Novel 20-carbonate linked prodrugs of camptothecin and 9-aminocamptothecin designed for activation by tumour-associated plasmin

被引：42

作者：

de Groot, FMH ^{[1
]}

Busscher, GF ^{[1
]}

Aben, RWM ^{[1
]}

Scheeren, HW ^{[1
]}

机构：

[1] Univ Nijmegen, Dept Organ Chem, NSR Ctr Mol Struct Design & Synth, NL-6525 ED Nijmegen, Netherlands

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2002年 / 12卷 / 17期

关键词：

D O I：

10.1016/S0960-894X(02)00388-8

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The first prodrugs of camptothecin and 9-aminocamptothecin that are activated by the tumour-associated protease plasmin are reported. The tripartate prodrugs consist of a tripeptide sequence recognised by plasmin, which is linked to the 20-hydroxyl group of the camptothecins via a 1,6-elimination spacer. After selective N-protection of 9-aminocamptothecin with an Aloc group, the promoiety (tripeptide-spacer conjugate) was linked to camptothecin or 9-Aloc-9-aminocamptothecin via a 20-carbonate linkage by reacting parent drugs with the p-nitrophenyl carbonate activated promoiety in the presence of DMAP. Both prodrugs showed to be stable in buffer solution and both parent drugs were released upon incubation in the presence of plasmin. Furthermore, the prodrugs showed an average 10-fold decreased cytotoxicity with respect to their parent drugs upon incubation in seven human tumour cell lines. (C) 2002 Elsevier Science Ltd. All rights reserved.

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页码：2371 / 2376

页数：6

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