Development of Ruthenium Antitumor Drugs that Overcome Multidrug Resistance Mechanisms

Abstract

Organometallic ruthenium(II) complexes of the general formula [Ru(eta6-p-cymene)Cl2(L)] and [Ru(eta6-p-cymene)Cl(L)2][BPh4] with modified phenoxazine- and anthracene-based multidrug resistance (MDR) modulator ligands (L) have been synthesized, spectroscopically characterized, and evaluated in vitro for their cytotoxic and MDR reverting properties in comparison with the free ligands. For an anthracene-based ligand, coordination to a ruthenium(II) arene fragment led to significant improvement of cytotoxicity as well as Pgp inhibition activity. A similar, but weaker effect was also observed when using a benzimidazole-phenoxazine derivative as Pgp inhibitor. The most active compound in terms of both Pgp inhibition and cytotoxicity is [Ru(eta6-p-cymene)Cl2(L)], where L is an anthracene-based ligand. Studies show that it induces cell death via inhibition of DNA synthesis. Moreover, because the complex is fluorescent, its uptake in cells was studied, and relative to the free anthracene-based ligand, uptake of the complex is accelerated and accumulation of the complex in the cell nucleus is observed.

Remarkable Anticancer Activity of Triruthenium-Arene Clusters Compared to Tetraruthenium-Arene Clusters

“…A feature of many of these compounds, notably those with the 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane (pta) ligand, is that although the activity is lower than that of cisplatin and related Pt(II) compounds in vitro, the activity against metastatic (secondary) tumours evaluated in vivo is high in the absence of activity against the primary cancers [9]. Furthermore, more cytotoxic agents can be prepared by incorporating specific ligands of known biological function [10].…”

Sawhorse-type diruthenium tetracarbonyl complexes containing porphyrin-derived ligands as highly selective photosensitizers for female reproductive cancer cells

“…The 3-(4,5-dimethyl-2-thiazoyl)-2,5-diphenyltetrazolium bromide cell survival test was performed 24 h after the irradiation. The LD 50 values (light dose necessary to inhibit 50% cell survival) were determined using the medium effect algorithm [27] that the complexes are taken up by HeLa, Ovcar, and A2780 cells and concentrate in the cell cytoplasm and organelles, but not in the nucleus, as did our previously reported compounds [19,20] but this contrasts with some ruthenium-based drugs known to accumulate in the nucleus [33,34]. Photodynamic studies provided coherent results compared with uptake studies since our complexes induce phototoxicities in HeLa cervix and A2780 ovary carcinoma cell lines and not in other cancer and normal fibroblast cells.…”

Anticancer activities of self-assembled molecular bowls containing a phenanthrene-based donor and Ru(II) acceptors

“…[15][16][17][18] Nanostructures based on halfsandwich arene-ruthenium complexes are promising candidates for cancer treatments, as they possess advantageous features such as low toxicity and a balance of hydrophilicity and hydrophobicity, a key issue for their transport in biological media. 19 Phenanthrene-derived synthetic and natural products have demonstrated a variety of pharmacological effects, such as cytotoxicity, phytotoxicity, and anti-inflammatory, antimicrobial, antioxidant, antiplatelet aggregation, and antiallergic activities. [20][21][22][23][24] These important findings laid the foundation for the design of new nano-sized self-assembled architectures with phenanthrene-derived donors and arene-Ru-based acceptors, with the expectation of improved biological results in comparison with available chemotherapeutic agents.…”