Amino Acid‐Triggered Activation of Double‐Masked Gossyzid–Metal Conjugates: Metal‐Dependent Stability, Photophysical Properties, and Anticancer Activity

ABSTRACT

Double‐masking strategies that layer classical prodrug chemistry with metal coordination offer a powerful route to widen the therapeutic window of reactive small molecules. Building on gossyzid, a pH‐activatable imine prodrug of the polyphenolic aldehyde gossypol, we introduce a family of gossyzid–metal conjugates (GMCs) that implement orthogonal masking: gossypol is first protected as gossyzid, then “locked” within coordination environments formed with first‐row transition metal ions (Mn, Fe, Co, Ni, Cu, and Zn). Spectroscopic analyses, powder x‐ray diffraction, and thermogravimetric profiling support the formation of coordination architectures, rationalizing the mass‐spectrometric intractability of these species. Photophysical studies reveal metal‐dependent binding stoichiometries and affinities, establishing a tunable stability series across the GMCs. Using amino acids as competitive chelators, we demonstrate selective, triggerable de‐chelation of the metal node that regenerates gossyzid under tumor‐mimicking conditions; subsequent tumor‐microenvironment (TME)‐relevant acidolysis completes its activation to gossypol. Notably, only specific amino acids effectively unmask defined GMC subsets, enabling control over activation kinetics and extent. In triple‐negative breast cancer models, GMC cytotoxicity correlates with intrinsic metal–ligand binding, thus showing the contributions of double masking. To our knowledge, this is the first systematic demonstration of amino‐acid‐triggered activation in double‐masked metal–prodrug conjugates, with direct implications for the design of next‐generation, TME‐responsive prodrugs.