Methyl-cyclopentadienyl Ruthenium Compounds with 2,2′-Bipyridine Derivatives Display Strong Anticancer Activity and Multidrug Resistance Potential

Abstract

New ruthenium methyl-cyclopentadienyl compounds bearing bipyridine derivatives with the general formula [Ru(η-MeCp)(PPh)(4,4'-R-2,2'-bpy)] (Ru1, R = H; Ru2, R = CH; and Ru3, R = CHOH) have been synthesized and characterized by spectroscopic and analytical techniques. Ru1 crystallized in the monoclinic P2/ c, Ru2 in the triclinic P1̅, and Ru3 in the monoclinic P2/ n space group. In all molecular structures, the ruthenium center adopts a "piano stool" distribution. Density functional theory calculations were performed for all complexes, and the results support spectroscopic data. Ru1 and Ru3 were poor substrates of the main multidrug resistance human pumps, ABCB1, ABCG2, ABCC1, and ABCC2, while Ru2 displayed inhibitory properties of ABCC1 and ABCC2 pumps. Importantly, all compounds displayed a very high cytotoxic profile for ovarian cancer cells (sensitive and resistant) that was much more pronounced than that observed with cisplatin, making them very promising anticancer agents.

New Findings in Metal Complexes with Antiproliferative Activity Containing 1,3,5‐Triaza‐7‐phosphaadamantane (PTA) and Derivative Ligands

“…These complexes could also act as carriers for metal ions through the blood-brain barrier, allowing them to act as metallotherapeutics in the central nervous system. [28] Recently new Pt-PTA complexes (16,17, Scheme 3) with improved antiproliferative properties have been published. Structure of Pt and Ru complexes of PTA 7-9.…”

“…[4][5][6]17] The ligands PTA and dmoPTA have showed to be excellent to stabilize low valence metal oxidation states and provide an adequate hydrophilic/hydrophobic balance. Ligands could stabilize a particular metal coordination geometry and oxidation state, and are also very important to determine the complex solubility.…”

One Step Up in Antiproliferative Activity: The Ru‐Zn Complex [RuCp(PPh3)2‐µ‐dmoPTA‐1κP:2κ2N,N′‐ZnCl2](CF3SO3)

“…Stabilized Ru II complexes containing adequate ligands display the suitable redox and ligand‐exchange properties needed to react with cancer cells. An accurate choice of the ligands coordinate to the metal could provide a selective antiproliferative activity of the formed complexes, killing the cancer cells selectively , . Additionally, the ligands are also useful for providing the optimal solubility for the complex both in water, the main component of living organism, and organic systems, such as the membrane cells.…”

“…The hydrophilic/hydrophobic balance of a specie determines the in vivo behaviour and efficient under physiological conditions. [3b], The first report on the use of a water‐soluble phosphine as ligand in developing anticancer ruthenium complexes dates back to 2011, when Dyson et al, prepared a family of organometallic ruthenium compounds containing the hydrophilic phosphine 1,3,5‐triaza‐7‐phosphaadamantane (PTA), which displayed significant anticancer activity towards different cancer cell lines, and particularly against platinum resistant cancer cells. Hydrolysis and the loss of one or more ligands are important processes in the mechanism of action of these water soluble ruthenium drugs due to increasing the number of potential targetable molecules.…”

CpRu Complexes Containing Water Soluble Phosphane PTA and Natural Purines Adenine, Guanine and Theophylline: Synthesis, Characterization, and Antiproliferative Properties

“…The design of antiproliferative metal complexes requires, additionally to an active metal, the adequate combination of appropriate ligands that modulate both the activity and the partition coefficient of the complex. The latter has been found to be a factor of main importance to increase the cytotoxicity: the complex has to solubilize in both the water‐rich plasma and the hydrophobic cell membrane …”