Design, synthesis, and anticancer activity of iridium(III) complex-peptide hybrids that contain hydrophobic acyl groups at the N-terminus of the peptide units

Abstract

In previous work, we reported on that Ir complex-cationic peptide hybrids (IPHs) that contain three KKGG or KKKGG sequences (K: lysine, G: glycine) induce cell death in cancer cells by an intracellular Ca²⁺-dependent pathway and function as luminescent detectors in dead cells. To identify the target biomolecules by photoaffinity labeling, we designed and synthesized IPH that contains a photoreactive and hydrophobic 4-[3-(trifluotomethyl)-3H-diazirine-3-yl]benzoyl (TFDB) group and found that it has more potent cytotoxicity against Jurkat cells than the previously prepared compounds. Herein, we report on the preparation of some new IPHs that contain hydrophobic acyl groups at the N-terminus of the peptide portions of the molecules. Among them, an IPH containing a n-dodecanoyl group was found to have much more potent cancer cell death activity and superior selectivity for cancer cells (Jurkat cells) over normal cells. The results of mechanistic studies suggest that the cell death of Jurkat cells is induced via different pathway from that induced by the previously synthesized IPHs. The results of this study are described herein.