2. Academic Validation
  3. 10-Boronic acid substituted camptothecin as prodrug of SN-38

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

  • Eur J Med Chem. 2016 Jun 30:116:84-89. doi: 10.1016/j.ejmech.2016.03.063.
Lei Wang 1,  Shao Xie 2,  Longjun Ma 1,  Yi Chen 3,  Wei Lu 4
Affiliations

Affiliations

  • 1 School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China.
  • 2 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
  • 3 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China. Electronic address: ychen@simm.ac.cn.
  • 4 School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, PR China. Electronic address: wlu@chem.ecnu.edu.cn.
PMID: 27060760 DOI: 10.1016/j.ejmech.2016.03.063
Abstract

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.

Keywords

Antitumor; Boric acid; Camptothecin; Hydrogen peroxide; Prodrug.

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