(+)- and (−)-Ecarlottones, Uncommon Chalconoids from Fissistigma latifolium with Pro-Apoptotic Activity

Four new compounds, (+)- and (−)-ecarlottone (1), (±)-fislatifolione (5), (±)-isofislatifolione (6), and (±)-fislatifolic acid (7), and the known desmethoxyyangonin (2), didymocarpin-A (3), and dehydrodidymocarpin-A (4) were isolated from the stem bark of Fissistigma latifolium, by means of bioassay-guided purification using an in vitro affinity displacement assay based on the modulation of Bcl-xL/Bak and Mcl-1/Bid interactions. The structures of the new compounds were elucidated by NMR spectroscopic data analysis, and the absolute configurations of compounds (+)-1 and (−)-1 were assigned by comparison of experimental and computed ECD spectra. (−)-Ecarlottone 1 exhibited a potent antagonistic activity on both protein–protein associations with Ki values of 4.8 μM for Bcl-xL/Bak and 2.4 μM for Mcl-1/Bid.

本研究从大叶瓜馥木（Fissistigma latifolium）的茎皮中分离得到4个新化合物与3个已知化合物：4个新化合物为(+)-与(-)-ecarlottone（1）、(±)-fislatifolione（5）、(±)-isofislatifolione（6）以及(±)-fislatifolic acid（7）；3个已知化合物为去甲氧基扬戈宁（desmethoxyyangonin，2）、双花堇菜素A（didymocarpin-A，3）与脱氢双花堇菜素A（dehydrodidymocarpin-A，4）。本次分离采用基于调控Bcl-xL/Bak与Mcl-1/Bid相互作用的体外亲和置换实验开展生物活性导向纯化。新化合物的结构通过核磁共振波谱（Nuclear Magnetic Resonance spectroscopy，NMR）数据分析得以解析；(+)-1与(-)-1的绝对构型通过对比实验测得与理论计算得到的电子圆二色谱（Electronic Circular Dichroism，ECD）光谱得以确定。其中(-)-ecarlottone（1）对上述两种蛋白-蛋白相互作用均表现出强效拮抗活性，其对Bcl-xL/Bak的抑制常数Ki为4.8 μM，对Mcl-1/Bid的Ki为2.4 μM。