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

doi:10.1021/acs.molpharmaceut.5b00771

CNU IR > Pharmacy and Science > Dept. of Pharmacy > Periodical Articles > Item 310902800/30961

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题名:	Synthesis and Antitumor Properties of BQC-Glucuronide, a Camptothecin Prodrug for Selective Tumor Activation
作者:	Prijovich, Zeljko M. Burnouf, Pierre-Alain Chou, Hua-Cheng Huang, Ping-Ting Chen, Kai-Chuan Cheng, Tian-Lu Leu, Yu-Lin Roffler, Steve R.
贡献者:	Acad Sinica, Inst Biomed Sci, Acad Rd Natl Yang Ming Univ, Taiwan Int Grad Program Mol Med Acad Sinica, Acad Rd Kaohsiung Med Univ, Fac Biomed Sci & Environm Biol Chia Nan Univ
关键词:	camptothecin glucuronide prodrug cancer targeted therapy beta-glucuronidase albumin influence ADEPT metastasis
日期:	2016-04
上传时间:	2018-01-18 11:38:46 (UTC+8)
出版者:	Amer Chemical Soc
摘要:	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 5,6dihydro-4H-benzo [de] quinoline-camptothecin (BQC) displays greater cytotoxicity against cancer cells than the clinically used Norma tissue 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.
關聯:	Molecular Pharmaceutics, v.13 n.4, pp.1242-1250
显示于类别:	[Dept. of Pharmacy] Periodical Articles

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