Platinum(IV)-Estramustine Multiaction Prodrugs Are Effective Antiproliferative Agents against Prostate Cancer Cells

Herein, we describe the synthesis, characterization, and biological properties of Pt­(IV) derivatives of cisplatin with estramustine at the first axial position, which is known to disrupt the microtubule assembly and act as an androgen antagonist, and varying the second axial position using an innocent ligand (acetate or hydroxyl) to prepare dual-action and triple-action prodrugs with known inhibitors of histone deacetylase, cyclooxygenase, and pyruvate dehydrogenase kinase. We demonstrate superior antiproliferative activity at submicromolar concentrations of the prodrugs against a panel of cancer cell lines, particularly against prostate cancer cell lines. The results obtained in this study exemplify the complex mode of action of “multiaction” Pt­(IV) prodrugs. Interestingly, changing the second axial ligand in the Pt–estramustine complex has a significant effect on the mode of action, suggesting that all three components of the Pt­(IV) prodrugs (platinum moiety and axial ligands) contribute to the killing of cells and not just one dominant component.