Design and Characterization of a Natural Arf-GEFs Inhibitor Prodrug with Potent Anti-Hepatocellular Carcinoma Efficacy

Brefeldin A (BFA), a well-known natural Arf-GEFs inhibitor, is effective against hepatocellular carcinoma (HCC), while the poor solubility, serious toxicity, and short half-life limit its potential. Herein, distinct corresponding prodrugs of BFA, including esters -, carbonates - and -, and carbamates -, were synthesized and evaluated. () with improved aqueous solubility (15-20 mg/mL) demonstrated favorable pharmacokinetic profiles. It behaved as expected by undergoing rapid conversion to BFA , and achieved sufficient high plasma exposure, prolonged half-life, as well as the improved bioavailability of BFA ( = 18.96%). Meanwhile, significantly suppressed tumor growth (TGI = 61.0%) at a dose of 45 mg/kg (p.o.) in the xenograft model. Notably, the improved safety profile of (MTD > 750 mg/kg, p.o.) was confirmed to be superior to that of BFA (MTD < 506 mg/kg). Overall, may serve as a safe and effective new anti-HCC prodrug.