Synthesis and anti-tumor activity of nitrogen-containing derivatives of the natural product diphyllin

Yang Li; Qing Lu; Ruoxuan Xiao; Jing Ma; Yuqi Tang; Wantao Chen; Ruihan Zhang; Lingxi Jiang; Hao Chen; Baiyong Shen; Ao Zhang; Chunyong Ding

doi:10.1016/j.ejmech.2022.114708

Synthesis and anti-tumor activity of nitrogen-containing derivatives of the natural product diphyllin

Eur J Med Chem. 2022 Dec 5:243:114708. doi: 10.1016/j.ejmech.2022.114708. Epub 2022 Aug 26.

Authors

Yang Li¹, Qing Lu¹, Ruoxuan Xiao¹, Jing Ma¹, Yuqi Tang², Wantao Chen³, Ruihan Zhang⁴, Lingxi Jiang⁵, Hao Chen⁵, Baiyong Shen⁵, Ao Zhang⁶, Chunyong Ding⁷

Affiliations

¹ Targeted Drug Research Center of Digestive Tract Tumor, Pharm-X Center, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
² Targeted Drug Research Center of Digestive Tract Tumor, Pharm-X Center, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China; Department of Oral and Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China.
³ Department of Oral and Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, China.
⁴ WLSA Shanghai Academy, Shanghai, 200433, China.
⁵ Research Institute of Pancreatic Disease, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, 200025, Shanghai, China.
⁶ Targeted Drug Research Center of Digestive Tract Tumor, Pharm-X Center, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. Electronic address: ao6919zhang@sjtu.edu.cn.
⁷ Targeted Drug Research Center of Digestive Tract Tumor, Pharm-X Center, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. Electronic address: chunding@sjtu.edu.cn.

PMID: 36122549
DOI: 10.1016/j.ejmech.2022.114708

Abstract

The natural product diphyllin has demonstrated great potential in the treatment of various human cancers, especially pancreatic cancer. However, its relative weak potency, low aqueous solubility, and poor metabolic stability limits its development ability. In this study, we designed and synthesized two series of novel nitrogen-containing diphyllin derivatives with the aim to improve both antitumor efficacy and drug-like properties. Among them, the amino derivative 15 showed an IC₅₀ value of 3 nM against pancreatic cancer CFPAC-1 cells and is about 69-fold more potent than diphyllin. In addition, compound 15 possesses improved aqueous solubility and metabolic stability in liver microsomes. This compound not only significantly induced cell cycle arrest at G0/G1 phase with down-regulation of CDK4 and cyclinD1 in a dose-dependent manner, but also blocked the later stage of autophagy in CFPAC-1 cells. In pancreatic cancer xenograft model, treatment of 15 with 10 mg/kg exhibited much more potent efficacy in suppressing the growth of transplanted PANC02 tumors than diphyllin without obvious safety concern.

Keywords: Anticancer activity; Diphyllin derivatives; Druglike property; Natural product; Pancreatic cancer.

MeSH terms

Antineoplastic Agents* / pharmacology
Apoptosis
Benzodioxoles / pharmacology
Biological Products* / pharmacology
Cell Line, Tumor
Cell Proliferation
Drug Screening Assays, Antitumor
Humans
Nitrogen / pharmacology
Pancreatic Neoplasms* / drug therapy
Structure-Activity Relationship

Substances

diphyllin
Biological Products
Nitrogen
Benzodioxoles
Antineoplastic Agents