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.
Highlights
Camptothecin (CPT 1, Figure 1) derivatives are potent topoisomerase I inhibitors with strong antitumor activities both in vitro and in vivo and are the only antitumor agents with topoisomerase I inhibitory activity used in the clinic [1,2]
It is believed that the low bioconversion efficiency (4%–5%) from irinotecan to the active form SN-38 is responsible for high interpatient variability in terms of the pharmacokinetics, which leads to considerable individual variation in efficacy and toxicity [7,8,9]
The synthesis of the prodrugs is shown in Scheme 1
Summary
Camptothecin (CPT 1, Figure 1) derivatives are potent topoisomerase I inhibitors with strong antitumor activities both in vitro and in vivo and are the only antitumor agents with topoisomerase I inhibitory activity used in the clinic [1,2]. The carboxyl groups(-COOH) in amino acids or dipeptides can be converted to sodium or potassium salt to improve water solubility of prodrugs.The target compounds were prepared by conjugating an amino acid or dipeptide to the 10-hydroxyl group of SN-38 via a carbamate linker These prodrugs were stable in aqueous solutions at acidic pH levels but were rapidly converted to active SN-38 in pH 7.4 buffer or in human plasma (Figure 2). These new CPT prodrugs exhibited much greater antitumor activity and less AChE inhibitory activity than irinotecan in vitro
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