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

Author:

Kanbe Azusa1,Yokoi Kenta1ORCID,Umezawa Masakazu2ORCID,Tsuchiya Koji3,Aoki Shin134ORCID

Affiliation:

1. Faculty of Pharmaceutical Science Tokyo University of Science 2641 Yamazaki, Noda Chiba 278-8510 Japan

2. Faculty of Advanced Engineering Tokyo University of Science 6-3-1 Niijuku, Kasushika Tokyo 125-8585 Japan

3. Research Institute for Science and Technology (RIST) Tokyo University of Science 2641 Yamazaki, Noda Chiba 278-8510 Japan

4. Research Institute for Biomedical Science (RIBS) Tokyo University of Science 2641 Yamazaki, Noda Chiba 278-8510 Japan

Abstract

AbstractWe 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(tpyCO2H)3 by optical resolution via the diastereomeric intermediates that are conjugated with the chiral alcohol, (1R,2R)‐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 EC50 values were evaluated by MTT assays. We also performed TEM (transmission electron microscope) analyses of Jurkat cells treated with Λ13 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 EC50 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.

Funder

Ministry of Education, Culture, Sports, Science and Technology

Uehara Memorial Foundation

Publisher

Wiley

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