Design and Characterization of a Natural Arf-GEFs Inhibitor Prodrug CHNQD-01255 with Potent Anti-Hepatocellular Carcinoma Efficacy In Vivo.

Abstract

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 1-15, carbonates 16-24 and 30-32, and carbamates 25-29, were synthesized and evaluated. CHNQD-01255 (16) with improved aqueous solubility (15-20 mg/mL) demonstrated favorable pharmacokinetic profiles. It behaved as expected by undergoing rapid conversion to BFA in vivo, and achieved sufficient high plasma exposure, prolonged half-life, as well as the improved bioavailability of BFA (F = 18.96%). Meanwhile, CHNQD-01255 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 CHNQD-01255 (MTD > 750 mg/kg, p.o.) was confirmed to be superior to that of BFA (MTD < 506 mg/kg). Overall, CHNQD-01255 may serve as a safe and effective new anti-HCC prodrug.

• Authors: Yao-Yao Jiang, Yang Gao, Jian-Yu Liu, Ying Xu, Mei-Yan Wei, Chang-Yun Wang, Yu-Cheng Gu, Chang-Lun Shao
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 18 Pg. 11970-11984 (09 22 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 36089748 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carbamates
• Prodrugs
• Brefeldin A

Topics

• Animals
• Brefeldin A (pharmacology)
• Carbamates
• Carcinoma
• Cell Line
• Cell Proliferation (drug effects)
• Humans
• Mice
• Prodrugs (chemical synthesis, pharmacokinetics, pharmacology, therapeutic use)