7,8-Disubstituted- but not 6,7-disubstituted coumarins selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic ones I and II in the low nanomolar/subnanomolar range

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• 作者：Alfonso Maresca ; Andrea Scozzafava ; Claudiu T. Supuran
• 关键词：Carbonic anhydrase ; Tumor associated isoforms ; Coumarin ; Isoform-selective inhibitor ; Fries rearrangement
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2010
• 出版时间：15 December 2010
• 年：2010
• 卷：20
• 期：24
• 页码：7255-7258
• 全文大小：366 K

文摘

Two series of disubstituted coumarins incorporating ether and acetyl/propionyl moieties in positions 6,7- and 7,8- of the heterocyclic ring were synthesized investigated for the inhibition of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). All these coumarins were very weak or ineffective as inhibitors of the housekeeping, offtarget isoforms CA I and II. The 6,7-disubstituted series showed ineffective inhibition also for the transmembrane tumor-associated isoforms CA IX and XII, whereas the corresponding isomeric 7,8-disubstituted coumarins showed nanomolar/subnanomolar inhibition of CA IX/XII. The nature and position of the groups substituting the coumarin ring in the 7,8-positions greatly influenced CA inhibitory properties, with C1–C4 alkyl ethers being the most effective inhibitors.