期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 77, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2022.117111
关键词
1; 2; 3-triazole; Benzenesulfonamide; Carbonic anhydrase; In silico study; Isoindoline
A series of novel inhibitors of human alpha-carbonic anhydrase (hCA) were designed using a tail approach. These inhibitors showed remarkable selectivity for tumor isoforms hCA IX and XII. Adding a lipophilic naphthyl tail to the analogues increased the inhibitory and selective activities against hCA XII. The compounds also exhibited inhibitory effects against a human lung adenocarcinoma cancer cell line.
A novel series of 1,2,3-triazole benzenesulfonamide substituted 1,3-dioxoisoindolin-5-carboxylate (7a-l) in-hibitors of human alpha-carbonic anhydrase (hCA) was designed using a tail approach. The design method relies on the hybridization of a benzenesulfonamide moiety with a tail of 1,3-dioxoisoindoline-5-carboxylate and a zinc- binding group on a 1,2,3-triazole scaffold. Among the synthesized analogues, 2-iodophenyl (7f, KI of 105.00 nM and SI of 2.98) and 2-naphthyl (7h, KI of 32.11 nM and SI of 3.48) analogues (over off-target hCA I) and phenyl (7a, KI of 50.13 nM and SI of 2.74) and 2,6-dimethylphenyl (7d, KI of 50.60 nM and SI of 3.35) analogues (over off-target hCA II) exhibited a remarkable selectivity for tumor isoforms hCA IX and XII, respectively. Meanwhile, analogue 7a displayed a potent inhibitory effect against the tumor-associated isoform hCA IX (KI of 18.29 nM) compared with the reference drug acetazolamide (AAZ, KI of 437.20 nM), and analogue 7h showed higher potency (KI of 9.22 nM) than AAZ (KI of 338.90 nM) against another tumor-associated isoform hCA XII. However, adding the lipophilic large naphthyl tail to the 1,3-dioxoisoindolin-5-carboxylate analogues increased both the hCA inhibitory and selective activities against the target isoform, hCA XII. Additionally, these analogues (7a-l) showed IC50 values against the human lung (A549) adenocarcinoma cancer cell line ranging from 129.71 to 352.26 mu M. The results of the molecular docking study suggested that the sulfonamide moiety fits snugly into the hCAs active sites and interacts with the Zn2+ion. At the same time, the tail extension engages in various hy-drophilic and hydrophobic interactions with the nearby amino acids, which affects the potency and selectivity of the hybrids
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