Synthesis and Antitumor Properties of BQC-Glucuronide, a Camptothecin Prodrug for Selective Tumor Activation

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• 作者：Zeljko M. Prijovich ; Pierre-Alain Burnouf ; Hua-Cheng Chou ; Ping-Ting Huang ; Kai-Chuan Chen ; Tian-Lu Cheng ; Yu-Lin Leu ; Steve R. Roffler
• 刊名：Molecular Pharmaceutics
• 出版年：2016
• 出版时间：April 4, 2016
• 年：2016
• 卷：13
• 期：4
• 页码：1242-1250
• 全文大小：430K
• ISSN：1543-8392

文摘

Major 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.