{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:26:06Z","timestamp":1760239566733,"version":"build-2065373602"},"reference-count":39,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2020,11,28]],"date-time":"2020-11-28T00:00:00Z","timestamp":1606521600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Cambridge Research Biochemicals Ltd and European Development Agency Funding (ERDF - Intensive Industrial Innovation Programme)","award":["34R17P02148"],"award-info":[{"award-number":["34R17P02148"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Peptidyl mono-fluoromethyl ketones (FMKs) are a class of biologically active molecules that show potential as both protease inhibitors for the treatment of a range of diseases and as chemical probes for the interrogation of cellular processes. This review describes the current solid- and solution-phase routes employed for the synthesis of peptidyl mono-FMKs. In addition, it provides a brief overview of some of the key applications of FMKs in the fields of chemical biology and medicinal chemistry.<\/jats:p>","DOI":"10.3390\/molecules25235601","type":"journal-article","created":{"date-parts":[[2020,11,29]],"date-time":"2020-11-29T21:55:31Z","timestamp":1606686931000},"page":"5601","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Current Synthetic Routes to Peptidyl Mono-Fluoromethyl Ketones (FMKs) and Their Applications"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5229-3675","authenticated-orcid":false,"given":"Carissa M.","family":"Lloyd","sequence":"first","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Durham University, Durham DH1 3LE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neil","family":"Colgin","sequence":"additional","affiliation":[{"name":"Cambridge Research Biochemicals, 17-18 Belasis Court, Belasis Hall Technology Park, Billingham, Cleveland TS23 4AZ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven L.","family":"Cobb","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Durham University, Durham DH1 3LE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,28]]},"reference":[{"key":"ref_1","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. Pharmacol."},{"key":"ref_2","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_3","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1016\/j.bmcl.2019.03.046","article-title":"Peptide-based covalent inhibitors of MALT1 paracaspase","volume":"29","author":"Hatcher","year":"2019","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_4","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_5","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1021\/acsmedchemlett.6b00208","article-title":"Discovery of Fluoromethylketone-Based Peptidomimetics as Covalent ATG4B (Autophagin-1) Inhibitors","volume":"7","author":"Qiu","year":"2016","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_6","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_7","first-page":"220","article-title":"A sensitive near-infrared fluorescent probe for caspase- mediated apoptosis: Synthesis and application in cell imaging","volume":"5","author":"Yepeng","year":"2012","journal-title":"Drug Discov. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4576","DOI":"10.1039\/C6OB00529B","article-title":"Design, synthesis, and in vitro evaluation of a fluorescently labeled irreversible inhibitor of the catalytic subunit of cAMP-dependent protein kinase (PKAC\u03b1)","volume":"14","author":"Coover","year":"2016","journal-title":"Org. Biomol. Chem."},{"key":"ref_9","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_10","doi-asserted-by":"crossref","first-page":"4501","DOI":"10.1021\/cr000033x","article-title":"Serine Protease Mechanism and Specificity","volume":"102","author":"Hedstrom","year":"2002","journal-title":"Chem. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3576","DOI":"10.1248\/cpb.35.3576","article-title":"Synthesis of peptide chloromethyl ketones and examination of their inhibitory effects on human spleen fibrinolytic proteinase(SFP) and human leukocyte elastase(LE)","volume":"35","author":"Tsuda","year":"1987","journal-title":"Chem. Pharm. Bull."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1080\/00397911.2010.521290","article-title":"Efficient Synthesis of New Peptidyl Chloromethyl Ketones for the Application of Proteinase K Inhibitors","volume":"42","author":"Taylor","year":"2012","journal-title":"Synth. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3153","DOI":"10.1021\/jm051141k","article-title":"Synthesis of EF24\u2014Tripeptide Chloromethyl Ketone: A Novel Curcumin-Related Anticancer Drug Delivery System","volume":"49","author":"Sun","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/S0040-4039(00)83960-X","article-title":"A versatile synthesis of peptidyl fluoromethyl ketones","volume":"27","author":"Imperiali","year":"1986","journal-title":"Tetrahedron Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4279","DOI":"10.1016\/S0040-4039(00)74238-9","article-title":"A Method For The Stereoselective Synthesis of Peptidyl Trifluoromethyl Ketones","volume":"33","author":"Edwards","year":"1992","journal-title":"Tetrahedron Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1021\/jo9815204","article-title":"Solid-Phase Synthesis of Peptidyl Trifluoromethyl Ketones","volume":"64","author":"Poupart","year":"1999","journal-title":"J. Org. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Citarella, A., and Micale, N. (2020). Peptidyl Fluoromethyl Ketones and Their Applications in Medicinal Chemistry. Molecules, 25.","DOI":"10.3390\/molecules25174031"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1016\/S0040-4039(00)84319-1","article-title":"Synthesis of Fluorinated alpha-amino Ketones Part I: Alpha-Benzamidoalkyl mono- di- and Trifluoromethyl Ketones","volume":"27","author":"Kolb","year":"1986","journal-title":"Tetrahedron Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1002\/hlca.19700530520","article-title":"Synthese von Diazoketonen aus Acylaminosauren unter Verwendung von gemischten Anhydriden bzw. N, N\u2019 -Dicyclohexyl-carbodiimid","volume":"53","author":"Penke","year":"1970","journal-title":"Helv. Chim. Acta"},{"key":"ref_20","unstructured":"Becker, H. (1968). Organikum: Organisch-Chemisches Grundpraktikum, Deutscher Verl. d. Wissenschaften. [8th ed.]."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2480","DOI":"10.1021\/jo00406a041","article-title":"Oxidation of Long-chain and Related Alcohols to Carbonyls by Dimethyl Sulfoxide \u201cActivated\u201d by Oxalyl Chloride","volume":"43","author":"Mancuso","year":"1978","journal-title":"J. Org. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/jlac.199019900101","article-title":"Preparation of Fluorinated Ketone Analogues of Phenylalanine, Lysine, and p-(Guanidino)phenylalanine","volume":"1990","author":"Kolb","year":"1990","journal-title":"Liebigs Ann. Chem."},{"key":"ref_23","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":"Bioorganic Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1042\/bj2390633","article-title":"The synthesis of peptidylfluoromethanes and their properties inhibitors of serine proteinases and cysteine proteinases","volume":"239","author":"Rauber","year":"1986","journal-title":"Biochem. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/S0022-1139(00)85282-3","article-title":"Fluorine-containing reagents in organic synthesis","volume":"33","author":"Olah","year":"1986","journal-title":"J. Fluor. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4359","DOI":"10.1016\/j.tet.2018.07.010","article-title":"The Dakin-West reaction: Past, present and future","volume":"74","author":"Vechia","year":"2018","journal-title":"Tetrahedron"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9693","DOI":"10.1016\/0040-4039(94)88361-0","article-title":"Synthesis of Pl Aspartate-Based Peptide Acyloxymethyl and Fluoromethyl Ketones as Inhibitors of Interleukin-1 beta-Converting Enzyme","volume":"35","author":"Revesz","year":"1994","journal-title":"Tetrahedron Lett."},{"key":"ref_28","unstructured":"Palmer, J.T. (1991). Reagents and Methods for Stereospecific Fluoromethylation. (EP0442754A2), EU Patent."},{"key":"ref_29","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_30","unstructured":"Palmer, J.T. (1992). Magnesium Fluoromalonates. (US005101068A), US Patent."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4516","DOI":"10.1039\/c2ob25096a","article-title":"A general solid phase method for the synthesis of sequence independent peptidyl-fluoromethyl ketones","volume":"10","author":"Roiban","year":"2012","journal-title":"Org. Biomol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"La Manna, S., Di Natale, C., Florio, D., and Marasco, D. (2018). Peptides as Therapeutic Agents for Inflammatory-Related Diseases. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092714"},{"key":"ref_33","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-CH 2 -F, a peptidyl fluoromethyl ketone protease inhibitor","volume":"16","author":"Eichhold","year":"1997","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1007\/s00109-013-1074-5","article-title":"Pathologies at the nexus of blood coagulation and inflammation: Thrombin in hemostasis, cancer, and beyond","volume":"91","author":"Danckwardt","year":"2013","journal-title":"J. Mol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1111\/j.1538-7836.2006.01861.x","article-title":"Fibrin structure and wound healing","volume":"4","author":"Laurens","year":"2006","journal-title":"J. Thromb. Haemost."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/ncpgasthep0846","article-title":"Mechanisms of disease: Protease functions in intestinal mucosal pathobiology","volume":"4","author":"Antalis","year":"2007","journal-title":"Nat. Clin. Pract. Gastroenterol. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/978-3-540-79086-0_4","article-title":"Viral protease inhibitors","volume":"189","author":"Swanstrom","year":"2009","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.2174\/156802606777951064","article-title":"Peptidyl Fluoro-Ketones as Proteolytic Enzyme Inhibitors","volume":"6","author":"Sani","year":"2006","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1126\/science.1085658","article-title":"Coronavirus Main Proteinase (3CL pro) Structure: Basis for Design of Anti-SARS Drugs","volume":"300","author":"Anand","year":"2003","journal-title":"Science"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/23\/5601\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:38:56Z","timestamp":1760179136000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/25\/23\/5601"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,28]]},"references-count":39,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["molecules25235601"],"URL":"https:\/\/doi.org\/10.3390\/molecules25235601","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2020,11,28]]}}}