14-Aminocamptothecins: Their Synthesis, Preclinical Activity, and Potential Use for Cancer Treatment

被引：20

作者：

Duan, Jian-Xin ^{[1
]}

Cai, Xiaohong ^{[1
]}

Meng, Fanying ^{[1
]}

Sun, Jessica D. ^{[1
]}

Liu, Qian ^{[1
]}

Jung, Donald ^{[1
]}

Jiao, Hailong ^{[1
]}

Matteucci, Jackson ^{[1
]}

Jung, Brian ^{[1
]}

Bhupathi, Deepthi ^{[1
]}

Ahluwalia, Dharmendra ^{[1
]}

Huang, Heli ^{[1
]}

Hart, Charles P. ^{[1
]}

Matteucci, Mark ^{[1
]}

机构：

[1] Threshold Pharmaceut, Redwood City, CA 94063 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 06期

关键词：

TOPOISOMERASE-I INHIBITORS; PLANT ANTITUMOR AGENTS; CAMPTOTHECIN DERIVATIVES; HUMAN BLOOD; RESISTANCE; TOPOTECAN; DRUG; 9-AMINO-20(S)-CAMPTOTHECIN; PROTEINS; ANALOGS;

D O I：

10.1021/jm101354u

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by I reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (313) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.

引用

页码：1715 / 1723

页数：9

共 30 条

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