Sum Tze Han, Sum Tze Jing, Collins Súil, Galloway Warren R J D, Twigg David G, Hollfelder Florian, Spring David R
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
Org Biomol Chem. 2017 May 31;15(21):4554-4570. doi: 10.1039/c7ob00804j.
Biflavonoids are associated with a variety of biologically useful properties. However, synthetic biflavonoids are poorly explored within drug discovery. There is considerable structural diversity possible within this compound class and large regions of potentially biologically relevant biflavonoid chemical space remain untapped or underexplored. Herein, we report the development of a modular and divergent strategy towards biflavonoid derivatives which enabled the step-economical preparation of a structurally diverse collection of novel unnatural biflavonoids. Preliminary studies established that the strategy could also be successfully extended to the preparation of very rare triflavonoids, which are also expected to be useful tools for biological intervention. Prompted by previous inhibitory studies with flavonoid libraries, amyloid anti-aggregation screening was performed, which led to the identification of several structurally novel inhibitors of the aggregation of the amyloid β peptide (Aβ). Aggregated Aβ is a pathological hallmark of Alzheimer's disease and the use of small molecules to inhibit the aggregation process has been identified as a potentially valuable therapeutic strategy for disease treatment. Methylated biaurones were associated with highest levels of potency (the most active compound had an IC value of 16 μM), establishing this scaffold as a starting point for inhibitor development.
双黄酮类化合物具有多种生物学活性。然而，在药物研发中，合成双黄酮类化合物的研究较少。这类化合物具有相当大的结构多样性，且潜在的具有生物学相关性的双黄酮类化合物化学空间的大片区域仍未被开发或研究不足。在此，我们报告了一种针对双黄酮类衍生物的模块化和发散性策略的开发，该策略能够以步骤经济的方式制备一系列结构多样的新型非天然双黄酮类化合物。初步研究表明，该策略还可成功扩展至制备非常罕见的三黄酮类化合物，预计这些化合物也是生物干预的有用工具。受先前黄酮类化合物库抑制研究的启发，进行了淀粉样蛋白抗聚集筛选，从而鉴定出几种结构新颖的淀粉样β肽（Aβ）聚集抑制剂。聚集的Aβ是阿尔茨海默病的病理标志，利用小分子抑制聚集过程已被确定为一种潜在有价值的疾病治疗策略。甲基化双金合欢素具有最高的活性水平（最具活性的化合物的IC值为16 μM），确立了该支架作为抑制剂开发的起点。
