{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T15:34:04Z","timestamp":1790868844609,"version":"4.1.0"},"reference-count":110,"publisher":"Wiley","issue":"43","license":[{"start":{"date-parts":[[2021,8,7]],"date-time":"2021-08-07T00:00:00Z","timestamp":1628294400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"published-print":{"date-parts":[[2021,10,18]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The insertion of fluorine atoms and\/or fluoroalkyl groups can lead to many beneficial effects in biologically active molecules, such as enhanced metabolic stability, bioavailability, lipophilicity, and membrane permeability, as well as a strengthening of protein\u2013ligand binding interactions. However, this \u201cmagic effect\u201d of fluorine atom(s) insertion can often be meaningless. Taking advantage of the wide range of data coming from the quest for carbonic anhydrase (CA) fluorinated inhibitors, this Minireview attempts to give \u201cgeneral guidelines\u201d on how to wisely insert fluorine atom(s) within an inhibitor moiety to precisely enhance or disrupt ligand\u2013protein interactions, depending on the target location of the fluorine substitution in the ligand. Multiple approaches such as ITC, kinetic and inhibition studies, X\u2010ray crystallography, and NMR spectroscopy are useful in dissecting single binding contributions to the overall observed effect. The exploitation of innovative directions made in the field of protein and ligand\u2010based fluorine NMR screening is also discussed to avoid misconduct and finely tune the exploitation of selective fluorine atom insertion in the future.<\/jats:p>","DOI":"10.1002\/anie.202103211","type":"journal-article","created":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T12:07:42Z","timestamp":1621858062000},"page":"23068-23082","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Modulating the Efficacy of Carbonic Anhydrase Inhibitors through Fluorine Substitution"],"prefix":"10.1002","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4258-0678","authenticated-orcid":false,"given":"Emanuela","family":"Berrino","sequence":"first","affiliation":[{"name":"University of Florence NEUROFARBA Dept. Sezione di Scienze Farmaceutiche e Nutraceutiche  Via Ugo Schiff 6 50019 Sesto Fiorentino Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3248-5781","authenticated-orcid":false,"given":"Bastien","family":"Michelet","sequence":"additional","affiliation":[{"name":"Superacid Group in \u201cOrganic Synthesis\u201d Team Universit\u00e9 de Poitiers CNRS UMR 7285 IC2MP  B\u00e2t. B28, 4 rue Michel Brunet, TSA 51106 86073 Poitiers Cedex 09 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agn\u00e8s","family":"Martin\u2010Mingot","sequence":"additional","affiliation":[{"name":"Superacid Group in \u201cOrganic Synthesis\u201d Team Universit\u00e9 de Poitiers CNRS UMR 7285 IC2MP  B\u00e2t. B28, 4 rue Michel Brunet, TSA 51106 86073 Poitiers Cedex 09 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1141-6146","authenticated-orcid":false,"given":"Fabrizio","family":"Carta","sequence":"additional","affiliation":[{"name":"University of Florence NEUROFARBA Dept. Sezione di Scienze Farmaceutiche e Nutraceutiche  Via Ugo Schiff 6 50019 Sesto Fiorentino Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-0323","authenticated-orcid":false,"given":"Claudiu T.","family":"Supuran","sequence":"additional","affiliation":[{"name":"University of Florence NEUROFARBA Dept. Sezione di Scienze Farmaceutiche e Nutraceutiche  Via Ugo Schiff 6 50019 Sesto Fiorentino Florence Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6246-5829","authenticated-orcid":false,"given":"S\u00e9bastien","family":"Thibaudeau","sequence":"additional","affiliation":[{"name":"Superacid Group in \u201cOrganic Synthesis\u201d Team Universit\u00e9 de Poitiers CNRS UMR 7285 IC2MP  B\u00e2t. B28, 4 rue Michel Brunet, TSA 51106 86073 Poitiers Cedex 09 France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,7]]},"reference":[{"key":"e_1_2_7_1_1","volume-title":"Chimie Bioorganique et M\u00e9dicinale Du Fluor","author":"B\u00e9gu\u00e9 D.","year":"2005"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr4002879"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.5b00392"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1039\/B711844A"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo400301u"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/9781444312096"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.200700059"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b00258"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201102027"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201102027"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201403071"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201403071"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201509460"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201509460"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201202059"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201202059"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.2232"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jfluchem.2016.06.016"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm100112j"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201702950"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201702950"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2467"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20160115"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.26.15184"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41396-019-0426-8"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr200176r"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbapap.2009.07.025"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/9419521"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543776.2018.1523897"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1039\/C4CC07320G"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1039\/C8CC08562E"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1039\/c2cc16395k"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.6b00462"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.3109\/14756366.2015.1072177"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1039\/c2cc34275h"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.4155\/fmc.14.68"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm1003667"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules21121649"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1080\/17460441.2019.1651289"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr050262p"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1517\/13543776.10.5.575"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3554"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b00208"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm9900523"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm001051"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)74305-1"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(94)00798-5"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2007.12.022"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1107\/S1744309106020446"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/asia.200600360"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.200300910"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.200900386"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom10040509"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja4075776"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1114107108"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201301813"},{"key":"e_1_2_7_51_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201301813"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b01643"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.9b00895"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm021123s"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.5b00151"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407607101"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1021\/cb400526n"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4486"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2011.05.006"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm00013a005"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja2045293"},{"key":"e_1_2_7_62_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.analchem.0c00163"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2012.05.037"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.1039\/c3cc40858b"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.3762\/bjoc.6.38"},{"key":"e_1_2_7_66_1","doi-asserted-by":"publisher","DOI":"10.1021\/ar00035a005"},{"key":"e_1_2_7_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/0009-2614(81)85228-1"},{"key":"e_1_2_7_68_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jpcb.7b02259"},{"key":"e_1_2_7_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/1871021a0"},{"key":"e_1_2_7_70_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.199216551"},{"key":"e_1_2_7_70_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.19921041230"},{"key":"e_1_2_7_71_1","doi-asserted-by":"publisher","DOI":"10.1039\/b822963p"},{"key":"e_1_2_7_72_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.200300801"},{"key":"e_1_2_7_73_1","doi-asserted-by":"publisher","DOI":"10.1039\/C8CE01187G"},{"key":"e_1_2_7_74_1","doi-asserted-by":"publisher","DOI":"10.1021\/jp067313m"},{"key":"e_1_2_7_75_1","doi-asserted-by":"publisher","DOI":"10.1021\/ol006193c"},{"key":"e_1_2_7_76_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja002627n"},{"key":"e_1_2_7_77_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja042666p"},{"key":"e_1_2_7_78_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm000296j"},{"key":"e_1_2_7_79_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm031116j"},{"key":"e_1_2_7_80_1","doi-asserted-by":"publisher","DOI":"10.1080\/1475636031000119337"},{"key":"e_1_2_7_81_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2004.09.062"},{"key":"e_1_2_7_82_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2004.01.095"},{"key":"e_1_2_7_83_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2005.06.054"},{"key":"e_1_2_7_84_1","doi-asserted-by":"publisher","DOI":"10.1080\/14756360400028101"},{"key":"e_1_2_7_85_1","doi-asserted-by":"publisher","DOI":"10.1039\/c0cc02707c"},{"key":"e_1_2_7_86_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2017.03.026"},{"key":"e_1_2_7_87_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm101541x"},{"key":"e_1_2_7_88_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-019-09799-0"},{"key":"e_1_2_7_89_1","doi-asserted-by":"publisher","DOI":"10.1097\/COC.0000000000000691"},{"key":"e_1_2_7_90_1","doi-asserted-by":"publisher","DOI":"10.1002\/cphc.201701253"},{"key":"e_1_2_7_91_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd748"},{"key":"e_1_2_7_92_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.8b01210"},{"key":"e_1_2_7_93_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b01447"},{"key":"e_1_2_7_94_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9CS00099B"},{"key":"e_1_2_7_95_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201000412"},{"key":"e_1_2_7_96_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(86)80216-2"},{"key":"e_1_2_7_97_1","doi-asserted-by":"publisher","DOI":"10.1039\/c0sc00513d"},{"key":"e_1_2_7_98_1","doi-asserted-by":"publisher","DOI":"10.1039\/c3cc39205h"},{"key":"e_1_2_7_99_1","doi-asserted-by":"publisher","DOI":"10.1039\/C8SC05683H"},{"key":"e_1_2_7_100_1","first-page":"349","volume-title":"Mod. Synth. Process. React. Fluorinated Compd. Prog. Fluor. Sci.","author":"Thibaudeau S.","year":"2017"},{"key":"e_1_2_7_101_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2019.11.004"},{"key":"e_1_2_7_102_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.9b01901"},{"key":"e_1_2_7_103_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.joc.0c01830"}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.202103211","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/anie.202103211","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.202103211","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,20]],"date-time":"2023-08-20T17:19:44Z","timestamp":1692551984000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.202103211"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,7]]},"references-count":110,"journal-issue":{"issue":"43","published-print":{"date-parts":[[2021,10,18]]}},"alternative-id":["10.1002\/anie.202103211"],"URL":"https:\/\/doi.org\/10.1002\/anie.202103211","archive":["Portico"],"relation":{},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,7]]},"assertion":[{"value":"2021-03-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-08-07","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}