Synthesis of Optically Pure Cyclometalated Iridium(III) Complex‐Peptide Hybrids and Their Anticancer Activity.

We report on the synthesis of optically pure cyclometalated iridium(III) complex‐peptide hybrids as amphiphilic peptide conjugates (IPH‐ACs) and the effect of the stereochemistry with respect to their Ir(tpy) 3 (tpy: 2‐(4′‐tolyl)pyridine) core on their cytotoxicity against cancer cells. Stereochemically pure IPH‐ACs were synthesized from Δ ‐ and Λ ‐Ir(tpyCO 2 H) 3 by optical resolution via the diastereomeric intermediates that are conjugated with the chiral alcohol, (1 R ,2 R )‐2‐aminocyclohexanol (( R , R )‐ 11 ), followed by the hydrolysis of the ester moieties, as we reported very recently, and their spectroscopic spectra are reported. It was found that both optically pure Δ ‐ and Λ ‐forms of IPH‐ACs induce paraptotic cell death in Jurkat cells and the EC 50 values were evaluated by MTT assays. We also performed TEM (transmission electron microscope) analyses of Jurkat cells treated with Λ ‐ 13 to observe morphological changes in paraptosis processes. The intracellular uptake of Λ ‐forms of IPH‐ACs in the cells measured by ICP‐MS (inductively coupled plasma‐mass spectrometry) was higher than those of Δ ‐forms and the EC 50 values of the Λ ‐forms were smaller than those of the Δ ‐IPH‐ACs. The analysis of these results suggests that the intrinsic cytotoxicity is almost equal for the Δ ‐ and Λ ‐forms and that the difference in cytotoxicity against Jurkat cells is due to the selectivity in the intracellular uptake of each stereoisomer.