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

Shuang Li; Yanli He; Xuelin Li; Yongxia Xiong; Yan Peng; Chengkun Wang; Linsheng Zhuo; Weifan Jiang; Xianzhou Lu; Zhen Wang

doi:10.3389/fphar.2023.1118397

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

Front Pharmacol. 2023 Jul 11:14:1118397. doi: 10.3389/fphar.2023.1118397. eCollection 2023.

Authors

Shuang Li¹, Yanli He², Xuelin Li¹, Yongxia Xiong¹, Yan Peng¹, Chengkun Wang³, Linsheng Zhuo^{1

4}, Weifan Jiang¹, Xianzhou Lu⁵, Zhen Wang^{1

4}

Affiliations

¹ School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
² Department of Pain Rehabilitation, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
³ Hunan Province Key Laboratory of Tumor Cellular & Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of, South China.
⁴ Postdoctoral Station for Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
⁵ Department of Hepatobiliary Surgery, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China.

Abstract

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.

Keywords: antitumor; o-aminobenzamide derivate; salt formation; undifferentiated gastric cancer; water solubility.

Grants and funding

This research was supported by Gansu Province Science Foundation for Distinguished Young Scholars (No. 20JR5RA304), National Natural Science Foundation of China (No. 22107034), China Postdoctoral Science Foundation (2022M721544), Hunan Provincial Natural Science Foundation of China (No. 2022JJ40356, 2023JJ40571, 2023JJ30527), Key Research Project of Science and Technology Department of Hunan Province (No. 2020SKC2009) and Major Research Fund of Hunan Provincial Health and Family Planning Commission (No. A2017012).