Ruthenium(II) Polypyridyl Complexes Containing Simple Dioxo Ligands: a Structure‐Activity Relationship Study Shows the Importance of the Charge

Abstract

Cancer is one of the main causes of death worldwide. Platinum complexes (i. e., cisplatin, carboplatin, and others) are currently heavily used for the treatment of different types of cancer, but unwanted effects occur. Ruthenium complexes have been shown to be potential promising alternatives to these metalbased drugs. In this work, we performed a structure-activity relationship (SAR) study on two small series of Ru(II) polypyridyl complexes of the type [Ru(L1) 2 (O^O)]Cl n (3-8), where L1 is 4,7diphenyl-1,10-phenantroline (DIP) or 1,10-phenantroline (phen), and O^O is a symmetrical anionic dioxo ligand: oxalate (ox, n = 0), malonate (mal, n = 0), or acetylacetonate (acac, n = 1). These two self-consistent series of compounds allowed us to perform a systematic investigation for establishing how the nature of the ligands and the charge affect the anticancer properties of the complexes. Cytotoxicity tests on different cell lines demonstrated that some of the six compounds 3-8 have a promising anticancer activity. More specifically, the cationic complex [Ru(DIP) 2 (η 2 -acac)]Cl (4) has IC 50 values in the mid-nanomolar concentration range, lower than those of cisplatin on the same cell lines. Interestingly, [Ru(DIP) 2 (η 2 -acac)]Cl was found to localize mainly in the mitochondria, whereas a smaller fraction was detected in the nucleus. Overall, our SAR investigation demonstrates the importance of combining the positive charge of the complex with the highly lipophilic diimine ligand DIP.

A monoadduct generating Ru(ii) complex induces ribosome biogenesis stress and is a molecular mimic of phenanthriplatin

“…Ru( ii ) molecules containing dip ligands have been shown to induce mitochondrial dysfunction, 62 due to their lipophilicity and cationic charge. 63 As compound 2 contains the dip ligand, its impact on mitochondrial function was assessed. The Seahorse MitoStress profile for cells pre-treated with 2 at 6× the IC 50 value did not show any significant difference in response compared to the vehicle control ( Fig.…”

Strategies for the Nuclear Delivery of Metal Complexes to Cancer Cells

“…[116] SAR studies led on ruthenium(II) polypyridyl complexes (22-24; Figure 12) also showed that a slight change of dioxo ligand was enough to change the preferential localization of complex 24 to the mitochondria compared to complexes 22 and 23. [113,114] It is unclear whether the molecular target of all these compounds stayed the same, but an increase in lipophilicity is likely to be responsible for the higher cellular uptake observed and the mitochondrial localization.…”

“…However, a loss of nuclear localization was observed. [ 114 ] Barton and co‐workers reported a rhodium(III) metallo‐insertor that targets DNA mismatches and displays selectivity towards MMR‐deficient cells ( 25a ; Figure 12). [ 115 ] As expected, the complex was found to accumulate in the nucleus due to its DNA‐binding affinity, but interestingly, the introduction of a methyl substituent instead of a hydroxyl on two of the ligands redirected the resulting complex 25b to the mitochondria (Figure 12).…”

Photocytotoxic kinetically stable ruthenium(ii)-N,N-donor polypyridyl complexes of oxalate with anticancer activity against HepG2 liver cancer cells

“…These ligands provide multiple features for the modulation of physicochemical properties due to their redox non-innocent nature, electronic effects, variable charge and kinetic labilities, lipophilicities, etc., which are important parameters towards dictating the pharmacokinetic profiles of the designed cytotoxic Ru(II) complexes. 14 A. Notaro et al reported an in-depth structureactivity relationship (SAR)-based cytotoxicity study for a series of [Ru(DIP) 2 (sq/cat)] complexes via tuning the electronic structure of the dioxo (η 2 -O^O) ligands showing excellent in vitro and in vivo cytotoxicity involving multi-cellular targets appropriate to overcome acquired drug resistance. 15,16 Oxalic acid is opted as a ligand considering its biocompatibility, broad applications in industry and medicine, etc.…”