6539","article-title":"Structure of recombinant human CPP32 in complex with the tetrapeptide acetyl-Asp-Val-Ala-Asp fluoromethyl ketone","volume":"272","author":"Mittl","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1016\/j.bmcl.2005.01.007","article-title":"Dipeptidyl aspartyl fluoromethylketones as potent caspase inhibitors: Peptidomimetic replacement of the P2 \u03b1-amino acid by a \u03b1-hydroxy acid","volume":"15","author":"Wang","year":"2005","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6178","DOI":"10.1016\/j.bmcl.2007.09.030","article-title":"Dipeptidyl aspartyl fluoromethylketones as potent caspase inhibitors: Peptidomimetic replacement of the P2 amino acid by 2-aminoaryl acids and other non-natural amino acids","volume":"17","author":"Wang","year":"2007","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"R97","DOI":"10.1016\/S1074-5521(98)90615-9","article-title":"Caspases: Key mediators of apoptosis","volume":"5","author":"Thornberry","year":"1998","journal-title":"Chem. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.1084\/jem.184.5.2067","article-title":"Systemic injection of a tripeptide inhibits the intracellular activation of CPP32-like proteases in vivo and fully protects mice against Fas-mediated fulminant liver destruction and death","volume":"184","author":"Rodriguez","year":"1996","journal-title":"J. Exp. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"10815","DOI":"10.1074\/jbc.273.18.10815","article-title":"Different subcellular distribution of caspase-3 and caspase-7 following Fas-induced apoptosis in mouse liver","volume":"273","author":"Chandler","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1073\/pnas.94.5.2007","article-title":"Inhibition of interleukin 1\u03b2 converting enzyme family proteases reduces ischemic and excitotoxic\u2009neuronal\u2009damage","volume":"94","author":"Hara","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1097\/00004647-199803000-00002","article-title":"Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the caspase family","volume":"18","author":"Endres","year":"1998","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_45","first-page":"53","article-title":"Protective effect of a caspase inhibitor in models for cerebral ischemia in vitro and in vivo","volume":"46","author":"Wiessner","year":"2000","journal-title":"Cell Mol. Biol. (Noisy-Le-Grand)"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1161\/01.STR.31.1.176","article-title":"Caspase inhibitors reduce neuronal injury after focal but not global cerebral ischemia in rats","volume":"31","author":"Li","year":"2000","journal-title":"Stroke"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1161\/01.CIR.97.3.276","article-title":"Attenuation of ischemia\/reperfusion injury in rats by a caspase inhibitor","volume":"97","author":"Yaoita","year":"1998","journal-title":"Circulation"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/S0014-2999(00)00477-5","article-title":"In vivo myocardial infarct size reduction by a caspase inhibitor administered after the onset of ischemia","volume":"402","author":"Huang","year":"2000","journal-title":"Eur. J. Pharm."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/sj.bjp.0703336","article-title":"Caspase inhibition and limitation of myocardial infarct size: Protection against lethal reperfusion injury","volume":"130","author":"Mocanu","year":"2000","journal-title":"Br. J. Pharm."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/S0741-5214(99)70115-1","article-title":"A specific inhibitor of apoptosis decreases tissue injury after intestinal ischemia-reperfusion in mice","volume":"30","author":"Farber","year":"1999","journal-title":"J. Vasc. Surg."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1182\/blood-2002-03-0752","article-title":"The caspase inhibitor z-VAD is more effective than CD18 adhesion blockade in reducing muscle ischemia-reperfusion injury: Implication for clinical trials","volume":"100","author":"Iwata","year":"2002","journal-title":"Blood"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1172\/JCI6974","article-title":"Inhibition of apoptosis induced by ischemia-reperfusion prevents inflammation","volume":"104","author":"Daemen","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"9693","DOI":"10.1016\/0040-4039(94)88361-0","article-title":"Synthesis of P1 aspartate-based peptide acyloxymethyl and fluoromethyl ketones as inhibitors of interleukin-1\u03b2-converting enzyme","volume":"35","author":"Revesz","year":"1994","journal-title":"Tetrahedron Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/sj.cdd.4401247","article-title":"Inhibition of papain-like cysteine proteases and legumain by caspase-specific inhibitors: When reaction mechanism is more important than specificity","volume":"10","author":"Bogyo","year":"2003","journal-title":"Cell Death Differ."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1038\/6514","article-title":"Neuroprotection by a caspase inhibitor in acute bacterial meningitis","volume":"5","author":"Braun","year":"1999","journal-title":"Nat. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"6627","DOI":"10.1093\/emboj\/20.23.6627","article-title":"Apoptosis-associated release of Smac\/DIABLO from mitochondria requires active caspases and is blocked by Bcl-2","volume":"20","author":"Adrain","year":"2001","journal-title":"EMBO J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1023\/A:1024116916932","article-title":"Q-VD-OPh, a broad spectrum caspase inhibitor with potent antiapoptotic properties","volume":"8","author":"Caserta","year":"2003","journal-title":"Apoptosis"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/sj.bjp.0704075","article-title":"Synergistic protective effect of caspase inhibitors and bFGF against brain injury induced by transient focal ischaemia","volume":"133","author":"Ma","year":"2001","journal-title":"Br. J. Pharm."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3386","DOI":"10.4049\/jimmunol.170.6.3386","article-title":"A broad-spectrum caspase inhibitor attenuates allergic airway inflammation in murine asthma model","volume":"170","author":"Iwata","year":"2003","journal-title":"J. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1006\/bbrc.1999.2049","article-title":"The effect of apoptosis inhibitors on experimental autoimmune encephalomyelitis: Apoptosis as a regulatory factor","volume":"267","author":"Okuda","year":"2000","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1080\/13543776.2016.1230201","article-title":"Necroptosis inhibitors as therapeutic targets in inflammation mediated disorders\u2014A review of the current literature and patents","volume":"26","author":"Kopalli","year":"2016","journal-title":"Expert Opin. Ther. Pat."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.molimm.2017.12.018","article-title":"Caspases are key regulators of inflammatory and innate immune responses mediated by TLR3 in vivo","volume":"94","author":"Shaalan","year":"2018","journal-title":"Mol. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.3389\/fimmu.2019.01824","article-title":"The Caspase Inhibitor Z-VAD-FMK Alleviates Endotoxic Shock via Inducing Macrophages Necroptosis and Promoting MDSCs-Mediated Inhibition of Macrophages Activation","volume":"10","author":"Li","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.pan.2016.06.002","article-title":"Caspase inhibitor zVAD-fmk protects against acute pancreatitis-associated lung injury via inhibiting inflammation and apoptosis","volume":"16","author":"Liu","year":"2016","journal-title":"Pancreatology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.theriogenology.2017.11.031","article-title":"Inhibition of apoptosis by caspase inhibitor Z-VAD-FMK improves cryotolerance of in vitro derived bovine embryos","volume":"108","author":"Pero","year":"2018","journal-title":"Theriogenology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1007\/BF03044967","article-title":"Caspase inhibitors in prevention of apoptosis","volume":"24","author":"Rudel","year":"1999","journal-title":"Herz"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"4914","DOI":"10.1523\/JNEUROSCI.18-13-04914.1998","article-title":"Induction of caspase-3-like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia","volume":"18","author":"Chen","year":"1998","journal-title":"J. Neurosci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1097\/00004647-200105000-00007","article-title":"Both caspase-dependent and caspase-independent pathways may be involved in hippocampal CA1 neuronal death because of loss of cytochrome c from mitochondria in a rat forebrain ischemia model","volume":"21","author":"Zhan","year":"2001","journal-title":"J. Cerebr. Blood Flow Met."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1038\/sj.jcbfm.9600111","article-title":"Biphasic cytochrome c release after transient global ischemia and its inhibition by hypothermia","volume":"25","author":"Zhao","year":"2005","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.resuscitation.2008.02.010","article-title":"The effect of intracerebroventricular application of the caspase-3 inhibitor zDEVD-FMK on neurological outcome and neuronal cell death after global cerebral ischaemia due to cardiac arrest in rats","volume":"78","author":"Teschendorf","year":"2008","journal-title":"Resuscitation"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1097\/01.WCB.0000117688.98763.23","article-title":"Dynamic fMRI and EEG recordings during spike-wave seizures and generalized tonic-clonic seizures in WAG\/Rij rats","volume":"24","author":"Nersesyan","year":"2004","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1242\/jcs.110.18.2165","article-title":"Involvement of caspases in sympathetic neuron apoptosis","volume":"110","author":"McCarthy","year":"1997","journal-title":"J. Cell Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1016\/j.freeradbiomed.2006.08.016","article-title":"A novel peptide inhibitor targeted to caspase-3 cleavage site of a proapoptotic kinase protein kinase C delta (PKC\u03b4) protects against dopaminergic neuronal degeneration in Parkinson\u2019s disease models","volume":"41","author":"Kanthasamy","year":"2006","journal-title":"Free Radic. Biol. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1046\/j.1460-9568.2003.02864.x","article-title":"Caspase-3 dependent proteolytic activation of protein kinase C delta mediates and regulates 1-methyl-4-phenylpyridinium (MPP+)-induced apoptotic cell death in dopaminergic cells: Relevance to oxidative stress in dopaminergic degeneration","volume":"18","author":"Kaul","year":"2003","journal-title":"Eur. J. Neurosci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.bbapap.2011.08.005","article-title":"Calpains\u2014An elaborate proteolytic system","volume":"1824","author":"Ono","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1021\/jm00080a004","article-title":"Structure-function studies in a series of carboxyl-terminal octapeptide analogues of anaphylatoxin C5a","volume":"35","author":"Kawai","year":"1992","journal-title":"J. Med. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3820","DOI":"10.1021\/jm970197e","article-title":"Synthesis and biological activity of a series of potent fluoromethyl ketone inhibitors of recombinant human calpain I","volume":"40","author":"Chatterjee","year":"1997","journal-title":"J. Med. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1016\/0960-894X(96)00209-0","article-title":"Potent fluoromethyl ketone inhibitors of recombinant human calpain I+","volume":"6","author":"Chatterjee","year":"1996","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"12489","DOI":"10.1016\/S0021-9258(18)90773-8","article-title":"Comparative specificity and kinetic studies on porcine calpain I and calpain II with naturally occurring peptides and synthetic fluorogenic substrates","volume":"259","author":"Sasaki","year":"1984","journal-title":"J. Biol. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1096\/fj.01-0889rev","article-title":"Cytoplasmic peptide:N-glycanase (PNGase) in eukaryotic cells: Occurrence, primary structure, and potential functions","volume":"16","author":"Suzuki","year":"2002","journal-title":"FASEB J."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/sj.cdd.4401716","article-title":"z-VAD-fmk inhibits peptide:N-glycanase and may result in ER stress","volume":"13","author":"Misaghi","year":"2006","journal-title":"Cell Death Differ."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1016\/j.chembiol.2004.11.010","article-title":"Using a small molecule inhibitor of peptide: N-glycanase to probe its role in glycoprotein turnover","volume":"11","author":"Misaghi","year":"2004","journal-title":"Chem. Biol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"22152","DOI":"10.1074\/jbc.M603236200","article-title":"Site-specific labeling of cytoplasmic peptide:N-glycanase by N,N\u2032-diacetylchitobiose-related compounds","volume":"281","author":"Suzuki","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"3690","DOI":"10.1039\/b711531h","article-title":"Bodipy-VAD-Fmk, a useful tool to study yeast peptide N-glycanase activity","volume":"5","author":"Witte","year":"2007","journal-title":"Org. Biomol. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/nrm2707","article-title":"An additional role for SUMO in ubiquitin-mediated proteolysis","volume":"10","author":"Geoffroy","year":"2009","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Kunz, K., Piller, T., and Muller, S. (2018). SUMO-specific proteases and isopeptidases of the SENP family at a glance. J. Cell Sci., 131.","DOI":"10.1242\/jcs.211904"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1002\/cbic.201100645","article-title":"Glycine Fluoromethylketones as SENP-Specific Activity Based Probes","volume":"13","author":"Fasci","year":"2012","journal-title":"ChemBioChem"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1042\/BJ20052030","article-title":"The structure of SENP1\u2013SUMO-2 complex suggests a structural basis for discrimination between SUMO paralogues during processing","volume":"397","author":"Shen","year":"2006","journal-title":"Biochem. J."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1042\/BJ20060526","article-title":"Crystal structure of the SENP1 mutant C603S\u2013SUMO complex reveals the hydrolytic mechanism of SUMO-specific protease","volume":"398","author":"Xu","year":"2006","journal-title":"Biochem. J."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1172\/JCI115456","article-title":"Antimalarial effects of peptide inhibitors of a Plasmodium falciparum cysteine proteinase","volume":"88","author":"Rosenthal","year":"1991","journal-title":"J. Clin. Investig."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1002\/med.20163","article-title":"Falcipain-2 inhibitors","volume":"30","author":"Ettari","year":"2010","journal-title":"Med. Res. Rev."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1172\/JCI116262","article-title":"Inhibition of a Plasmodium vinckei cysteine proteinase cures murine malaria","volume":"91","author":"Rosenthal","year":"1993","journal-title":"J. Clin. Investig."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Sajid, M., Robertson, S.A., Brinen, L.S., and McKerrow, J.H. (2011). Cruzain. Cysteine Proteases of Pathogenic Organisms, Springer.","DOI":"10.1007\/978-1-4419-8414-2_7"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/0166-6851(93)90086-D","article-title":"Peptide-fluoromethyl ketones arrest intracellular replication and intercellular transmission of Trypanosoma cruzi","volume":"58","author":"Harth","year":"1993","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1002\/pro.5560060801","article-title":"Structural determinants of specificity in the cysteine protease cruzain","volume":"6","author":"Gillmor","year":"1997","journal-title":"Protein Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"S88","DOI":"10.1038\/nm1143","article-title":"Severe acute respiratory syndrome","volume":"10","author":"Peiris","year":"2004","journal-title":"Nat. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1099\/0022-1317-83-3-595","article-title":"Conservation of substrate specificities among coronavirus main proteases","volume":"83","author":"Hegyi","year":"2002","journal-title":"J. Gen. Virol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1126\/science.1085658","article-title":"Coronavirus main proteinase (3CLpro) structure: Basis for design of anti-SARS drugs","volume":"300","author":"Anand","year":"2003","journal-title":"Science"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1080\/22221751.2020.1723441","article-title":"An emerging coronavirus causing pneumonia outbreak in Wuhan, China: Calling for developing therapeutic and prophylactic strategies","volume":"9","author":"Jiang","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1080\/22221751.2020.1737580","article-title":"Timely development of vaccines against SARS-CoV-2","volume":"9","author":"Lu","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1021\/jm0507678","article-title":"Design and synthesis of dipeptidyl glutaminyl fluoromethyl ketones as potent severe acute respiratory syndrome coronovirus (SARS-CoV) inhibitors","volume":"49","author":"Zhang","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/S0968-0896(97)88649-X","article-title":"In vitro and ex vivo inhibition of hepatitis A virus 3C proteinase by a peptidyl monofluoromethyl ketone","volume":"5","author":"Morris","year":"1997","journal-title":"Bioorg. Med. Chem."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"8261","DOI":"10.1021\/acs.orglett.9b03024","article-title":"Direct and Chemoselective Synthesis of Tertiary Difluoroketones via Weinreb Amide Homologation with a CHF2-Carbene Equivalent","volume":"21","author":"Miele","year":"2019","journal-title":"Org. Lett."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"3520","DOI":"10.1002\/ejoc.201800532","article-title":"Methods for the Synthesis of \u03b1, \u03b1-Difluoroketones","volume":"2018","author":"Pattison","year":"2018","journal-title":"Eur. J. Org. Chem."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"3760","DOI":"10.1021\/bi00361a005","article-title":"Inhibition of serine proteases by peptidyl fluoromethyl ketones","volume":"25","author":"Imperiali","year":"1986","journal-title":"Biochemistry"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/0014-5793(75)80116-5","article-title":"The binding of specific and non-specific aldehyde substrate analogs to alpha-chymotrypsin","volume":"56","author":"Breaux","year":"1975","journal-title":"FEBS Lett."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"4767","DOI":"10.1021\/bi00747a032","article-title":"Active-site specific inhibitors of elastase","volume":"12","author":"Powers","year":"1973","journal-title":"Biochemistry"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Sham, H.L., Wideburg, N.E., Spanton, S.G., Kohlbrenner, W.E., Betebenner, D.A., Kempf, D.J., Norbeck, D.W., Plattner, J.J., and Erickson, J.W. (1991). Synthesis of (2s,5s,4r)-2,5-Diamino-3,3-Difluoro-1,6-Diphenylhydroxyhexane\u2014The Core Unit of a Potent Hiv Proteinase-Inhibitor. J. Chem. Soc. Chem. Commun., 110\u2013112.","DOI":"10.1039\/c39910000110"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/S0969-2126(02)00720-7","article-title":"Substrate shape determines specificity of recognition for HIV-1 protease: Analysis of crystal structures of six substrate complexes","volume":"10","author":"Nalivaika","year":"2002","journal-title":"Structure"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/337615a0","article-title":"Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1","volume":"337","author":"Navia","year":"1989","journal-title":"Nature"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1126\/science.2548279","article-title":"Conserved folding in retroviral proteases: Crystal structure of a synthetic HIV-1 protease","volume":"245","author":"Wlodawer","year":"1989","journal-title":"Science"},{"key":"ref_112","unstructured":"Haufe, G., and Leroux, F. (2018). Fluorine in Life Sciences: Pharmaceuticals, Medicinal Diagnostics, and Agrochemicals: Progress in Fluorine Science Series, Academic Press."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1124\/pr.110.002733","article-title":"Neutrophil Elastase, Proteinase 3, and Cathepsin G as Therapeutic Targets in Human Diseases","volume":"62","author":"Korkmaz","year":"2010","journal-title":"Pharm. Rev."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1111\/j.1749-6632.1991.tb17022.x","article-title":"Biochemistry and pharmacology of ICI 200,880, a synthetic peptide inhibitor of human neutrophil elastase","volume":"624","author":"Williams","year":"1991","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1093\/cvr\/28.7.947","article-title":"Neutrophil elastase inhibitor ICI 200,880 protects against attenuation of coronary flow reserve and myocardial dysfunction following temporary coronary artery occlusion in the dog","volume":"28","author":"Mehta","year":"1994","journal-title":"Cardiovasc. Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/0022-2836(88)90148-9","article-title":"X-ray diffraction analysis of the inhibition of porcine pancreatic elastase by a peptidyl trifluoromethylketone","volume":"201","author":"Takahashi","year":"1988","journal-title":"J. Mol. Biol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1021\/jm00035a004","article-title":"Design of orally active, non-peptidic inhibitors of human leukocyte elastase","volume":"37","author":"Brown","year":"1994","journal-title":"J. Med. Chem."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1021\/jm00001a015","article-title":"Nonpeptidic inhibitors of human leukocyte elastase. 5. Design, synthesis, and X-ray crystallography of a series of orally active 5-aminopyrimidin-6-one-containing trifluoromethyl ketones","volume":"38","author":"Veale","year":"1995","journal-title":"J. Med. Chem."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"3173","DOI":"10.1021\/jm970250z","article-title":"Orally active trifluoromethyl ketone inhibitors of human leukocyte elastase","volume":"40","author":"Veale","year":"1997","journal-title":"J. Med. Chem."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1021\/jm00163a063","article-title":"Synthesis of Peptidyl Fluoromethyl Ketones and Peptidyl Alpha-Keto Esters as Inhibitors of Porcine Pancreatic Elastase, Human Neutrophil Elastase, and Rat and Human Neutrophil Cathepsin-G","volume":"33","author":"Peet","year":"1990","journal-title":"J. Med. Chem."},{"key":"ref_121","unstructured":"Neil, D., Rawlings, N.D., and Salvesen, G. (2013). Handbook of Proteolytic Enzymes, Academ Press."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1006\/jmbi.1998.2462","article-title":"The 2.2 \u00c5 crystal structure of human chymase in complex with succinyl-Ala-Ala-Pro-Phe-chloromethylketone: Structural explanation for its dipeptidyl carboxypeptidase specificity","volume":"286","author":"Pereira","year":"1999","journal-title":"J. Mol. Biol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/S0968-0896(00)00244-3","article-title":"Non-Peptidic inhibitors of human chymase. Synthesis, structure\u2013activity relationships, and pharmacokinetic profiles of a series of 5-amino-6-oxo-1, 6-dihydropyrimidine-containing trifluoromethyl ketones","volume":"9","author":"Akahoshi","year":"2001","journal-title":"Bioorg. Med. Chem."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1002\/cmdc.201300433","article-title":"The effect of various zinc binding groups on inhibition of histone deacetylases 1\u201311","volume":"9","author":"Madsen","year":"2014","journal-title":"ChemMedChem"},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Milazzo, G., Mercatelli, D., Di Muzio, G., Triboli, L., De Rosa, P., Perini, G., and Giorgi, F.M. (2020). Histone Deacetylases (HDACs): Evolution, Specificity, Role in Transcriptional Complexes, and Pharmacological Actionability. Genes (Basel), 11.","DOI":"10.3390\/genes11050556"},{"key":"ref_126","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_127","doi-asserted-by":"crossref","first-page":"5343","DOI":"10.1016\/j.bmcl.2004.08.016","article-title":"Novel histone deacetylase inhibitors: Cyclic tetrapeptide with trifluoromethyl and pentafluoroethyl ketones","volume":"14","author":"Jose","year":"2004","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"5854","DOI":"10.1016\/j.bmcl.2011.07.100","article-title":"Synthesis of a new trifluoromethylketone analogue of l-arginine and contrasting inhibitory activity against human arginase I and histone deacetylase 8","volume":"21","author":"Ilies","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"4037","DOI":"10.1055\/s-0037-1609945","article-title":"Synthesis of Trifluoromethyl Ketone Containing Amino Acid Building Blocks for the Preparation of Peptide-Based Histone Deacetylase (HDAC) Inhibitors","volume":"50","author":"Olsen","year":"2018","journal-title":"Synth. Stuttg."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"e00045-17","DOI":"10.1128\/JVI.00045-17","article-title":"Dengue Virus NS2B\/NS3 Protease Inhibitors Exploiting the Prime Side","volume":"91","author":"Lin","year":"2017","journal-title":"J. Virol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.bmcl.2005.09.062","article-title":"Peptide inhibitors of Dengue virus NS3 protease. Part 1: Warhead","volume":"16","author":"Yin","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1021\/acs.biochem.7b01127","article-title":"Inhibitor Bound Dengue NS2B-NS3pro Reveals Multiple Dynamic Binding Modes","volume":"57","author":"Gibbs","year":"2018","journal-title":"Biochemistry"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"8601","DOI":"10.1016\/j.tet.2006.06.052","article-title":"Synthesis of glutamic acid and glutamine peptides possessing a trifluoromethyl ketone group as SARS-CoV 3CL protease inhibitors","volume":"62","author":"Sydnes","year":"2006","journal-title":"Tetrahedron"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"4652","DOI":"10.1016\/j.bmc.2008.02.040","article-title":"Design, synthesis, and evaluation of trifluoromethyl ketones as inhibitors of SARS-CoV 3CL protease","volume":"16","author":"Shao","year":"2008","journal-title":"Bioorg. Med. Chem."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1111\/j.1747-0285.2008.00679.x","article-title":"Development of Broad-Spectrum Halomethyl Ketone Inhibitors Against Coronavirus Main Protease 3CLpro","volume":"72","author":"Bacha","year":"2008","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"2722","DOI":"10.1016\/j.bmcl.2009.03.118","article-title":"New developments for the design, synthesis and biological evaluation of potent SARS-CoV 3CLpro inhibitors","volume":"19","author":"Regnier","year":"2009","journal-title":"Bioorg. Med. Chem. Lett."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/17\/4031\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:06:27Z","timestamp":1760177187000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/17\/4031"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,3]]},"references-count":136,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["molecules25174031"],"URL":"https:\/\/doi.org\/10.3390\/molecules25174031","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,3]]}}}