Design, Synthesis, and Biological Activity of Conformationally Restricted Analogues of Silibinin
Design, Synthesis, and Biological Activity of Conformationally Restricted Analogues of Silibinin
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DOI：
10.1021/acsomega.0c02936
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发表时间：
2020-08
期刊：
影响因子：
4.1
通讯作者：
Mirei Mizuno;K. Mori;Keisuke Tsuchiya;T. Takaki;Takashi Misawa;Yosuke Demizu;M. Shibanuma;K. Fukuhara
中科院分区：
文献类型：
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作者：
Mirei Mizuno;K. Mori;Keisuke Tsuchiya;T. Takaki;Takashi Misawa;Yosuke Demizu;M. Shibanuma;K. Fukuhara
水飞蓟素(Sib)是水飞蓟提取物的主要成分之一，因其具有多种生物活性而备受关注，其中包括抗氧化活性以及对糖尿病和阿尔茨海默病(AD)的潜在作用。在先前的研究中，我们通过限制(+)-儿茶素和(−)-表儿茶素的几何构型来合成儿茶素类似物。受限制的类似物显示出增强的生物活性，两者之间唯一的主要区别是它们的三维结构。(+)-儿茶素中的约束几何构型导致了高度的平面性(PCAT)，而(−)-表儿茶素未能保持平面性(PEC)。SIB的三维结构可能与其抑制淀粉样β蛋白(Aβ)聚集的能力有关。因此，我们将PCAT和PEC引入到SIB中，以展示受限的分子几何结构和三维结构中的差异如何增强这种活性。在Sib中引入PCAT后，Aβ聚集率、α-葡萄糖苷酶活性和细胞生长均受到有效抑制，这表明不仅柔韧性降低，而且高度的平面性可能会提高其生物学活性。SIBC有望成为治疗多种疾病的一种有前途的先导化合物。
Silibinin (Sib), one of the main components of milk thistle extract, has attracted considerable attention because of its various biological activities, which include antioxidant activity and potential effects in diabetes and Alzheimer’s disease (AD). In a previous study, we synthesized catechin analogues by constraining the geometries of (+)-catechin and (−)-epicatechin. The constrained analogues exhibited enhanced bioactivities, with the only major difference between the two being their three-dimensional structures. The constrained geometry in (+)-catechin resulted in a high degree of planarity (PCat), while (−)-epicatechin failed to maintain planarity (PEC). The three-dimensional structure of Sib may be related to its ability to inhibit aggregation of amyloid beta (Aβ). We therefore introduced PCat and PEC into Sib to demonstrate how the constrained molecular geometry and differences in three-dimensional structures may enhance such activities. Introduction of PCat into Sib (SibC) resulted in effective inhibition of Aβ aggregation, α-glucosidase activity, and cell growth, suggesting that not only reduced flexibility but also the high degree of planarity may enhance the biological activity. SibC is expected to be a promising lead compound for the treatment of several diseases.