Development of Prodrug–Payloads for Targeted Therapeutic Applications of Platinum–Acridine Anticancer Agents

Abstract

A synthetic platform has been developed that provides access to platinum(IV) prodrugs of highly cytotoxic platinum–acridine anticancer agents (PAs) and allows them to be incorporated into conjugation-ready prodrug–payloads (PPLs). The PPLs can be conveniently assembled in highly efficient microscale reactions utilizing strain-promoted azide–alkyne cycloaddition chemistry (SPAAC). Model reactions were performed to study the stability of the PPLs in buffers and media, and to assess their compatibility with cysteine–maleimide Michael addition chemistry. Amide coupling was a successful strategy to generate a conjugate containing integrin-targeted cyclo[RGDfK] peptide. Reactions with ascorbate were performed to mimic the reductive activation of the PPLs and the latter conjugate, and a cyanine (Cy5) fluorophore-labeled PPL was used to probe reduction of platinum(IV) in cancer cells by confocal microscopy. The PPL concept introduced here should be evaluated for treating solid tumors with PAs using cancer-targeting vehicles, such as antibody–drug conjugates (ADCs).