Overcoming multidrug resistance by a singlet oxygen releasing camptothecin-endoperoxide
Guangyu Zhang1, Lei Wang1, Yuan Qiao1
1State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, 116024 Dalian, P. R. China.
Abstract:
We made structural modifications on the A-ring of camptothecin (CPT) by incorporating methyl substituents on positions 9 and 12. This allows conversion of the camptothecin-derivative to an endoperoxide (ENDO-CPT). The endoperoxide obtained this way thermally releases singlet oxygen, reverting back to the original 9,12-dimethylcamptothecin (DM-CPT) with a half-life of 1.4 hours at 37 °C. Endoperoxide modification yields a significant improvement in cytotoxicity against MDR-cell lines, compared to both CPT and DM-CPT. It appears that the simultaneous action of singlet oxygen and CPT is highly effective due to the targeting of P-glycoprotein by singlet oxygen.
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