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CHEMISTRY OF NATURAL COMPOUNDS · 2024 ·Vol. 60 ·期 1 ·92-97 · IF 0.8

Synthesis of Novel Stigmasterol Derivatives with 1,2,3-Triazole Substituent at the C-3 Position and Their Cytotoxicity Toward HeLa, HGC-27, and HEK-293T Cells

Wang Yong,Wang Wei,Liu Cong-Jun,Gao Song,Xiong Yong-Ge,Gao Tian-Zeng,Li Wei-Shi,Li Jing-Jing

Eight new stigmasterol derivatives possessing 1,2,3-triazoles moiety were synthesized by a 1,3-dipolar cycloaddition reaction. All the compounds were characterized by IR, NMR, and HR-MS. In addition, human cervical cancer cells (HeLa), human gastric cancer cells (HGC-27), and human renal epithelial cells (HEK-293T) were selected to study the antitumor activity of the synthesized compounds. The results demonstrated that compounds 3c and 3d exhibited better inhibitory activity against the tested tumor cell lines. The IC 50 value of the inhibitory activity on HeLa was 52.3 μmol·L –1 and 31.4 μmol·L –1 , and 40.6 μmol·L –1 and 44.6 μmol·L –1 for HGC-27, respectively.

研究领域: 有机合成 · 药物化学 · 药理学 · 癌症研究 · 细胞生物学

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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY · 2022 · IF 7.088

Discovery of novel VEGFR-2-PROTAC degraders based on the localization of lysine residues via recruiting VHL for the treatment of gastric cancer

Xing-Rong Wang,Shuai Wang,Hong-Xia Mu,Kai-Yan Xu,Xue-Ting Wang,Jian-Tao Shi,Qi-Hang Cui,Li-Wen Zhang,Shi-Wu Chen

VEGFR-2 is an attractive therapeutic target for antitumor drug research by blocking tumor angiogenesis and PROTAC provides a new technology for targeted protein knockout. Herein, a library of novel VEGFR-2-PROTAC degraders were rationally designed and synthesized based on the Lys residue region on the surface of VEGFR-2 protein using protein structure-based drug design strategy. Among them, P7 exhibited preferable antitumor activity against HGC-27 cells and less toxic to human normal HUVEC, HEK293T and GES-1 cells in vitro , as well as the potent degradation activity of VEGFR-2 protein in HGC-27 cells (DC 50 : 0.084 ± 0.04 μM, D max : 73.7%) and HUVEC cells (DC 50 : 0.51 ± 0.10 μM, Dmax: 76.6%). Additionally, P7 degraded VEGFR-2 protein by the formation of ternary complex and the ubiquitin proteasome pathway in HGC-27 cells. Furthermore, P7 shortened the half-life of VEGFR-2 protein synthesis and had no inhibitory effect on the expression of VEGFR-2 mRNA in HGC-27 cells. Moreover, P7 inhibited the colony formation, migration and invasion of HGC-27 cells in a time- and dose-dependent manner, and meanwhile induced G 2 /M phase cycle arrest and apoptosis . All the results demonstrated that P7 could be as a promising VEGFR-2-PROTAC degrader for gastric cancer therapy.

CAS / MDL: 284461-73-0

研究领域: 肿瘤学 · 药理学 · 分子生物学 · 细胞生物学

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Synthesis of Novel Stigmasterol Derivatives with 1,2,3-Triazole Substituent at the C-3 Position and Their Cytotoxicity Toward HeLa, HGC-27, and HEK-293T Cells

Discovery of novel VEGFR-2-PROTAC degraders based on the localization of lysine residues via recruiting VHL for the treatment of gastric cancer