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

  • J Med Chem. 2022 Sep 22;65(18):11970-11984. doi: 10.1021/acs.jmedchem.2c00532.
Yao-Yao Jiang  1  2 ,  Yang Gao  1 ,  Jian-Yu Liu  1 ,  Ying Xu  1 ,  Mei-Yan Wei  1 ,  Chang-Yun Wang  1  2 ,  Yu-Cheng Gu  3 ,  Chang-Lun Shao  1  2
Affiliations
  • 1. Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, College of Food Science and Engineering, Ocean University of China, Qingdao 266003, China.
  • 2. Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266200, China.
  • 3. Syngenta Jealott's Hill International Research Centre, Bracknell, Berkshire RG42 6EY, U.K.
PMID: 36089748 DOI: 10.1021/acs.jmedchem.2c00532
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.

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