Pereira Rui, Ribeiro Daniela, Silva Vera L M, Fernandes Eduarda
LAQV-REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal.
LAQV-REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313, Porto, Portugal; Faculty of Agrarian Sciences and Environment, University of the Azores, 9700-042, Angra do Heroísmo, Açores, Portugal.
Eur J Med Chem. 2025 Jul 5;291:117669. doi: 10.1016/j.ejmech.2025.117669. Epub 2025 Apr 21.
The continuous search for novel and safer drug candidates remains imperative to address ever-evolving health challenges. Nature has long served as a source of inspiration for drug discovery, particularly through bioactive compounds such as flavonoids. Among them, flavonoid dimers, first identified nearly a century ago, have shown promising biological activities that often surpass those of their monomeric counterparts while showing minimal side effects. Nonetheless, these compounds suffer from limitations such as low bioavailability and moderate potency. To mitigate these challenges, researchers have developed synthetic strategies to obtain them, expand their structural diversity, and optimize their properties. The design of completely unnatural flavonoid dimers offers new opportunities for drug discovery. In contrast to previous review articles, this review explores the potential of synthetic flavonoid dimers. It provides an overview of the main synthetic methodologies to obtain them, illustrating how the evolution of the synthetic protocols has also driven the development of novel unnatural compounds. It then focuses on highlighting the bioactivities reported for synthetic flavonoid dimers, in particular anti-inflammatory, anticancer, and antimicrobial. Finally, this review highlights a specific subclass of synthetic flavonoid dimers that emerged in the last decade but remains underexplored, proposing its classification as fused bis-flavonoids. The aim is to drawattention to their potential importance by giving them a unique nomenclature from other subclasses and highlighting their biological activities.
持续寻找新型且更安全的候选药物对于应对不断演变的健康挑战而言仍然至关重要。长期以来，自然一直是药物发现的灵感来源，尤其是通过黄酮类等生物活性化合物。其中，近一个世纪前首次被发现的黄酮类二聚体已显示出有前景的生物活性，其活性往往超过单体同类物，同时副作用极小。尽管如此，这些化合物存在生物利用度低和效力中等之类的局限性。为了应对这些挑战，研究人员已开发出合成策略来获取它们、扩大其结构多样性并优化其性质。完全非天然黄酮类二聚体的设计为药物发现提供了新机遇。与之前的综述文章不同，本综述探讨了合成黄酮类二聚体的潜力。它概述了获取它们的主要合成方法，阐明了合成方案的演变如何也推动了新型非天然化合物的开发。然后它着重强调了合成黄酮类二聚体所报道的生物活性，特别是抗炎、抗癌和抗菌活性。最后，本综述突出了在过去十年中出现但仍未得到充分探索的合成黄酮类二聚体的一个特定子类，提议将其归类为稠合双黄酮类。目的是通过赋予它们与其他子类不同的独特命名并突出其生物活性来引起对其潜在重要性的关注。
