Camptothecin analogs with bulky, hydrophobic substituents at the 7-position via a Grignard reaction

被引:16
作者
Manikumar, G
Wadkins, RM
Bearss, D
Von Hoff, DD
Wani, MC
Wall, ME
机构
[1] Res Triangle Inst, Res Triangle Pk, NC 27709 USA
[2] Univ Mississippi, Dept Chem & Biochem, University, MS 38677 USA
[3] Univ Arizona, Ctr Canc, Tucson, AZ 85724 USA
关键词
topoisomerase I; poison; inhibitor; kinetics;
D O I
10.1016/j.bmcl.2004.08.010
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
By developing a new synthetic procedure for introduction of side chains onto the camptothecin ring system, we were able to achieve the preparation of a number of analogs bearing bulky, hydrophobic groups directly attached to the 7-position. These include 7-tert-butylcamptothecin, 7-benzylcamptothecin and the corresponding 10,11-methylenedioxycamptothecins. This method involves the reaction of an appropriate orthoaminobenzonitrile with various Grignard reagents to give the corresponding orthoaminoketones. Friedlander condensation of the latter with the key tricyclic ketone leads to 7-substituted camptothecin analogs. We report the activity of these compounds as topoisomerase I poisons and their ability to inhibit growth of selected tumor cell lines. (C) 2004 Elsevier Ltd. All rights reserved.
引用
收藏
页码:5377 / 5381
页数:5
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