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

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