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The new compounds were designed in such a way as to possess high affinity for Cu<jats:sup>II<\/jats:sup> ions, exploiting four pendant carboxylate moieties in the DTPA derivatives, as well as the cyclen\/cyclam macrocyles, and three pendant acetate moieties in the DOTA and TETA derivatives. The new derivatives showed modest inhibition of the cytosolic isoform CA\u2005I (<jats:italic>K<\/jats:italic><jats:sub>I<\/jats:sub> values in the range of 66\u20132130\u2005n<jats:sc>M<\/jats:sc>), were better CA\u2005II inhibitors (<jats:italic>K<\/jats:italic><jats:sub>I<\/jats:sub> values in the range of 21\u2013360\u2005n<jats:sc>M<\/jats:sc>), and excellent inhibitors of the tumor\u2010associated isoform CA\u2005IX (<jats:italic>K<\/jats:italic><jats:sub>I<\/jats:sub> values in the range of 4.1\u2013110\u2005n<jats:sc>M<\/jats:sc>), with selectivity ratios for the inhibition of the tumor (CA\u2005IX) over the cytosolic (CA\u2005II) isozyme in the range of 10.74\u201320.88 for the best derivatives. Copper complexes were more inhibitory than the corresponding ligand sulfonamides, and showed membrane impermeability, thus, having the possibility to specifically target the transmembrane CA\u2005IX that has an extracellular active site. Incorporation of radioactive copper isotopes in this type of CA inhibitor may lead to interesting diagnostic\/therapeutic applications for such compounds.<\/jats:p>","DOI":"10.1002\/cmdc.200800267","type":"journal-article","created":{"date-parts":[[2008,10,27]],"date-time":"2008-10-27T02:48:29Z","timestamp":1225075709000},"page":"1780-1788","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Carbonic Anhydrase Inhibitors: Design of Membrane\u2010Impermeant Copper(II) Complexes of DTPA\u2010, DOTA\u2010, and TETA\u2010Tailed Sulfonamides Targeting the Tumor\u2010Associated Transmembrane Isoform IX"],"prefix":"10.1002","volume":"3","author":[{"given":"Marouan","family":"Rami","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Cecchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Louis","family":"Montero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessio","family":"Innocenti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Vullo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Scozzafava","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Yves","family":"Winum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudiu\u2005T.","family":"Supuran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2008,11,6]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr050262p"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature06636"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2467"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1201\/9780203475300.ch1"},{"key":"e_1_2_6_5_2","unstructured":"\u00a0"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/med.10025"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2007.04.020"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2008.03.012"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R100045200"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2005.10.040"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi001416s"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja802214x"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/ange.200701189"},{"key":"e_1_2_6_13_3","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200701189"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.2174\/138161208783877875"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.2174\/138161208783877893"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/med.20112"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2006.09.002"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2004.10.043"},{"key":"e_1_2_6_19_2","unstructured":"\u00a0"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja061574s"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm0501073"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm701526d"},{"key":"e_1_2_6_23_2","unstructured":"\u00a0"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm800121c"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm060531j"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2007.04.018"},{"key":"e_1_2_6_27_2","unstructured":"\u00a0"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2007.11.025"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm0108202"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(00)00722-8"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.2174\/138161207779313768"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinorgbio.2004.06.009"},{"key":"e_1_2_6_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0969-8051(96)00130-8"},{"key":"e_1_2_6_34_2","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.107.048520"},{"key":"e_1_2_6_35_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.98.3.1206"},{"key":"e_1_2_6_36_2","first-page":"3608","volume":"5","author":"Lewis J. 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