Isonimesulide and its carborane analogues as isoform-selective COX inhibitors and antitumor agents

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used therapeutics against pain, fever and inflammation; additionally, antitumor properties have been reported. NSAIDs reduce the synthesis of prostaglandins (PG) by inhibiting the cyclooxygenase (COX) isoforms COX-1 and COX-2. As non-selective inhibition is associated with off-target effects, strategies to achieve selectivity for the clinically preferred isoform COX-2 are of high interest. The modification of NSAIDs using carborane clusters as phenyl mimetics has been reported to alter the selectivity profile through size exclusion. Inspired by these findings, we have prepared isonimesulide and its carborane derivatives. The biological screening showed that the carborane containing compounds exhibit a stronger antitumor potential compared to nimesulide and isonimesulide. Furthermore, the replacement of the phenyl ring of isonimesulide with a carborane moiety resulted in a shift of the COX activity from non-active to COX-active compounds.