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Carborane-Containing Cyclooxygenase Inhibitors

含碳硼烷环加氧酶抑制剂

基本信息

批准号：
299283572
负责人：
Professorin Dr. Evamarie Hey-Hawkins
金额：
--
依托单位：
Marnett Research Laboratory
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/299283572?language=en
关键词：
Carborane Containing Cyclooxygenase Inhibitors

项目摘要

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.

环加氧酶抑制剂是最常用的药物之一，主要用于治疗疼痛和炎症。这些药物抑制环氧化酶（COX），这是参与重要的生物介质的生物合成。这种酶存在于两种异构体（COX-1和COX-2）中，它们的结构只有轻微的不同。然而，COX-1主要控制正常的生理过程，COX-2的活性通常与病理功能（炎症、肿瘤发生）有关。传统的非甾体抗炎药（非甾体抗炎药），如阿司匹林和布洛芬，通常是两种同工酶的抑制剂。然而，抑制COX-1通常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）的开发，如塞来昔布和罗非昔布，它们具有良好的抗炎活性和降低胃肠道毒性。然而，长期使用coxib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）中起着重要作用，因此coxib的进一步发展备受关注。在这个项目中，COX抑制剂的生物学特性将通过直接引入碳硼烷来修饰。后者是二十面体硼簇，越来越多地用作三维苯基模拟物来设计生物活性药物。在已建立的非甾体抗炎药中替换苯环将使抑制剂的选择性转向COX-2。由于COX-2的结合袋略大于COX-1，因此碳硼烷的选择性可以通过尺寸排斥效应来实现。此外，仅在吲哚类COX抑制剂中观察到的异构体依赖性活性谱，将通过引入不同的碳硼烷异构体进一步研究。该项目的第二个重点将是将碳硼烷纳入coxib。后者通常在体内受到明显的氧化代谢，导致效力降低和抑制剂的快速消除。因此，相应的苯环将被碳硼烷取代，以减少coxib的代谢。除了对含碳硼烷的COX抑制剂的构效关系进行全面的研究外，该项目还将有助于对碳硼烷的药理潜力的全面了解，特别是开发新的合成策略来修饰这些簇。