Building up Pt(II)-thiosemicarbazone-lysine-sC18 conjugates.

Chiral tridentate N^N^S coordinating pyridine-carbaldehyde (S )-N 4-(α-methylbenzyl)thiosemicarbazones (HTSCmB) were synthesised alongside with lysine-modified derivatives (HTSCLp) (Lp = boc-protected lysine) for covalent conjugation to the cell-penetrating peptide sC18. The HTSCmB model ligands, the HTSCLp derivatives and the peptide conjugate form rapidly and quantitatively, very stable Pt(II) chlorido complexes [Pt(TSC)Cl] and Pt(CN) derivatives were obtained through Cl - → CN - exchange. The Pt-TSC-sC18 conjugates [Pt(dpyTSCL-sC18)X] (X = Cl or CN) are stable for at least 72 h in FBS buffer solution. The Cl - ligand is not fully stable towards hydrolysis under these conditions but the complex fragment [Pt(dpyTSCL-sC18)] + remains intact. For the CN - derivative a Pt de-coordination of less than 20% after 72 h was recorded. The HdpyTSCmB ligand showed anti-proliferative properties against MCF-7 and HT-29 cancer cells and also HEK-293 embryonic kidney cells with toxicities comparable to the established derivative Dp44mT. Remarkably, the corresponding PtCl and Pt(CN) complexes showed largely reduced anti-proliferative activities, which we ascribe to tight Pt-binding of the TSC ligand preventing its binding to intracellular Fe. Even more surprising was, that neither sC18 or the lysine-tagged HdpyTSCLp, or its sC18 conjugate HdpyTSCL-sC18, nor the PtCl and Pt(CN) conjugate complexes showed a decrease in cell viability for all three cell-lines.