Carborane-Containing Cyclooxygenase Inhibitors

环氧合酶抑制剂是最常用的药物之一，主要用于治疗疼痛和炎症。这些药物抑制环氧合酶(COX)，该酶参与重要生物介体的生物合成。该酶以两种亚型(COX-1和COX-2)存在，结构上只有很小的差异。然而，虽然COX-1主要控制正常的生理过程，但COX-2的活性往往与病理功能(炎症、肿瘤发生)有关。传统的非类固醇抗炎药，如阿司匹林和布洛芬，通常都是这两种同工酶的抑制剂。然而，COX-1的抑制往往会导致强烈的副作用(出血、胃肠道溃疡)。COX-1相关的副作用和COX-2的病理相关性促使了COX-2选择性抑制剂(COXIB)的发展，如塞来昔布和罗非昔布，它们具有良好的抗炎活性，并减少了胃肠道毒性。然而，长期使用高昔洛韦也会导致副作用(心血管毒性)。然而，由于COX-2在许多相关疾病(癌症、神经退行性疾病)中扮演着重要的角色，因此进一步开发COXIB具有重要的意义。在这个项目中，COX抑制剂的生物学特性将通过定向引入碳硼烷来改变。后者是二十面体的硼簇合物，越来越多地被用作三维苯基模拟物来设计生物活性物质。已建立的非甾体抗炎药中苯环的替换将用于将抑制剂的S选择性转移到COX-2。由于COX-2的结合口袋略大于COX-1的结合口袋，因此可以通过尺寸排斥效应来实现选择性，而碳硼烷似乎注定要这样做。此外，同分异构体依赖的活性分布，目前仅在吲哚类环氧合酶抑制剂中观察到，将通过引入不同的碳硼烷异构体来进一步研究。该项目的第二个重点将是将碳硼烷纳入Coxib。后者通常会在体内发生明显的氧化代谢，导致抑制物效力降低，并迅速消除。因此，相应的苯环将被碳硼烷取代，以减少Coxibs的新陈代谢。除了全面研究含碳硼烷的环氧合酶抑制剂的构效关系外，该项目还将有助于全面了解碳硼烷的药理潜力，特别是开发用于修饰这些簇合物的新的合成策略。

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.