2. Academic Validation
  3. Design, synthesis, and evaluation of phosphorylated rhein derivatives with enhanced antiproliferative activity

Design, synthesis, and evaluation of phosphorylated rhein derivatives with enhanced antiproliferative activity

  • Bioorg Chem. 2025 Nov:166:109172. doi: 10.1016/j.bioorg.2025.109172.
Jiaojiao Li 1,  Qili Zhang 2,  Dan Wu 3,  Pengfei Xia 4,  Yongfeng Wang 5,  Jie Wang 1,  Xuejing Peng 6,  Lei Zhao 7
Affiliations

Affiliations

  • 1 College of Pharmacy, Gansu University of Chinese Medicine, 35 Dingxi East Road, Chengguan District, Lanzhou 730000, PR China.
  • 2 College of Pharmacy, Gansu University of Chinese Medicine, 35 Dingxi East Road, Chengguan District, Lanzhou 730000, PR China; Northwest Collaborative Innovation Center for Traditional Chinese Medicine Co-Constructed by Gansu Province & MOE of PRC, Gansu University of Chinese Medicine, 35 Dingxi East Road, Chengguan District, Lanzhou 730000, PR China.
  • 3 College of Pharmacy, Gansu University of Chinese Medicine, 35 Dingxi East Road, Chengguan District, Lanzhou 730000, PR China; The First Hospital of Lanzhou University, 1 Donggang West Road, Chengguan District, Lanzhou 730000, PR China.
  • 4 College of Pharmacy, Gansu University of Chinese Medicine, 35 Dingxi East Road, Chengguan District, Lanzhou 730000, PR China; Key Laboratory of Chemistry and Quality of TCM of the College of Gansu Province, Gansu University of Chinese Medicine, 35 Dingxi East Road, Chengguan District, Lanzhou 730000, PR China; Gansu Province Engineering Laboratory for TCM Standardization Technology and Popularization, Gansu University of Chinese Medicine, 35 Dingxi East Road, Chengguan District, Lanzhou 730000, PR China.
  • 5 Gansu Medical College, 18 Jinghe Avenue, Kongtong District, Pingliang 744000, PR China.
  • 6 College of Pharmacy, Gansu University of Chinese Medicine, 35 Dingxi East Road, Chengguan District, Lanzhou 730000, PR China; Northwest Collaborative Innovation Center for Traditional Chinese Medicine Co-Constructed by Gansu Province & MOE of PRC, Gansu University of Chinese Medicine, 35 Dingxi East Road, Chengguan District, Lanzhou 730000, PR China. Electronic address: [email protected].
  • 7 College of Pharmacy, Gansu University of Chinese Medicine, 35 Dingxi East Road, Chengguan District, Lanzhou 730000, PR China; Northwest Collaborative Innovation Center for Traditional Chinese Medicine Co-Constructed by Gansu Province & MOE of PRC, Gansu University of Chinese Medicine, 35 Dingxi East Road, Chengguan District, Lanzhou 730000, PR China; Key Laboratory of Chemistry and Quality of TCM of the College of Gansu Province, Gansu University of Chinese Medicine, 35 Dingxi East Road, Chengguan District, Lanzhou 730000, PR China; Gansu Province Engineering Laboratory for TCM Standardization Technology and Popularization, Gansu University of Chinese Medicine, 35 Dingxi East Road, Chengguan District, Lanzhou 730000, PR China; Gansu Pharmaceutical Industry Innovation Research Institute, 35 Dingxi East Road, Chengguan District, Lanzhou 730000, PR China. Electronic address: [email protected].
PMID: 41172785 DOI: 10.1016/j.bioorg.2025.109172
Abstract

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 μM, 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.

Keywords

CDK1 inhibitor; Cell-cycle arrest; Hepatocellular carcinoma; Molecular dynamics simulation; Phosphorylation; Rhein.

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