A series of adamantyl carboxamide derivatives containing sulfonate or sulfonamide moiety were designed as multitargeted inhibitors of ectonucleotide pyrophosphatases/phosphodiesterases (NPPs) and carbonic anhydrases (CAs). The target compounds were investigated for their antiproliferative activity against NCI-60 cancer cell lines panel. Three main series composed of 3- and 4-aminophenol, 4-aminoaniline, and 5-hydroxyindole scaffolds were designed based on a lead compound (A). Compounds 1e (benzenesulfonyl) and 1i (4-fluorobenzenesulfonyl) of 4-aminophenol backbone exhibited the most promising antiproliferative activity. Both compounds exhibited a broad-spectrum and potent inhibition against all the nine tested cancer subtypes. Both compounds showed nanomolar IC₅₀ values over several cancer cell lines that belong to leukemia and colon cancer such as K-562, RPMI-8226, SR, COLO 205, HCT-116, HCT-15, HT29, KM12, and SW-620 cell lines. Compounds 1e and 1i induced apoptosis in K-562 leukemia cells in a dose-dependent manner. Compound 1i showed the highest cytotoxic activity with IC₅₀ value of 200 nM against HT29 cell line. In addition, compounds 1e and 1i were tested against normal breast cells (HME1) and normal skin fibroblast cells (F180) and the results revealed that the compounds are safe toward normal cells compared to cancers cells. Enzymatic assays against NPP1-3 and carbonic anhydrases II, IX, and XII were performed to investigate the possible molecular target(s) of compounds 1e and 1i. Furthermore, a molecular docking study was performed to predict the binding modes of compounds 1e and 1i in the active site of the most sensitive enzymes subtypes.

一系列含有磺酸盐或磺酰胺部分的金刚烷基甲酰胺衍生物被设计为外核苷酸焦磷酸酶/磷酸二酯酶（NPP）和碳酸酐酶（CA）的多靶点抑制剂。研究了目标化合物对 NCI-60 癌细胞系的抗增殖活性。基于先导化合物（A）设计了由3-和4-氨基苯酚、4-氨基苯胺和5-羟基吲哚支架组成的三个主要系列。4-氨基苯酚骨架的化合物1e（苯磺酰基）和1i（4-氟苯磺酰基）表现出最有希望的抗增殖活性。这两种化合物对所有九种测试的癌症亚型都表现出广谱和有效的抑制作用。两种化合物对属于白血病和结肠癌的几种癌细胞系（例如 K-562、RPMI-8226、SR、COLO 205、HCT-116、HCT-15、HT29、KM12 和 SW-620）均显示出纳摩尔 IC 50_值细胞系。化合物1e和1i以剂量依赖性方式诱导K-562白血病细胞凋亡。化合物1i对HT29细胞系表现出最高的细胞毒活性，IC ₅₀值为200 nM。此外，化合物1e和1i针对正常乳腺细胞 (HME1) 和正常皮肤成纤维细胞 (F180) 进行了测试，结果表明，与癌细胞相比，这些化合物对正常细胞是安全的。对 NPP1-3 和碳酸酐酶 II、IX 和 XII 进行酶测定，以研究化合物1e和1i的可能分子靶标。此外，还进行了分子对接研究来预测化合物1e和1i在最敏感酶亚型活性位点的结合模式。