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

Abstract

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 GI50 values ranging between 0.22 and 250 nM. Remarkably, in the Du145 prostate cell line, 6 elicited a GI50 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.

Platinum(IV) Prodrugs Incorporating an Indole-Based Derivative, 5-Benzyloxyindole-3-Acetic Acid in the Axial Position Exhibit Prominent Anticancer Activity

“…Because DMSO-d6 was used for the NMR experiments, amine proton resonances were observed in the aromatic region (8-10 ppm) (Figures S9-S11). The acquired NMR data are comparable to published data [40,[61][62][63].…”

“…Subsequently, a multiplet was recorded at 8.32 ppm which was induced by S11). The acquired NMR data are comparable to published data [40,[61][62][63].…”

“…While these distinctions are mostly attributed to the coordination 5B3A ligand, another factor that contributes to these is the methylation of the heterocyclic rings of 5-5B3A and 56-5B3A. This phenomenon has been observed previously with similar complexes in the literature [59,61,65]. Finally, the 1 H-195 Pt-HMQC spectra of 5-5B3A and 56-5B3A (Figures S17-S20) also confirmed the successful coordination of 5B3A to the respective platinum(IV) scaffolds, indicating the axial ligand only occupying one axial position.…”

“…Upon coordinating 5B3A to the platinum(IV) scaffold, PHENSS(IV)(OH) 2 , an upfield shift was detected for the following phen protons: H4, H7, H3, H8, H5 and H6 (Figure 6). This phenomenon may have been caused by the possible π-π stacking interactions between the aromatic rings of 5B3A and the phen, and this upfield movement was also observed by structurally related complexes in the literature [59,61]. Overall, the variations in multiplicity reported for P-5B3A is primarily influenced by the coordination of the axial ligand, 5B3A.…”

“…The 1 H-NMR and 2D-COSY spectra of the uncoordinated axial ligand, 5B3A were also acquired for reference and used to assist in assigning the protons for its NHS ester deriva-tive, NHS-5B3A (Figures S4 and S5). To synthesise the proposed platinum(IV) complexes, [Pt IV (H L )(A L )(X)(OH)] 2+ (P-5B3A, 5-5B3A and 56-5B3A) (Figure 5), established protocols were adapted [61]. The resultant complexes were purified via a flash chromatography system to acquire purity of above 95%.…”