BQC-G, A TUMOR-SELECTIVE ANTI-CANCER PRODRUG

摘要

The invention relates to the synthesis of a second-generation camptothecin glucuronide prodrug (BQC-G) of a potent anticancer camptothecin derivative 5,6-dihydro-4H-benzo[de]quinoline-camptothecin (BQC). BQC-G was over 4000 times more water soluble than BQC, displayed good stability in human plasma and was an excellent substrate for enzymatic hydrolysis by bacterial and human β-glucuronidases. BQC-G was about 30 times less toxic than BQC, but was as toxic as BQC after hydrolysis of the glucuronide moiety by β-glucuronidase. In the presence of human serum albumin, BQC-G displayed lower cytotoxicity (IC₅₀=1080 nM) but could be activated by β-glucuronidase to display potent activity (IC₅₀=13.3 nM).