The Fluorine Effect in Zwitterionic Half-Sandwich Iridium(III) Anticancer Complexes

Abstract

The rational design by the introduction of fluorine into a compound has achieved success in the development of organic anticancer drugs. However, the fluorine effect in metal-based anticancer complexes has rarely been reported. In this contribution, we report the synthesis, characterization, chemical reactivity, and biological activity of a series of half-sandwich zwitterionic iridium(III) complexes containing different substituents in the η 5 -Cp R ring. The molecular structures for complexes Ir1−Ir4 and Ir7 were determined by single-crystal X-ray crystallography techniques. Notably, the asymmetrically substituted fluoro complexes Ir4 and Ir6 in solution show two conformational isomers. These complexes have sufficient stability, exhibit fluorescence emission, and show potent catalytic activity in converting NADH to NAD + . The effect of the substituents in the η 5 -Cp R ring for these zwitterionic complexes on their anticancer activity was systematically investigated. Surprisingly, the presence of fluorinated substituents gives rise to a significant increase in the anticancer activity. The lipophilicity and cellular uptake levels of these complexes appeared to be the primary factors for their cytotoxicity in this system. A microscopic mechanism study showed that the typical complex Ir4 entered A549 cancer cells through an energy-dependent pathway and was mainly located in lysosomes. Furthermore, an increase in ROS level, apoptosis induction, and cell-cycle perturbation together contribute to the anticancer potency of these zwitterionic complexes.

16-Electron Half-Sandwich Rhodium(III), Iridium(III), and Ruthenium(II) Complexes as Lysosome-Targeted Anticancer Agents

“…Pt drugs have achieved great success in the field of cancer chemotherapy. − However, the side effect of these Pt drugs has led chemotherapy research toward alternate anticancer agents such as Ru, Rh, Ir, and Os complexes. − In particular, organometallic half-sandwich complexes of some platinum group metals (Ru, Rh, Ir, and Os) have received considerable attention due to their easy tunable structure, high potency toward cancer cells, and specific mechanism of actions (MoAs). − Generally, the central metals of these 18-electron complexes [(η 5 -Cp)/(η 6 -arene)­M­(XY)­Cl] 0/+ (Cp = functionalized cyclopentadienyl; M = Ru, Rh, Ir, Os; XY = bidentate ligands) have adopted six-coordinated geometry, where the chlorine atom, the bidentate ligand XY, and η 5 -Cp/η 6 -arene occupy one coordination site, two coordination sites, and three coordination sites, respectively (Scheme , I ). It should be noted that hydrolysis of M–Cl bonds, i.e., Cl – /H 2 O exchange, usually represents an activation step for these 18-electron complexes, since M–H 2 O aqua were usually more reactive than the corresponding chloride analogues .…”

Formation of Iridium(III) and Rhodium(III) Amine, Imine, and Amido Complexes Based on Pyridine–Amine Ligands: Structural Diversity Arising from Reaction Conditions, Substituent Variation, and Metal Centers

“…Platinum metal-based anticancer drugs have achieved great success in the treatment of various tumors. − However, side effects and drug resistance have stimulated exploration of alternative metal complexes. − Among these complexes, half-sandwich organometallic platinum group metal-based (ruthenium, iridium, rhodium, and osmium) complexes with the piano-stool configuration have been well studied as anticancer agents. − These complexes have shown promising anticancer activity and some different mechanisms of action (MoAs) with platinum drugs. For example, Sadler and co-workers reported that the high-potency phenylpyridine iridium­(III) complexes (Scheme , I ) induced a significant increase in reactive oxygen species (ROS) in cancer cells, which involved catalytic hydride transfer from the coenzyme NADH to oxygen to generate the ROS hydrogen peroxide (H 2 O 2 ). , Our group has also found that the cationic half-sandwich pyridyl–imine iridium­(III) and ruthenium­(II) complexes could produce significant levels of ROS, disrupt the mitochondrial membrane, and show potent anticancer activity toward A549 cancer cells (Scheme , II and III ). , Interestingly, some ruthenium­(II) complexes achieved good selectivity toward cancer cells and normal cells. , More recently, we further demonstrated that the metal variation in the zwitterionic pyridyl–imine half-sandwich complexes and the introduction of fluorinated substituents resulted in a significant increase in the anticancer activity (Scheme , IV ). − Notably, the coordination fashion of the abovementioned pyridyl–imine half-sandwich iridium­(III) complexes was imine-metal. Along this line, we became interested in expanding our investigation to the synthesis and biological evaluation of the corresponding amine–metal and amido–metal complexes (Scheme ).…”

Synthesis of NNN Chiral Ruthenium Complexes and Their Cytotoxicity Studies

“…While considerable research has been made on nonplatinum drugs based on titanium, iron, gallium, tin, iridium, and gold, the ruthenium , -based drugs have received special attention in cancer treatment, as they are not only less toxic , with an attractive redox kinetics property but also demonstrate in vivo performances that are quite similar to those of platinum-based drugs . In addition, ruthenium faithfully mimics iron in its interaction with proteins, which leads to a selective communication with cancer cells via two favorable oxidation states (II) and (III).…”