Carborane Analogues of Fenoprofen Exhibit Improved Antitumor Activity

The carborane analogues of fenoprofen bearing a nitrile (3 c and 4 c) or carboxylic acid group (3 d and 4 d) show superior antitumor activity compared to fenoprofen. Their antitumor action is realized through inhibition of proliferation and caspase-independent apoptosis. Furthermore, they were equally efficient in COX-2 non-expressing cells, indicating the existence of potential off-targets inside the cells.

Abstract

Fenoprofen is a widely used nonsteroidal anti-inflammatory drug (NSAID) against rheumatoid arthritis, degenerative joint disease, ankylosing spondylitis and gout. Like other NSAIDs, fenoprofen inhibits the synthesis of prostaglandins by blocking both cyclooxygenase (COX) isoforms, COX-1 the “house-keeping” enzyme and COX-2 the induced isoform from pathological stimuli. Unselective inhibition of both COX isoforms results in many side effects, but off-target effects have also been reported. The steric modifications of the drugs could afford the desired COX-2 selectivity. Furthermore, NSAIDs have shown promising cytotoxic properties. The structural modification of fenoprofen using bulky dicarba-closo-dodecaborane(12) (carborane) clusters and the biological evaluation of the carborane analogues for COX inhibition and antitumor potential showed that the carborane analogues exhibit stronger antitumor potential compared to their respective aryl-based compounds.

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