Yamaguchi Takamasa, Sasaki Hiroaki, Yatsu Genki, Koyama Kiyotaka, Kinoshita Kaoru
Department of Pharmacognosy and Phytochemistry, Meiji Pharmaceutical University, Noshio 2-522-1, Kiyose-Shi, 204-8588, Japan.
J Nat Med. 2025 Jan;79(1):233-241. doi: 10.1007/s11418-024-01862-7. Epub 2024 Nov 30.
Alzheimer disease (AD) is the most common type of dementia and accounts for the largest proportion of dementia cases. The amyloid cascade hypothesis is known for the pathogenesis of AD, in which excessive accumulation of amyloid-β (Aβ) leads to the formation of senile plaques and ultimately to AD. Inhibition of β-secretase (BACE1) may contribute to the treatment of AD by suppressing Aβ production. In this study, we isolated and characterized the activity of new and known BACE1-inhibiting compounds from two mushrooms of the Boletales order, Suillus bovinus and Boletinus cavipes, using a BACE1-inhibitory activity-guided separation approach. Three compounds (1-3) were isolated from Suillus bovinus CHCl extract and three compounds (4-6) were isolated from Boletinus cavipes CHCl extract. Compound 1 was a new compound. The structures were elucidated using MS, IR, and NMR. Compounds 1-6 showed BACE1-inhibitory activity (IC; 21.2, 17.8, 1.0, 1.6, 23.7, and 22.8 μM, respectively). To examine the structure-activity relationship, we also evaluated the activity of geranylgerniol, farnesol, 2,5-dihydroxy-1,4-benzoquinone and mesaconic acid. These compounds showed no activity, and these results indicate that chain terpenes alone do not show BACE1-inhibitory activity, but only when mesaconic acid or a quinone with a hydroxyl group is bound. In addition, the mode of inhibition of 2 and 3 were competitive and 4 was uncompetitive inhibition, respectively, as determined by analysis of Lineweaver-Burk and Dixon plots.
阿尔茨海默病（AD）是最常见的痴呆类型，在痴呆病例中占比最大。淀粉样蛋白级联假说以AD的发病机制而闻名，其中β淀粉样蛋白（Aβ）的过度积累导致老年斑的形成并最终引发AD。抑制β分泌酶（BACE1）可能通过抑制Aβ的产生有助于AD的治疗。在本研究中，我们使用BACE1抑制活性导向分离方法，从牛肝菌目（Boletales order）的两种蘑菇——褐环乳牛肝菌（Suillus bovinus）和空柄小牛肝菌（Boletinus cavipes）中分离并鉴定了新的和已知的BACE1抑制化合物的活性。从褐环乳牛肝菌的氯仿提取物中分离出三种化合物（1 - 3），从空柄小牛肝菌的氯仿提取物中分离出三种化合物（4 - 6）。化合物1是一种新化合物。通过质谱（MS）、红外光谱（IR）和核磁共振（NMR）对其结构进行了阐明。化合物1 - 6显示出BACE1抑制活性（IC50分别为21.2、17.8、1.0、1.6、23.7和22.8 μM）。为了研究构效关系，我们还评估了香叶基香叶醇、法尼醇、2,5 - 二羟基 - 1,4 - 苯醌和甲基丙烯酸的活性。这些化合物没有活性，这些结果表明单独的链状萜烯不显示BACE1抑制活性，而是只有当与甲基丙烯酸或带有羟基的醌结合时才显示活性。此外，通过Lineweaver - Burk和Dixon图分析确定，化合物2和3的抑制模式分别为竞争性抑制和非竞争性抑制，化合物4为非竞争性抑制。
