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  3. Synthesis and pharmacological evaluation of natural product diphyllin derivatives against head and neck squamous cell carcinoma

Synthesis and pharmacological evaluation of natural product diphyllin derivatives against head and neck squamous cell carcinoma

  • Eur J Med Chem. 2025 Mar 5:285:117215. doi: 10.1016/j.ejmech.2024.117215.
Yuqi Tang 1,  Xinhua Pan 2,  Fan-Fan Shang 3,  Yang Li 3,  Chaojun Zhang 2,  Hexin Ma 2,  Ao Zhang 4,  Xu Wang 2,  Chunyong Ding 5,  Wantao Chen 6
Affiliations

Affiliations

  • 1 Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, 200011, China; Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; Digital Diagnosis and Treatment Innovation Center for Cancer, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 2 Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, 200011, China; Digital Diagnosis and Treatment Innovation Center for Cancer, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 3 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 4 Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 5 Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China; Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China. Electronic address: chunding@sjtu.edu.cn.
  • 6 Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, 200011, China; Digital Diagnosis and Treatment Innovation Center for Cancer, Institute of Translational Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China. Electronic address: chenwantao196323@sjtu.edu.cn.
PMID: 39788063 DOI: 10.1016/j.ejmech.2024.117215
Abstract

Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignant tumors, but clinical drug treatments are limited. The natural product diphyllin was identified as a lead compound suppressing the proliferation of HNSCC cells through phenotypic screening of natural product library. However, further developments of diphyllin as an anti-HNSCC agent were restricted by the weak bioactivity and poor metabolic stability. Herein, we designed and synthesized two series of novel diphyllin derivatives that were achieved by introducing various pyranose rings or hydrophilic groups to block the easily metabolic C-4 site with the aim to improve antitumor activity and drug-like properties. Among these compounds, compound A3 showed the most potent inhibitory effects against HNSCC cells with IC50 values ranging from 4.37 to 77.81 nM and much less potent cytotoxicity against normal cells (IC50 > 10 μM). Mechanistically, it effectively inhibited cell proliferation and migration and induced the cell cycle arrest and Apoptosis in a concentration-dependent manner. Besides, A3 possessed greatly improved pharmacokinetic properties including over 10-fold higher plasma exposure (AUC0-t: 541 vs 43.6 h∗ng/mL) and better oral bioavailability (F: 20.85 % vs 2.70 %), lower systemic plasma clearance (CL:1897 vs 24523 mL/h/kg), as well as longer half-life (T1/2: 0.530 vs 0.108 h) when compared to diphyllin. In a tumor cell xenograft model, A3 significantly suppressed the CAL27 tumor growth with a TGI of 42.2 % without obvious safety concern, which is superior to that of diphyllin (TGI = 23.3 %), suggesting great potential for treatment of HNSCC.

Keywords

Diphyllin derivatives; Head and neck squamous cell carcinoma; Natural products; Phenotypic-based screening.

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