Development of o-aminobenzamide salt derivatives for improving water solubility and anti-undifferentiated gastric cancer

Frontiers in Pharmacology

Pharmacology

Xianzhou Lu¹  Yanli He²  Chengkun Wang³  Yan Peng⁴  Yongxia Xiong⁴  Weifan Jiang⁴  Xuelin Li⁴  Shuang Li⁴  Linsheng Zhuo⁵  Zhen Wang⁵ 

[1] Department of Hepatobiliary Surgery, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China;Department of Pain Rehabilitation, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China;Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of, South China;School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China;School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China;Postdoctoral Station for Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, China;

关键词: o;    salt formation;    undifferentiated gastric cancer;    antitumor;    water solubility;   

DOI  :  10.3389/fphar.2023.1118397

 received in 2022-12-07, accepted in 2023-06-19,  发布年份 2023

来源: Frontiers

【 摘 要 】

Background: Gastric cancer is one of the cancers with wide incidence, difficult treatment and high mortality in the world, especially in Asia and Africa. In our previous work, a novel o-aminobenzamide analogue F8 was identified as an early preclinical candidate for treatment of undifferentiated gastric cancer (IC50 of 0.26 μM for HGC-27). However, the poor water solubility of compound F8 prevents its further progress in preclinical studies.Aim: To improve the water solubility and drug-likeness of F8 via salt formation.Method: Different acids and F8 were reacted to obtain different salt forms. Physicochemical property screening, pharmacokinetic property research, and antitumor biological activity evaluation in vitro and in vivo were used to obtain the optimal salt form with the best druggability.Results: our continuous efforts have finally confirmed F8·2HCl as the optimal salt form with maintained in vitro antitumor activity, improved water solubility and pharmacokinetic properties. Importantly, the F8·2HCl displayed superior in vivo antitumor efficacy (TGI of 70.1% in 75 mg/kg) in HGC-27 xenograft model. The further immunohistochemical analysis revealed that F8·2HCl exerts an antitumor effect through the regulation of cell cycle-related protein (CDK2 and p21), apoptosis-related protein Cleaved Caspase-3, proliferation marker Ki67, and cell adhesion molecule E-cadherin. In addition, F8·2HCl showed acceptable safety in the in vivo acute toxicity assay.Conclusion: Salting is an effective means to improve the drug-like properties of compound F8, and F8·2HCl can serve as a promising therapeutic agent against undifferentiated gastric cancer.

【 授权许可】

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Copyright © 2023 Li, He, Li, Xiong, Peng, Wang, Zhuo, Jiang, Lu and Wang.