Carborane-Containing Cyclooxygenase Inhibitors

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Cyclooxygenase inhibitors are among the most used medications and are mainly applied for the treatment of pain and inflammation. These drugs inhibit the enzyme cyclooxygenase (COX), which is involved in the biosynthesis of important biological mediators. The enzyme exists in two isoforms (COX-1 and COX-2), which differ only slightly in their structures. However, whereas COX-1 mainly controls normal physiological processes, the activity of COX-2 is often associated with pathological functions (inflammation, tumourigenesis). Conventional NSAIDs (non-steroidal anti-inflammatory drugs), such as aspirin and ibuprofen, are generally inhibitors of both isozymes. However, the inhi-bition of COX-1 often results in strong side effects (bleeding, ulcers in the gastrointestinal tract). The COX-1-related side effects and the pathological relevance of COX-2 have thus motivated the development of COX-2-selective inhibitors (COXIBs), such as celecoxib and rofecoxib, which exhibit a good anti-inflammatory activity with reduced gastrointestinal toxicity. However, the long-term use of COXIBs also leads to side effects (cardiovascular toxicity). However, as COX-2 plays an important role in many relevant diseases (cancer, neurodegenerative diseases) the further development of COXIBs is of high interest.Within this project, the biological properties of COX inhibitors will be modified by directed introduction of carboranes. The latter are icosahedral boron cluster which are increasingly used as three-dimensional phenyl mimetics for the design of bioactive agents. Replacement of phenyl rings in established NSAIDs will be used to shift the inhibitor´s selectivity towards COX-2. As the binding pocket of COX-2 is slightly larger than that of COX-1, selectivity can be achieved by a size-exclusion effect for which the carboranes seem predestined. Additionally, the isomer-dependent activity profile, which has yet only been observed for indole-based COX inhibitors, will be further investigated by the introduction of different carborane isomers. The second focus of the project will be the incorporation of carboranes into COXIBs. The latter are often subject to pronounced oxidative metabolisation in the body, resulting in decreased potency and fast elimination of the inhibitors. Thus, the respective phenyl rings will be replaced by carboranes to reduce the metabolisation of COXIBs. Besides comprehensive studies on structure-activity relationships of carboran-containing COX inhibitors, this project will contribute to the general understanding of the pharmacological potential of carboranes and especially to the development of new synthetic strategies for the modification of these clusters.