文献类型：期刊文献

英文题名：Design, synthesis, and evaluation of phosphorylated rhein derivatives with enhanced antiproliferative activity

作者：Li, Jiaojiao[1];Zhang, Qili[1,2,3];Wu, Dan[1,7];Xia, Pengfei[1,4,5];Wang, Yongfeng[8];Wang, Jie[1];Peng, Xuejing[1,2,3];Zhao, Lei[1,2,3,4,5,6]

第一作者：李金娟

通信作者：Peng, XJ[1];Zhao, L[1];Peng, XJ[2];Zhao, L[2];Peng, XJ[3];Zhao, L[3];Zhao, L[4];Zhao, L[5];Zhao, L[6]

机构：[1]Gansu Univ Chinese Med, Coll Pharm, 35 Dingxi East Rd, Lanzhou 730000, Peoples R China;[2]Gansu Univ Chinese Med, Northwest Collaborat Innovat Ctr Tradit Chinese Me, 35 Dingxi East Rd, Lanzhou 730000, Peoples R China;[3]Gansu Univ Chinese Med, MOE PRC, 35 Dingxi East Rd, Lanzhou 730000, Peoples R China;[4]Gansu Univ Chinese Med, Key Lab Chem Qual, TCM Coll Gansu Prov, 35 Dingxi East Rd, Lanzhou 730000, Peoples R China;[5]Gansu Univ Chinese Med, Gansu Prov Engn Lab TCM Standardizat Technol & Pop, 35 Dingxi East Rd, Lanzhou 730000, Peoples R China;[6]Gansu Pharmaceut Ind Innovat Res Inst, 35 Dingxi East Rd, Lanzhou 730000, Peoples R China;[7]Lanzhou Univ, Hosp 1, 1 Donggang West Rd, Lanzhou 730000, Peoples R China;[8]Gansu Med Coll, 18 Jinghe Ave, Pingliang 744000, Peoples R China

第一机构：甘肃中医药大学药学院（西北中藏药协同创新中心办公室）

通信机构：[1]corresponding author), Gansu Univ Chinese Med, Coll Pharm, 35 Dingxi East Rd, Lanzhou 730000, Peoples R China;[2]corresponding author), Gansu Univ Chinese Med, Northwest Collaborat Innovat Ctr Tradit Chinese Me, 35 Dingxi East Rd, Lanzhou 730000, Peoples R China;[3]corresponding author), Gansu Univ Chinese Med, MOE PRC, 35 Dingxi East Rd, Lanzhou 730000, Peoples R China;[4]corresponding author), Gansu Univ Chinese Med, Key Lab Chem Qual, TCM Coll Gansu Prov, 35 Dingxi East Rd, Lanzhou 730000, Peoples R China;[5]corresponding author), Gansu Univ Chinese Med, Gansu Prov Engn Lab TCM Standardizat Technol & Pop, 35 Dingxi East Rd, Lanzhou 730000, Peoples R China;[6]corresponding author), Gansu Pharmaceut Ind Innovat Res Inst, 35 Dingxi East Rd, Lanzhou 730000, Peoples R China.|[10735]甘肃中医药大学;[1073501e14fb35863569f]甘肃中医药大学药学院（西北中藏药协同创新中心办公室）;

年份：2025

卷号：166

外文期刊名：BIOORGANIC CHEMISTRY

收录：;Scopus(收录号：2-s2.0-105020923852);WOS:【SCI-EXPANDED(收录号:WOS:001611952700001)】；

基金：This work was supported by the National Natural Science Foundation of China (no. 82160457, no. 81660577) ; the Gansu Provincial Department of Education 2024 University scientific research innovation platform major training project (no. 2024CXPT-18) ; the Young Doctor Support Project of Gansu Provincial Department of Education (no.2025QB-067) ; the Open Fund of Gansu Province Engineering Laboratory for TCM Standardization Technology and Popularization (no. ddyc-2022-03) ; the Industrial Support Program Project of the Education Department of Gansu Province (no.2025CYZC-052) ; the 'Innovation Star 'project of graduate students in Gansu Province in 2025 (no. 2025CXZX-925) .

语种：英文

外文关键词：Rhein; Phosphorylation; CDK1 inhibitor; Hepatocellular carcinoma; Molecular dynamics simulation; Cell-cycle arrest

摘要：Rhein, a natural anthraquinone, possesses anticancer properties but is hampered by modest potency and poor bioavailability. To overcome these limitations, we synthesized a series of novel phosphonate derivatives of rhein and evaluated their antiproliferative activity across several cancer cell lines. The derivative C9 emerged as the most potent compound against human hepatocellular carcinoma (HepG2) cells, with an IC50 value of 11.88 +/- 0.93 mu M, representing a 6.5-fold enhancement over the parent compound while maintaining a favorable selectivity index (SI = 8.0) against normal hepatocytes. Mechanistic studies in HepG2 cells showed that C9 inhibited cell migration, induced apoptosis, and arrested the cell cycle at the G2/M phase. To provide a molecular-level rationale for these observations, we employed a dual computational approach. Firstly, molecular dynamics simulations suggested a potential mechanism for enhanced cellular uptake, as C9 appeared to penetrate a model DPPC lipid bilayer more deeply than rhein. Secondly, molecular docking and subsequent ELISA validation supported CDK1, a key G2/M regulator, as a direct intracellular target. C9 treatment led to a significant downregulation of CDK1 protein levels in HepG2 cells. In conclusion, this work presents a successful dual-purpose modification of rhein, where phosphorylation appears to improve its predicted membrane permeability and enhance its inhibitory activity against CDK1, making C9 a promising lead compound for further development as a novel antiproliferative agent.