Center for Integrated Protein Science Munich (CIPSM), Technische Universität München, Institute of Advanced Study (IAS), Department of Chemistry, Lichtenbergstr. 4, 85747 Garching, Germany.
Nat Prod Rep. 2012 Jun;29(6):659-82. doi: 10.1039/c2np20012k. Epub 2012 Apr 16.
The study of biologically active natural products has resulted in seminal contributions to our understanding of living systems. In the case of electrophilic natural products, the covalent nature of their interaction has largely facilitated the identification of their biological binding partners. In this review, we provide a comprehensive compilation of electrophilic natural products from all major chemical classes together with their biological targets. Covering Michael acceptor systems, ring-strained compounds and other electrophiles, such as esters or carbamates, we highlight representative and instructive examples for over 20 electrophilic moieties. The fruitful cooperation of natural product chemistry, medicinal chemistry and chemical biology has produced a collection of well-studied examples for how electrophilic natural products exert their biological functions that range from antibiotic to antitumor effects. Special emphasis is put on the elucidation of their respective biological targets via activity-based protein profiling, which together with the recent advancements in mass spectrometry has been crucial to the success of the field. The wealth of naturally occurring electrophilic moieties and their chemical complexity enables binding of a large variety of biological targets, such as enzymes of all classes, nonenzymatic proteins, DNA and other cellular compounds. With approximately 30,000 genes in the human genome but only 266 confirmed protein drug targets, the study of biologically active, electrophilic natural products has the potential to provide insights into fundamental biological processes and to greatly aid the discovery of new drug targets.
生物活性天然产物的研究对我们理解生命系统做出了重要贡献。就亲电天然产物而言，其相互作用的共价性质在很大程度上促进了它们生物结合伙伴的鉴定。在这篇综述中，我们全面汇编了来自所有主要化学类别的亲电天然产物及其生物靶标。涵盖迈克尔受体体系、环张力化合物和其他亲电试剂，如酯或氨基甲酸酯，我们突出了 20 多个亲电基团的代表性和有启发性的例子。天然产物化学、药物化学和化学生物学的富有成效的合作，产生了一系列经过充分研究的例子，说明亲电天然产物如何发挥其生物功能，范围从抗生素到抗肿瘤作用。特别强调通过基于活性的蛋白质谱分析阐明它们各自的生物靶标，这与质谱的最新进展一起，对该领域的成功至关重要。大量天然存在的亲电基团及其化学复杂性使它们能够与各种生物靶标结合，如所有类别的酶、非酶蛋白、DNA 和其他细胞化合物。人类基因组中约有 30000 个基因，但只有 266 个确认的蛋白药物靶标，因此，研究具有生物活性的亲电天然产物有可能深入了解基本的生物学过程，并极大地帮助发现新的药物靶标。
