10-Boronic acid substituted camptothecin as prodrug of SN-38

Malignant tumor cells have been found to have high levels of reactive oxygen species such as hydrogen peroxide (H₂O₂), supporting the hypothesis that a prodrug could be activated by intracellular H₂O₂ and lead to a potential antitumor therapy. In this study, the 7-ethyl-10-boronic acid camptothecin (B1) was synthesized for the first time as prodrug of SN-38, by linking a cleavable aryl carbon-boron bond to the SN-38. Prodrug B1 selectively activated by H₂O₂, converted rapidly to the active form SN-38 under favorable oxidative conditions in cancer cells with elevated levels of H₂O₂. The cell survival assay showed that prodrug B1 was equally or more effective in inhibiting the growth of six different cancer cells, as compared to SN-38. Unexpectedly, prodrug B1 displayed even more potent Topo I inhibitory activity than SN-38, suggesting that it was not only a prodrug of SN-38 but also a typical Topo I inhibitor. Prodrug B1 also demonstrated a significant antitumor activity at 2.0 mg/kg in a xenograft model using human brain star glioblastoma cell lines U87MG.