Novel coumarins and 2-thioxo-coumarins as inhibitors of the tumor-associated carbonic anhydrases IX and XII

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• 作者：Fabrizio Carta ; Alfonso Maresca ; Andrea Scozzafava ; Claudiu T. Supuran ; ^{claudiu.supuran@unifi.it}
• 关键词：Carbonic anhydrase ; Coumarin ; Transmembrane isoform ; Tumor-associated enzyme ; Selective inhibition
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 出版时间：1 April, 2012
• 年：2012
• 卷：20
• 期：7
• 页码：2266-2273
• 全文大小：671 K

文摘

A series of coumarins incorporating tert-butyl-dimethylsilyloxy- or allyoxy- moieties in positions 4-, 6 or 7 of the heterocyclic ring have been synthesized and then converted to the corresponding 2-thioxo-coumarins. Other derivatives incorporating hydroxyethyloxy-, tosylethoxy- and 2-fluroethyloxy- moieties in position 7 of the coumarin ring were synthesized together with derivatives of 4-methyl-7-amino coumarin incorporating acetamido, 3,5-dimethylphenylureido- and tert-butyloxycarbonylamido functionalities. All these compounds were assayed as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The human (h) cytosolic isoforms hCA I and II were weakly inhibited (hCA I) or not inhibited at all (hCA II) by these (thioxo)coumarins whereas the tumor-associated transmembrane isoforms hCA IX and XII were inhibited with efficiencies from the submicromolar to the low micromolar range by many of these derivatives. The structure-activity relationship for these classes of less investigated CA inhibitors are delineated, with the potential of using them as leads to obtain isoform-selective inhibitors with excellent affinity for CA IX and XII (validated antitumor targets) which do not significantly inhibit the cytosolic offtarget isoforms hCA I and II.