Carborane-based Analogues of Celecoxib and Flurbiprofen, their COX Inhibition Potential and COX Selectivity Index.

Abstract

The cylcooxygenase isoforms COX-1 and COX-2 are involved in the production of prostaglandins in physiological and pathological processes. The overexpression of COX-2 under inflammatory conditions as well as its role in cancer and neurodegenerative diseases necessitates the need to develop and improve non-steroidal anti-inflammatory drugs. These COX inhibitors are used to reduce the symptoms of inflammation, with aspirin, indomethacin or flurbiprofen being prominent examples. To reduce unwanted side effects connected with unselective inhibition, the development of novel COX-2 selective inhibitors is important. We herein describe the synthesis, characterization, and in vitro biological evaluation of eight flurbiprofen- and celecoxib-based carborane analogues. Carboranes as hydrophobic surrogates are suitable substituents that can contribute to a selectivity increase towards COX-2, due to size-exclusion. The inhibitory efficacy for COX-1 and COX-2 of the four ortho- and four nido-carborane derivatives has been tested. The nido compounds are much more potent than their closo-carborane analogues. Celecoxib-based compound 10 showed an IC50 value in the sub-µM range for COX-2 and in contrast to its ortho-carborane derivative a reversed selectivity preference for COX-2 instead of COX-1. While none of these carborane derivatives outperformed their organic analogues, the flurbiprofen-based nido-carborane derivatives 14a and 14b surpassed the known carborane-based flurbiprofen analogues.