D'Ascenzio Melissa, Guglielmi Paolo, Carradori Simone, Secci Daniela, Florio Rosalba, Mollica Adriano, Ceruso Mariangela, Akdemir Atilla, Sobolev Anatoly P, Supuran Claudiu T
a School of Life Sciences , University of Dundee , Dundee , Scotland , UK.
b Dipartimento di Chimica e Tecnologie del Farmaco , Sapienza University of Rome , Rome , Italy.
J Enzyme Inhib Med Chem. 2017 Dec;32(1):51-59. doi: 10.1080/14756366.2016.1235040. Epub 2016 Oct 26.
A large number of novel secondary sulfonamides based on the open saccharin scaffold were synthesized and evaluated as selective inhibitors of four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). They were obtained by reductive ring opening of the newly synthesized N-alkylated saccharin derivatives and were shown to be inactive against the two cytosolic off-target hCA I and II (Ks > 10 µM). Interestingly, these compounds inhibited hCA IX in the low nanomolar range with Ks ranging between 20 and 298 nM and were extremely potent inhibitors of hCA XII isoenzyme (Ks ranging between 4.3 and 432 nM). Since hCA IX and XII are the cancer-related isoforms recently validated as drug targets, these results represent an important goal in the development of new anticancer candidates. Finally, a computational approach has been performed to better correlate the biological data to the binding mode of these inhibitors.
基于开放的糖精骨架合成了大量新型仲磺酰胺，并将其作为人碳酸酐酶四种不同同工型（hCA I、II、IX和XII，EC 4.2.1.1）的选择性抑制剂进行了评估。它们是通过新合成的N-烷基化糖精衍生物的还原开环得到的，并且对两种胞质脱靶hCA I和II无活性（Ks＞10 μM）。有趣的是，这些化合物在低纳摩尔范围内抑制hCA IX，Ks在20至298 nM之间，并且是hCA XII同工酶的极强抑制剂（Ks在4.3至432 nM之间）。由于hCA IX和XII是最近被确认为药物靶点的癌症相关同工型，这些结果代表了开发新的抗癌候选药物的一个重要目标。最后，进行了一种计算方法，以更好地将生物学数据与这些抑制剂的结合模式相关联。
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