Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
J Agric Food Chem. 2021 Oct 27;69(42):12433-12444. doi: 10.1021/acs.jafc.1c03215. Epub 2021 Oct 19.
Two previously undescribed compounds, moranigrine A () and morusamine (), along with 18 known compounds were isolated from the fruits of Linn. and structurally characterized using spectroscopic data and electronic circular dichroism analyses. All isolates were evaluated for their inhibitory effects on the 3-phosphoglycerate dehydrogenase (PHGDH) enzyme, which catalyzes the first committed step for the synthesis of glucose-derived serine and is associated with many kinds of cancers. Among these compounds, methyl caffeate () exhibited effective inhibition against PHGDH and was directly bound to PHGDH based on the microscale thermophoresis method and the cellular thermal shift assay. Further biochemical assays revealed that was a noncompetitive inhibitor with respect to the substrate of 3-phosphoglycerate and exhibited a concentration-dependent inhibition. Molecular docking demonstrated that coordinated in an allosteric site of PHGDH with low binding energy. Meanwhile, was selectively toxic to high PHGDH-expressing cancer cell lines and could cause apoptosis of cervical cancer cells in micromolar concentrations and could obviously inhibit tumor growth in the HeLa xenograft mouse model with low toxicities. Therefore, could be developed as a potential inhibitor of PHGDH for the treatment of cancers. Our present study provides information about as a functional food or pharmaceutical supplement in the application of cancer prevention and treatment.
从 Linn. 的果实中分离得到了两种以前未描述的化合物，即 moranigrine A () 和 morusamine ()，以及 18 种已知化合物。使用光谱数据和电子圆二色性分析对所有分离物进行了结构表征。所有分离物均评估了其对 3-磷酸甘油酸脱氢酶 (PHGDH) 酶的抑制作用，该酶催化葡萄糖衍生丝氨酸合成的第一步，与多种癌症有关。在这些化合物中，甲基咖啡酸 () 对 PHGDH 表现出有效抑制作用，并根据微量热泳动法和细胞热转移测定法直接与 PHGDH 结合。进一步的生化分析表明， 是 3-磷酸甘油酸底物的非竞争性抑制剂，并表现出浓度依赖性抑制。分子对接表明， 与 PHGDH 的变构位点配位，结合能低。同时， 对高表达 PHGDH 的癌细胞系具有选择性毒性，能够在微摩尔浓度下引起宫颈癌细胞凋亡，并能明显抑制荷瘤小鼠模型中的肿瘤生长，毒性低。因此， 可以作为 PHGDH 的潜在抑制剂用于癌症的治疗。本研究为 将 作为功能性食品或药物补充剂应用于癌症的预防和治疗提供了信息。
