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.