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.
Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266200, China.
J Med Chem. 2022 Sep 22;65(18):11970-11984. doi: 10.1021/acs.jmedchem.2c00532. Epub 2022 Sep 11.
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.
布雷菲德菌素 A（BFA）是一种众所周知的天然 Arf-GEFs 抑制剂，对肝细胞癌（HCC）有效，但其溶解度差、毒性大、半衰期短限制了其应用潜力。本研究合成并评价了 BFA 的酯类-、碳酸酯类-、氨基甲酸酯类-前药。其中，水溶性得到显著改善（15-20mg/mL）的酯类前药（）具有良好的药代动力学特性。它可以快速转化为 BFA，符合预期，并且能够实现 BFA 的充分高血浆暴露、半衰期延长和生物利用度提高（=18.96%）。同时，在异种移植模型中，45mg/kg（po）剂量的（TGI=61.0%）显著抑制肿瘤生长。值得注意的是，（MTD>750mg/kg，po）的安全性显著优于 BFA（MTD<506mg/kg）。总之，可能是一种安全有效的新型抗 HCC 前药。
