Design, Synthesis, and Biological Evaluation of Novel Benzimidazole Derivatives as Dual PI3K/HDAC8 Inhibitors with Potent Anti-Cervical Cancer Activity In Vivo

Abstract

The dual inhibition of phosphatidylinositol 3-kinase (PI3K) and histone deacetylase 8 (HDAC8) has emerged as a promising strategy for cervical cancer (CC) therapy. We synthesized 34 novel benzimidazole derivatives and evaluated their anti-CC cell line proliferation. The compound 50 exhibited equivalent antiproliferative effect to cisplatin (Pt) in CC cell lines SiHa, Ca Ski, and HeLa, especially in HeLa cells with an IC50 value at 1.42 ± 0.50 μM (Pt 1.70 ± 0.28 μM). Further assessment in the HeLa cell xenograft mouse model, the intraperitoneal medium- (30 mg/kg) and high-dose group (60 mg/kg) and and intragastric high-dose group (100 mg/kg) exhibited antitumor efficacy no less than that of Pt (i.p. 5 mg/kg) but much more safe during the experiment period. Mechanism studies demonstrated that 50 could inhibit the PI3K/Akt pathway and HDAC8 expression and function. These findings prove that the PI3K/HDAC8 dual inhibition may be an efficient way in cervical cancer treatment and compound 50 deserved for further development.