Cyclooxygenase-Inhibiting Platinum(IV) Prodrugs with Potent Anticancer Activity

Abstract

Platinum(IV) prodrugs of the [Pt(PL)(AL)(COXi)(OH)]2+ type scaffold (where PL is 1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, AL is 1S,2S-diaminocyclohexane, and COXi is a COX inhibitor, either indomethacin or aspirin) were synthesised and characterised, and their biological activity was explored. MTT assays showed that these complexes exhibit outstanding activity against a range of cancer cell lines, and nanomolar activities were observed. The most potent complex, 4, exhibited a GI50 of 3 nM in the Du145 prostate cancer cell line and was observed to display a 1614-fold increased activity against the HT29 colon cancer cell line relative to cisplatin. ICP-MS studies showed a linear correlation between increased cellular accumulation of the complexes and increased cytotoxicity, while an enzyme immunoassay showed that 1 and 2 inhibited COX-2 at 14 and 1.4 µM, respectively, which is comparable to the inhibition exhibited by indomethacin. These results suggest that while the cytotoxicity of prodrugs 1–4 was influenced by cellular uptake, it was not entirely dependent on either COX inhibition or lipophilicity.

Potent Chlorambucil-Platinum(IV) Prodrugs

“…The electronic transitions observed in the UV measurements were comparable to published examples, especially those of platinum(II) and (IV) precursor complexes [ 57 , 58 , 59 , 60 , 61 , 64 ]. The UV spectra of the platinum(IV)-CLB complexes ( Figures S23–S25 ) were obtained by titrations for each complex, in triplicate to attain consistency and accuracy.…”

“…The synthesis pathway ( Figure 5 ) employed to create the prodrugs was devised through the optimization of previously described techniques [ 43 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. Firstly, [Pt II (H L )(A L )] 2+ was synthesized and characterized by NMR ( Figures S1–S3 ), with results consistent with the literature data [ 57 , 58 , 59 , 60 , 61 , 62 ]. Secondly, [Pt II (H L )(A L )] 2+ was oxidized to afford [Pt IV (H L )(A L )(OH) 2 ] 2+ [ 57 , 58 , 59 , 60 , 61 ].…”

“…Firstly, [Pt II (H L )(A L )] 2+ was synthesized and characterized by NMR ( Figures S1–S3 ), with results consistent with the literature data [ 57 , 58 , 59 , 60 , 61 , 62 ]. Secondly, [Pt II (H L )(A L )] 2+ was oxidized to afford [Pt IV (H L )(A L )(OH) 2 ] 2+ [ 57 , 58 , 59 , 60 , 61 ]. [Pt IV (H L )(A L )(OH) 2 ] 2+ was also characterized by NMR ( Figures S4–S6 ), with results consistent with the literature data [ 57 , 58 , 59 , 60 , 61 ].…”

“…Secondly, [Pt II (H L )(A L )] 2+ was oxidized to afford [Pt IV (H L )(A L )(OH) 2 ] 2+ [ 57 , 58 , 59 , 60 , 61 ]. [Pt IV (H L )(A L )(OH) 2 ] 2+ was also characterized by NMR ( Figures S4–S6 ), with results consistent with the literature data [ 57 , 58 , 59 , 60 , 61 ]. The symmetrical anhydride of CLB was derived from a modified literature protocol [ 54 ].…”

“…Overall, this pattern is consistent with previously published examples of platinum(IV) complexes that contain S , S -DACH. They also exhibit negative absorption bands at lower wavelengths and positive absorption bands at higher wavelengths [ 57 , 58 , 59 , 60 , 61 , 64 ]. In contrary, platinum(IV) complexes containing the enantiomer of S , S -DACH generally demonstrate positive absorption bands at lower wavelengths and negative absorption bands at higher wavelengths [ 60 , 64 ].…”