245421-51-6

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) prodrugsOH2C-OH8Cbearing hydroxido ligands at the opposite axial position are slightly less stable in the dark than the corresponding prodrugsAC2C-AC8Ccontaining acetato ligands. The prodrugsOH3C-OH8Ccan be photoactivated under irradiation in eight minutes, and the photoactivation rate is further improved in prodrugsAC3C-AC8Cwhere only twenty seconds are needed. Moreover, the prodrugAC3C, in which the linker between the BODIPY photoabsorber and the platinum center has an appropriate length, is photoactivated the quickest among the acetylated prodrugsAC2C-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.

Exploration of the full potential of thioamide substitution as a tool in the chemical biology of peptides and proteins has been hampered by insufficient synthetic strategies for the site-specific introduction of a thioamide bond into a peptide backbone. A novel ynamide-mediated two-step strategy for thiopeptide bond formation with readily available monothiocarboxylic acids as thioacyl donors is described. The α-thioacyloxyenamide intermediates formed from the ynamides and monothiocarboxylic acids can be purified, characterized, and stored. The balance between their activity and stability enables them to act as effective thioacylating reagents to afford thiopeptide bonds under mild reaction conditions. Amino acid functional groups such as OH, CONH2, and indole NH groups need not be protected during thiopeptide synthesis. The modular nature of this strategy enables the site-specific incorporation of a thioamide bond into peptide backbones in both solution and the solid phase.

The present invention is directed to novel cytotoxic spliceostatin analogs (I) and derivatives, to antibody drug conjugates thereof, and to methods for using the same to treat medical conditions including cancer.