SLC-0111, an ureido substituted benzenesulfonamide, is a selective carbonic anhydrase (CA, EC 4.2.1.1) IX inhibitor that is currently in Phase I/II clinical trials for the treatment of advanced hypoxic tumors complicated with metastases. Herein we report the synthesis of two series of 3/4-(3-aryl-3-oxopropenyl) aminobenzenesulfonamides 5a–i and 6a–j as SLC-0111 enaminone congeners. The prepared enaminones were in vitro investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, II, IV and IX, using a stopped-flow CO₂ hydrase assay. All these isoforms were inhibited by the enaminones reported here in variable degrees. The target tumor-associated isoform hCA IX was undeniably the most affected one (K_Is: 0.21–7.1 nM), with 6- to 21-fold enhanced activity than SLC-0111 (K_I = 45 nM). All the prepared enaminones displayed interesting selectivity towards hCA IX over hCA I (SI: 32 – >35714), hCA II (SI: 2 – 1689) and hCA IV (SI: 11 – >45454). Of particular interest, bioisosteric replacement of phenyl tail with the bulkier 2-naphthyl tail, sulfonamide 6h, achieved the higher II/IX selectivity herein reported with SI of 1689.

SLC-0111是脲基取代的苯磺酰胺，是一种选择性碳酸酐酶（CA，EC 4.2.1.1）IX抑制剂，目前正在I / II期临床试验中，用于治疗晚期低氧肿瘤并发转移。在这里，我们报告了两个系列的3 / 4-（3-芳基-3-氧代丙烯基）氨基苯磺酰胺5a–i和6a–j的合成，它们是SLC-0111烯胺酮同类物。使用停止流动的CO ₂在体外研究了制备的烯胺酮作为金属酶碳酸酐酶（CA，EC 4.2.1.1）异构体hCA I，II，IV和IX的抑制剂水合酶测定。所有这些同工型均受到本文报道的烯胺酮的不同程度抑制。不可否认，与靶标肿瘤相关的同工型hCA IX是受影响最严重的同种型（K _I s：0.21–7.1 nM），其活性比SLC-0111（K _I  = 45 nM）提高了6到21倍。所有制备的烯胺酮对hCA IX的选择性都比hCA I（SI：32 –> 35714），hCA II（SI：2 – 1689）和hCA IV（SI：11 –> 45454）高。特别令人感兴趣的是，用更大的2-萘基尾巴磺酰胺6h进行生物等位取代苯基尾巴时，本文报道的更高的II / IX选择性（SI为1689）。