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

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

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1118397

DOI=10.3389/fphar.2023.1118397

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> 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 <italic>o</italic>-aminobenzamide analogue <bold>F8</bold> was identified as an early preclinical candidate for treatment of undifferentiated gastric cancer (IC<sub>50</sub> of 0.26 μM for HGC-27). However, the poor water solubility of compound <bold>F8</bold> prevents its further progress in preclinical studies.</p><p><bold>Aim:</bold> To improve the water solubility and drug-likeness of <bold>F8</bold> via salt formation.</p><p><bold>Method:</bold> Different acids and <bold>F8</bold> were reacted to obtain different salt forms. Physicochemical property screening, pharmacokinetic property research, and antitumor biological activity evaluation <italic>in vitro</italic> and<italic> in vivo</italic> were used to obtain the optimal salt form with the best druggability.</p><p><bold>Results:</bold> our continuous efforts have finally confirmed <bold>F8·2HCl</bold> as the optimal salt form with maintained <italic>in vitro</italic> antitumor activity, improved water solubility and pharmacokinetic properties. Importantly, the <bold>F8·2HCl</bold> displayed superior<italic> in vivo</italic> antitumor efficacy (TGI of 70.1% in 75 mg/kg) in HGC-27 xenograft model. The further immunohistochemical analysis revealed that <bold>F8·2HCl</bold> 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, <bold>F8·2HCl</bold> showed acceptable safety in the<italic> in vivo</italic> acute toxicity assay.</p><p><bold>Conclusion:</bold> Salting is an effective means to improve the drug-like properties of compound <bold>F8</bold>, and <bold>F8·2HCl</bold> can serve as a promising therapeutic agent against undifferentiated gastric cancer.</p>