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- Title
Synthesis and Biological Evaluation of Novel 10-Substituted-7- ethyl-10-hydroxycamptothecin (SN-38) Prodrugs.
- Authors
Mo Zhou; Meixia Liu; Xinhua He; Hong Yu; Di Wu; Yishan Yao; Shiyong Fan; Ping Zhang; Weiguo Shi; Bohua Zhong
- Abstract
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.
- Subjects
BIOSYNTHESIS; CHEMICAL reactions; ANTIBODY-directed enzyme prodrug therapy; CHEMICAL processes; CHEMICAL energy; CATALYSTS
- Publication
Molecules, 2014, Vol 19, Issue 12, p19718
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules191219718