Optimization of axial ligands to promote the photoactivation of BODIPY-conjugated platinum(iv) anticancer prodrugs

Abstract

Carboplatin-based platinum(IV) prodrugs containing axial carboxylates are relatively resistant to reduction to release active platinum(II) species and kill cancer cells. To facilitate the activation process, a boron dipyrromethene (BODIPY) ligand has been utilized as a photoabsorber at the axial position to photoactivate carboplatin-based platinum(IV) complexes. However, the influence of the axial ligands on the photoactivation rate of the platinum center and the subsequent biological activity are still unknown. In this study, we report the design and synthesis of a series of carboplatin-based photoactivable platinum(IV) prodrugs containing BODIPY axial ligands with different lengths. The resulting BODIPY-conjugated platinum(IV) prodrugs OH2C–OH8C bearing hydroxido ligands at the opposite axial position are slightly less stable in the dark than the corresponding prodrugs AC2C–AC8C containing acetato ligands. The prodrugs OH3C–OH8C can be photoactivated under irradiation in eight minutes, and the photoactivation rate is further improved in prodrugs AC3C–AC8C where only twenty seconds are needed. Moreover, the prodrug AC3C, in which the linker between the BODIPY photoabsorber and the platinum center has an appropriate length, is photoactivated the quickest among the acetylated prodrugs AC2C–AC8C. The high cellular accumulation may contribute more to the moderate photocytotoxicity of these prodrugs. Our research highlights the way to promote the photoactivation of BODIPY-conjugated platinum(IV) anticancer prodrugs by optimization of axial ligands and may contribute to the future rational design of photoactivable platinum-based complexes.