Synthesis and Anticancer Properties of Bis- and Mono(cationic peptide) Hybrids of Cyclometalated Iridium(III) Complexes: Effect of the Number of Peptide Units on Anticancer Activity

Cyclometalated iridium (Ir) complexes having Ir(tpy)₃ (tpy=2-(4’-tolyl)pyridine) scaffold exhibit promising potential for the diagnosis of cancer, as phosphorescent probes for cellular imaging and in the treatment of cancer, due to their high stability, tunable photophysical properties, and biological activities. We previously reported on the synthesis of some cationic amphiphilic Ir(III) complex-peptide hybrids (IPHs) such as 2 and 3 that contain KK(K)GG peptide units (K: lysine, G: glycine) that are attached via alkyl chain (C2∼C16) linkers and induce paraptosis-like cell death in Jurkat (T-lymphocyte leukemia) cancer cells through multiple cell death pathways. Herein, we report on the design and synthesis of two IPHs, 4 and 5, which possess two and one KKKGG sequences, respectively, and an examination of the effect of the number of peptide units on their anticancer activity. Our evaluations of the anticancer properties of 3–5 suggested that 3 and 4 are more cytotoxic than 5 against Jurkat cells, indicating a positive relationship between the number of H₂N-KKKGG units in 3–5 and their anticancer activity. In addition, a parallel relationship was observed between the cytotoxicity of 3–5 and Ca²⁺ overload in mitochondria, suggesting the direct transfer of Ca²⁺ from the endoplasmic reticulum to mitochondria.