PDF(Pubmed)
Abstract：
The Wnt signaling pathway controls multiple events during embryonic development of multicellular animals and is carcinogenic when aberrantly activated in adults. Breast cancer and triple-negative breast cancer (TNBC) in particular depend upon Wnt pathway overactivation. Despite this importance, no Wnt pathway-targeting drugs are currently available, which necessitates novel approaches to search for therapeutically relevant compounds targeting this oncogenic pathway. Stilbene analogs represent an under-explored field of therapeutic natural products research. In the present work, a library of complex stilbene derivatives was obtained through biotransformation of a mixture of resveratrol and pterostilbene using the enzymatic secretome of Botrytis cinerea. To improve the chemodiversity, the reactions were performed using i-PrOH, n-BuOH, i-BuOH, EtOH, or MeOH as cosolvents. Using this strategy, a series of 73 unusual derivatives was generated distributed among 6 scaffolds; 55 derivatives represent novel compounds. The structure of each compound isolated was determined by nuclear magnetic resonance and high-resolution mass spectrometry. The inhibitory activity of the isolated compounds against the oncogenic Wnt pathway was comprehensively quantified and correlated with their capacity to inhibit the growth of the cancer cells, leading to insights into structure-activity relationships of the derivatives. Finally, we have dissected mechanistic details of the stilbene derivatives activity within the pathway.
摘要：
Wnt信号通路在多细胞动物胚胎发育过程中控制多个事件，并且在成人中异常激活时致癌。乳腺癌和三阴性乳腺癌(TNBC)特别依赖于Wnt通路过度激活。尽管有这种重要性,目前尚无Wnt通路靶向药物,这需要新的方法来寻找靶向该致癌途径的治疗相关化合物。己烯类似物代表了治疗性天然产物研究的未开发领域。在目前的工作中,使用灰葡萄孢的酶促分泌组，通过白藜芦醇和蝶芪的混合物的生物转化获得了复杂的二苯乙烯衍生物文库。为了改善化学多样性，使用i-PrOH进行反应，n-BuOH,I-BuOH,EtOH,或MeOH作为共溶剂。使用这个策略，产生了一系列分布在6个支架中的73个不寻常的衍生物;55个衍生物代表新化合物。通过核磁共振和高分辨率质谱法确定分离的每种化合物的结构。对分离的化合物对致癌Wnt途径的抑制活性进行了全面定量，并与它们抑制癌细胞生长的能力相关。从而深入了解衍生物的结构-活性关系。最后,我们已经解剖了该途径中二苯乙烯衍生物活性的机制细节。
