Tuning the photoactivity of diazido Pt(IV) prodrugs with amino acid methyl esters

Photoactive Pt(IV) complexes conjugated to amino acid methyl esters trans,trans,trans-[Pt(py)₂(N₃)₂(OH)(succinate-amino acid methyl ester)] (amino acid = L-leucine (1), glycine (2), L-tyrosine (3) and L-tryptophan (4)) have been synthesised and characterised. Complexes 1-4 showed high dark stability, but were activated upon irradiation with blue light to generate azidyl and hydroxyl radicals and Pt(II) species. Interestingly, conjugated tryptophan in 4 quenched the formation of azidyl and hydroxyl radicals and Pt-guanosine 5'-monphosphate adducts, while the amino acids in complexes 1-3 showed no significant effects on the formation of their photoproducts. Improved photocytotoxicity but lower dark cellular Pt accumulation in A2780 human ovarian cancer cells were observed for 1-4, with 50 % inhibition of cell viability (IC₅₀) values of 1.4-7.0 μM) compared with the parent complex FM-190 (trans, trans, trans-[Pt(py)₂(N₃)₂(OH)₂]). Significant enhancement in Pt accumulation for 3 and 4 after irradiation probably contributes to their promising photocytotoxicity, especially for the tryptophan-conjugated complex 4.