Versatile Platinum(IV) Prodrugs of Naproxen and Acemetacin as Chemo-Anti-Inflammatory Agents

Simple Summary: Traditional intravenous platinum(II) chemotherapy drugs such as cisplatin, oxaliplatin and carboplatin are highly effective in treating multiple cancer types. Unfortunately, this treatment is most often beset with detrimental side effects that inevitably impact the patient's willingness to comply with treatment programs. Platinum(II) drugs are scarcely selective, have poor bioavailability, and exhibit inherent and acquired resistance. A promising approach to address these impediments is the development of kinetically stable octahedral platinum(IV) complexes. This design strategy has been exploited for cisplatin and its derivatives and has been reported widely in the literature. This is a highly attractive approach for synthetic chemists due to the versatility it offers. Here, we contribute to this paradigm shift by using structurally distinct platinum(IV) scaffolds as effective prodrugs. The findings reported are expected to advance our understanding of cancer treatment.Developing new and versatile platinum(IV) complexes that incorporate bioactive moieties is a rapidly evolving research strategy for cancer drug discovery. In this study, six platinum(IV) complexes (1-6) that are mono-substituted in the axial position with a non-steroidal anti-inflammatory molecule, naproxen or acemetacin, were synthesised. A combination of spectroscopic and spectrometric techniques confirmed the composition and homogeneity of 1-6. The antitumour potential of the resultant complexes was assessed on multiple cell lines and proved to be significantly improved compared with cisplatin, oxaliplatin and carboplatin. The platinum(IV) derivatives conjugated with acemetacin (5 and 6) were determined to be the most biologically potent, demonstrating GI(50) values ranging between 0.22 and 250 nM. Remarkably, in the Du145 prostate cell line, 6 elicited a GI(50) value of 0.22 nM, which is 5450-fold more potent than cisplatin. A progressive decrease in reactive oxygen species and mitochondrial activity was observed for 1-6 in the HT29 colon cell line, up to 72 h. The inhibition of the cyclooxygenase-2 enzyme was also demonstrated by the complexes, confirming that these platinum(IV) complexes may reduce COX-2-dependent inflammation and cancer cell resistance to chemotherapy.