mp5b00771_si_001.pdf (424.35 kB)
Synthesis and Antitumor Properties of BQC-Glucuronide, a Camptothecin Prodrug for Selective Tumor Activation
journal contribution
posted on 2016-01-29, 00:00 authored by Zeljko
M. Prijovich, Pierre-Alain Burnouf, Hua-Cheng Chou, Ping-Ting Huang, Kai-Chuan Chen, Tian-Lu Cheng, Yu-Lin Leu, Steve R. RofflerMajor limitations of camptothecin
anticancer drugs (toxicity, nonselectivity,
water insolubility, inactivation by human serum albumin) may be improved
by creating glucuronide prodrugs that rely on beta-glucuronidase for
their activation. We found that the camptothecin derivative 5,6-dihydro-4H-benzo[de]quinoline-camptothecin (BQC)
displays greater cytotoxicity against cancer cells than the clinically
used camptothecin derivatives SN-38 and topotecan even in the presence
of human serum albumin. We synthesized the prodrug BQC-glucuronide
(BQC-G), which was 4000 times more water soluble and 20–40
times less cytotoxic than BQC. Importantly, even in the presence of
human serum albumin, BQC-G was efficiently hydrolyzed by beta-glucuronidase
and produced greater cytotoxicity (IC50 = 13 nM) than camptothecin,
9-aminocamptothecin, SN-38, or topotecan (IC50 > 3000,
1370, 48, and 28 nM, respectively). BQC-G treatment of mice bearing
human colon cancer xenografts with naturally or artificially elevated
beta-glucuronidase activity produced significant antitumor activity,
showing that BQC-G is a potent prodrug suitable for selective intratumoral
drug activation.