P158-DEVELOPMENT OF FLEXIBLE ARYLSULFONAMIDES AS POTENTIAL MULTITARGET ANTICANCER AGENTS

Several compounds containing arylsulfonamide moiety have been reported in literature as potential anticancer agents and the most advanced molecule is the 4-ureidobenzenesulfonamide derivative SLC-011 (WBI-5111), which recently entered in clinical trials for the treatment of hypoxic tumors in the metastatic pancreatic ductal cancer.1 The anticancer effects of SLC-0111 are related to the inhibition of the tumor-associated human carbonic anhydrases (hCAs) isoforms IX and XII2 which catalyze the reversible hydration of carbon dioxide to bicarbonate and proton thus controlling the pH of tumor microenvironment (TME), which differs from normal tissue. It seems that hCA IX and hCA XII contribute thus maintaining a moderately alkaline cell pH and this acidification promotes local invasion and metastasis. Given the role of hCA IX and XII in cancer therapies, this class of CA inhibitors might offer therapeutic opportunities to obtain multitarget agents and overcome the drug resistance, which might occur in cancer cell. Looking for new hCA IX/XII inhibitors,we identified several 4-(4-aroylpiperazine-1-carbonyl)benzenesulfonamides, that exhibited Ki values in the low nanomolar range.3Encouraged by these promising results we designed a series of heteroaroylanalogs focused on modifying the 4-carbonylpiperazine core with a more flexible amino acetamide linker to evaluate interactions in the middle/top area of the hCA active pocket formed by lipophilic aminoacid side chains.