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Herein we report the design and synthesis of three chemotypes of barbituric acids derived from the thalidomide structure: phthalimido\u2010, tetrafluorophthalimido\u2010, and tetrafluorobenzamidobarbituric acids. The latter were obtained by a new tandem reaction, including a ring opening and a decarboxylation of the fluorine\u2010activated phthalamic acid intermediates. Thirty compounds of the three chemotypes were evaluated for their anti\u2010angiogenic properties in an ex\u2005vivo assay by measuring the decrease in microvessel outgrowth in rat aortic ring explants. Tetrafluorination of the phthalimide moiety in tetrafluorophthalimidobarbituric acids was essential, as all of the nonfluorinated counterparts lost anti\u2010angiogenic activity. An opening of the five\u2010membered ring and the accompanying increased conformational freedom, in case of the corresponding tetrafluorobenzamidobarbituric acids, was well tolerated. Their activity was retained, although their molecular structures differ in torsional flexibility and possible hydrogen\u2010bond networking, as revealed by comparative X\u2010ray crystallographic analyses.<\/jats:p>","DOI":"10.1002\/cmdc.201600496","type":"journal-article","created":{"date-parts":[[2016,11,2]],"date-time":"2016-11-02T10:53:16Z","timestamp":1478083996000},"page":"2621-2629","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Synthesis and Antiangiogenic Properties of Tetrafluorophthalimido and Tetrafluorobenzamido Barbituric Acids"],"prefix":"10.1002","volume":"11","author":[{"given":"Agnieszka","family":"Ambro\u017cak","sequence":"first","affiliation":[{"name":"Pharmaceutical Institute, Pharmaceutical Chemistry I University of Bonn  An der Immenburg\u20054 53121 Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Steinebach","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute, Pharmaceutical Chemistry I University of Bonn  An der Immenburg\u20054 53121 Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin R.","family":"Gardner","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Program National Cancer Institute, NIH  Bethesda MD 20892 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaunna L.","family":"Beedie","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology Section National Cancer Institute, NIH  Bethesda MD 20892 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregor","family":"Schnakenburg","sequence":"additional","affiliation":[{"name":"Institute of Inorganic Chemistry University of Bonn  Gerhard-Domagk-Str.\u20051 53121 Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William D.","family":"Figg","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology Section National Cancer Institute, NIH  Bethesda MD 20892 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"G\u00fctschow","sequence":"additional","affiliation":[{"name":"Pharmaceutical Institute, Pharmaceutical Chemistry I University of Bonn  An der Immenburg\u20054 53121 Bonn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,11,2]]},"reference":[{"key":"e_1_2_6_1_1","unstructured":"\u00a0"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1323"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2115"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.2174\/157489207780832478"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.3390\/ph3041241"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep23432"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.173.3.699"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.9.4082"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1177319"},{"key":"e_1_2_6_10_1","unstructured":"\u00a0"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1244851"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4128"},{"key":"e_1_2_6_13_1","unstructured":"\u00a0"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm960284r"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm970109q"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(98)00171-1"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(03)00778-9"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0896(00)00323-0"},{"key":"e_1_2_6_19_1","unstructured":"\u00a0"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo00103a013"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja963718g"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm0304820"},{"key":"e_1_2_6_23_1","first-page":"3189","volume":"63","author":"Ng S. 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