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Open AccessArticle

Synthesis and Biological Evaluation of Novel 10-Substituted-7-ethyl-10-hydroxycamptothecin (SN-38) Prodrugs

Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China
Cell Biology Laboratory of Jilin Province Tumor Institute, No 1018 Huguang Road, Changchun 130012, China
Tumor Centre, No.1 Hospital, Jilin University, 71 Xin-Min Street, Changchun 130012, China
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2014, 19(12), 19718-19731;
Received: 29 October 2014 / Revised: 19 November 2014 / Accepted: 19 November 2014 / Published: 27 November 2014
(This article belongs to the Special Issue Prodrugs)
In an attempt to improve the antitumor activity and reduce the side effects of irinotecan (2), novel prodrugs of SN-38 (3) were prepared by conjugating amino acids or dipeptides to the 10-hydroxyl group of SN-38 via a carbamate linkage. The synthesized compounds completely generated SN-38 in pH 7.4 buffer or in human plasma, while remaining stable under acidic conditions. All prodrug compounds demonstrated much greater in vitro antitumor activities against HeLa cells and SGC-7901 cells than irinotecan. The most active compounds, 5h, 7c, 7d, and 7f, exhibited IC50 values that were 1000 times lower against HeLa cells and 30 times lower against SGC-7901 cells than those of irinotecan, and the inhibitory activities of these prodrugs against acetylcholinesterase (AchE) were significantly reduced, with IC50 values more than 6.8 times greater than that of irinotecan. In addition, compound 5e exhibited the same level of tumor growth inhibitory activity as irinotecan (CPT-11) in a human colon xenograft model in vivo. View Full-Text
Keywords: antitumor agent; camptothecins; prodrugs; SN-38 antitumor agent; camptothecins; prodrugs; SN-38
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MDPI and ACS Style

Zhou, M.; Liu, M.; He, X.; Yu, H.; Wu, D.; Yao, Y.; Fan, S.; Zhang, P.; Shi, W.; Zhong, B. Synthesis and Biological Evaluation of Novel 10-Substituted-7-ethyl-10-hydroxycamptothecin (SN-38) Prodrugs. Molecules 2014, 19, 19718-19731.

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