Li Zongyang, Chen Meiying, Chen Fanfan, Li Weiping, Huang Guodong, Xu Xudong, Wang Sicen, Ma Guoxu, Cui Ping
Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China; Department of Neurosurgery, Shenzhen Key Laboratory of Neurosurgery, the First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, 3002# Sungang Road, Futian District, Shenzhen 518035, China.
Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China.
Bioorg Chem. 2022 Oct;127:106013. doi: 10.1016/j.bioorg.2022.106013. Epub 2022 Jul 9.
In the present study, six new cucurbitane type compounds, including three triterpenoids hemsleyacins P-R (6-7, 13) and three cucurbitane-type triterpenoid glycosides hemsleyaosides L-N (15-17), along with seventeen known cucurbitacin analogues were separated from the root tuber of Hemsleya penxianensis and elucidated based on NMR and HRESIMS. Then, 23 analogues of three types, namely, polyhydroxy-type (I) (1-7), monohydroxy-type (II) (8-13), and glycosides-type (III) (14-23), were assessed for their antitumor activity and structure-activity relationship analysis (SAR). We determined temozolomide (TMZ)-resistant GBM cell was the most sensitive to the tested compounds, and found hemsleyaoside N (HDN) displayed the best antineoplastic potency. Furthermore, we confirmed the anti-glioma activity of HDN in patient-derived recurrent GBM strains, GBM organoid (GBO) and orthotopic nude mouse models. Investigations exploring the mechanism made clear that HDN induced synchronous activation of UPR and MAPK signaling, which triggered deadly ER stress and apoptosis. Taken together, the potent antitumor activity of HDN warrants further comprehensive evaluation as a novel anti-glioma agent.
在本研究中，从彭县雪胆的块根中分离出6个新的葫芦素类化合物，包括3个三萜类化合物雪胆素P - R（6 - 7，13）和3个葫芦素型三萜糖苷雪胆皂苷L - N（15 - 17），以及17个已知的葫芦素类似物，并通过核磁共振（NMR）和高分辨电喷雾电离质谱（HRESIMS）对其进行了结构鉴定。然后，对三种类型的23个类似物，即多羟基型（I）（1 - 7）、单羟基型（II）（8 - 13）和糖苷型（III）（14 - 23）进行了抗肿瘤活性评估和构效关系分析（SAR）。我们确定替莫唑胺（TMZ）耐药的胶质母细胞瘤（GBM）细胞对测试化合物最敏感，发现雪胆皂苷N（HDN）表现出最佳的抗肿瘤效力。此外，我们在患者来源的复发性GBM菌株、GBM类器官（GBO）和原位裸鼠模型中证实了HDN的抗胶质瘤活性。对其作用机制的研究表明，HDN诱导未折叠蛋白反应（UPR）和丝裂原活化蛋白激酶（MAPK）信号的同步激活，从而引发致命的内质网应激和细胞凋亡。综上所述，HDN强大的抗肿瘤活性值得作为一种新型抗胶质瘤药物进行进一步的全面评估。
