Stability, Reduction, and Cytotoxicity of Platinum(IV) Anticancer Prodrugs Bearing Carbamate Axial Ligands: Comparison with Their Carboxylate Analogues.

Platinum(IV) complexes containing carboxylate and carbamate ligands at the axial position have been reported previously. A better understanding of the similarity and difference between the two types of ligands will provide us with new insights and more choices to design novel Pt(IV) complexes. In this study, we systematically investigated and compared the properties of Pt(IV) complexes bearing the two types of ligands. Ten pairs of unsymmetric Pt(IV) complexes bearing axial carbamate or carboxylate ligands were synthesized and characterized. The stability of these Pt(IV) complexes in a PBS buffer with or without a reducing agent was investigated, and most of these complexes exhibited good stability. Besides, most Pt(IV) prodrugs with carbamate axial ligands were reduced faster than the corresponding ones with carboxylate ligands. Furthermore, the aqueous solubilities and lipophilicities of these Pt(IV) complexes were tested. All the carbamate complexes showed better aqueous solubility and decreased lipophilicity as compared to those of the corresponding carboxylate complexes, due to the increased polarity of carbamate ligands. Biological properties of these complexes were also evaluated. Many carbamate complexes showed cytotoxicity similar to that of the carboxylate complexes, which may derive from the lower cellular accumulation but faster reduction of the former. Our research highlights the differences between the Pt(IV) prodrugs containing carbamate and carboxylate axial ligands and may contribute to the future rational design of Pt-based anticancer prodrugs.

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

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.