Half-Sandwich Iridium and Ruthenium Complexes: Effective Tracking in Cells and Anticancer Studies

Abstract

Half-sandwich metal-based anticancer complexes suffer from uncertain targets and mechanisms of action. Herein we report the observation of the images of half-sandwich iridium and ruthenium complexes in cells detected by confocal microscopy. The confocal microscopy images showed that the cyclopentadienyl iridium complex 1 mainly accumulated in nuclei in A549 lung cancer cells, whereas the arene ruthenium complex 3 is located in mitochondria and lysosomes, mostly in mitochondria, although both complexes entered A549 cells mainly through energy-dependent active transport. The nuclear morphological changes caused by Ir complex 1 were also detected by confocal microscopy. Ir complex 1 is more potent than cisplatin toward A549 and HeLa cells. DNA binding studies involved interaction with the nucleobases 9-ethylguanine, 9-methyladenine, ctDNA, and plasmid DNA. The determination of bovine serum albumin binding was also performed. Hydrolysis, stability, nucleobase binding, and catalytic NAD + / NADH hydride transfer tests for complexes 1 and 3 were also carried out. Both complexes activated depolarization of mitochondrial membrane potential and intracellular ROS overproduction and induced cell apoptosis. Complex 3 arrested the cell cycle at the G 0 /G 1 phase by inactivation of CDK 4/cyclin D1. This work paves the way to track and monitor half-sandwich metal complexes in cells, shines a light on understanding their mechanism of action, and indicates their potential application as theranostic agents.

Transfer hydrogenation catalysis in cells

“…This complex induced cell apoptosis and arrested the cell cycle at the G 0 /G 1 phase by cyclin-dependent kinase 4/cyclin D1 inactivation. 31 They also reported a new class of Ir III complexes (50-52, Fig. 15a) of N-heterocyclic carbenes (NHCs) with transfer hydrogenation ability.…”

“…7,11,19,20 However, recently, some progress has been achieved with transfer hydrogenation catalysis in cells by some second-and third-row transition metal low-spin d 6 Ru II , Rh III , Ir III and Os II complexes. [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] Here we describe recent work on catalytic transfer hydrogenation in cells. Several enzymes are known to be involved in the reduction of NAD(P) + to NAD(P)H, or oxidation of NAD(P)H to NAD(P) + (Table 1).…”

“…Several enzymes are known to be involved in the reduction of NAD(P) + to NAD(P)H, or oxidation of NAD(P)H to NAD(P) + (Table 1). [39][40][41][42][43][44][45][46][47][48][49][50] Intracellular NAD + /NADH interconversion has been achieved by numerous organometallic Ru II , Rh III , Ir III , Os II complexes via a transfer hydrogenation pathway in the presence of a hydride donor, [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] including catalytic reduction of pyruvate to lactate in cells, 37 and in-cell photo-redox catalysis of NADH oxidation. 51 We discuss these recent developments including detailed mechanisms of action, along with recent work on in-cell photo-catalytic reduction of metal complexes by flavines.…”

Unveiling the anti-cancer mechanism for half-sandwich and cyclometalated Ir(iii)-based complexes with functionalized α-lipoic acid

“…Cell cycle regulation is one of the effective therapeutic methods, and anticancer agents can arrest cancer cells at a certain checkpoint due to the inhibition of cancer cell proliferation. 27,28 Here, ow cytometric studies revealed that the mode of cell cycle arrest in A549 cells induced by Ir2 was in a concentration-dependent manner ( Fig. 5 and S24 †).…”

“…The previously reported Ir piano stool complex [(h 5 -Cp*)Ir(N^N)Cl]PF 6 (N^N ¼ (triphenylmethyl)(pyridine-2-ylmethylene)amine) showed a similar cellular uptake in A549 cells (4.5 ng per 10 6 cells) as complex Ir1. 27 Interaction with GSH and BSA Tripeptide glutathione (GSH) is an important cellular antioxidant that could bind to the metal-center of metal-arene analogues aer hydrolysis and participate in the detoxication and deactivation of metal-based anticancer drugs. 30,33 To study the interaction between the GSH and the resulting Ir1 and Ir2, titration experiments were carried out.…”