Alexey A. Nazarov

Organometallic Ruthenium(II) Arene Compounds with Antiangiogenic Activity

The antimetastatic ruthenium(II) compounds [Ru(η(6)-p-cymene)Cl(2)(PTA)] (PTA = 1,3,5-triaza-7-phosphaadamantane) (RAPTA-C) and [Ru(η(6)-toluene)Cl(2)(PTA)] (RAPTA-T), as well as their analogues [Ru(η(6)-p-cymene)Cl(2)(DAPTA)] (DAPTA = (3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane)) (DAPTA-C) and [Ru(η(6)-toluene)Cl(2)(DAPTA)] (DAPTA-T), respectively, were tested in in vitro bioassays for endothelial cell function. All compounds showed low toxicity profiles and similar dose-dependent antiproliferative effects in endothelial cells at ≥100 μg/mL (∼200 μM). EC migration, measured 6 h after drug exposure, was also efficiently inhibited (ED(50) of ∼300 μg/mL, ∼500 μM, for all compounds). Since no cytostatic effect was noted, the inhibition of proliferation was considered mainly to consist of antiangiogenic activity. RAPTA-T and DAPTA-C were also tested in vivo in the chicken chorioallantoic membrane (CAM) assay and found to inhibit CAM development. Importantly, effective prevention of revascularization of the CAM after vaso-occlusive photodynamic therapy was observed. The reported ruthenium complexes show promising antimetastatic activity involving inhibition of angiogenesis and therefore are attractive agents for development of anticancer therapies based on combination of chemo- and angiostatic treatments.

Ligand substitutions between ruthenium–cymene compounds can control protein versus DNA targeting and anticancer activity

Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favourable toxicity and clearance properties. Nonetheless, their molecular targeting and mechanism of action are poorly understood. Here we study two prototypical ruthenium-arene agents—the cytotoxic antiprimary tumour compound [(η6-p-cymene)Ru(ethylene-diamine)Cl]PF6 and the relatively non-cytotoxic antimetastasis compound [(η6-p-cymene)Ru(1,3,5-triaza-7-phosphaadamantane)Cl2]—and discover that the former targets the DNA of chromatin, while the latter preferentially forms adducts on the histone proteins. Using a novel ‘atom-to-cell’ approach, we establish the basis for the surprisingly site-selective adduct formation behaviour and distinct cellular impact of these two chemically similar anticancer agents, which suggests that the cytotoxic effects arise largely from DNA lesions, whereas the protein adducts may be linked to the other therapeutic activities. Our study shows promise for developing new ruthenium drugs, via ligand-based modulation of DNA versus protein binding and thus cytotoxic potential, to target distinguishing epigenetic features of cancer cells.

Transferring the concept of multinuclearity to ruthenium complexes for improvement of anticancer activity.

Multinuclear platinum anticancer complexes are a proven option to overcome resistance of established anticancer compounds. Transferring this concept to ruthenium complexes led to the synthesis of dinuclear Ru(II)-arene compounds containing a bis(pyridinone)alkane ligand linker. A pronounced influence of the spacer length on the in vitro anticancer activity was found, which is correlated to the lipophilicity of the complexes. IC(50) values in the same dimension as for established platinum drugs were found in human tumor cell lines. No cross-resistance to oxoplatin, a cisplatin prodrug, was observed for the most active complex in three resistant cell lines; in fact, a 10-fold reversal of sensitivity in two of the oxoplatin-resistant lines was found. (Bio)analytical characterization of the representative examples showed that the ruthenium complexes hydrolyze rapidly, forming predominantly diaqua species that exhibit affinity toward transferrin and DNA, indicating that both proteins and nucleobases are potential targets.

Metal-Based Inhibition of Poly(ADP-ribose) Polymerase - The Guardian Angel of DNA

The inhibition activity of a series of anticancer metal complexes based on platinum, ruthenium, and gold metal ions was evaluated on the zinc-finger protein PARP-1, either purified or directly on protein extracts from human breast cancer MCF7 cells. Information on the reactivity of the metal complexes with the PARP-1 zinc-finger domain was obtained by high-resolution ESI FT-ICR mass spectrometry. An excellent correlation between PARP-1 inhibition in protein extracts and the ability of the complexes to bind to the zinc-finger motif (in competition with zinc) was established. The results support a model whereby displacement of zinc from the PARP-1 zinc finger by other metal ions leads to decreased PARP-1 activity. In vitro combination studies of cisplatin with NAMI-A and RAPTA-T on different cancer cell lines (MCF7, A2780, and A2780cisR) showed that, in some cases, a synergistic effect is in operation.

Carbohydrate-Metal Complexes and their Potential as Anticancer Agents

Platinum complex-based chemotherapy is one of the major treatment options of many malignancies. Although severe side effects occur, and only a limited spectrum of tumors can be cured, Pt compounds are used in every second therapy scheme. Thus, many different drug design strategies have been employed for improving the properties of anticancer drugs including pH or redox activation in the tumor, variation of the metal center and therefore the redox and ligand exchange properties, the application of multinuclear metal complexes, the development of targeted approaches, etc. Application of carbohydrate-metal complexes is an example of a targeted approach exploiting the biochemical and metabolic functions of diverse sugars in living organisms for transport and accumulation. Natural carbohydrates and synthetic derivatives possess a manifold of donors endowing them with the ability to coordinate metal centers and providing some additional advantages over other ligands, e.g., biocompatibility, non-toxicity, enantiomeric purity, water solubility, and well-explored chemistry. In recent years, several examples of carbohydrate compounds have been developed for diverse medicinal applications ranging from compounds with antibiotic, antiviral, or fungicidal activity and anticancer compounds. Herein, metal complexes with carbohydrate ligands are reviewed and the role of the carbohydrate carriers on the antineoplastic activity of these compounds, both in vitro and in vivo, is described.

Polynuclear Ruthenium, Osmium and Gold Complexes. The Quest for Innovative Anticancer Chemotherapeutics

Polynuclear compounds are a relatively new and successful approach in metal-based cancer chemotherapy as typified by the trinuclear Pt compound BBR3464 which was evaluated in clinical trials. In this review, we discuss newer developments of polynuclear ruthenium, osmium and gold complexes, focusing on their anticancer activity. The compounds presented are often supposed to exert their anticancer activity by different modes of action as compared to established drugs, including newly proposed mechanisms such as enzyme inhibition, crosslinking of biomacromolecules or through photo-activation, though many of the examples are also capable of binding to DNA nucleobases. Important metabolization and chemical characteristics of such compounds are discussed, and if the appropriate data is available, molecular modes of action are highlighted.

Organometallic Antitumour Agents with Alternative Modes of Action

The therapeutic index of drugs that target DNA, a ubiquitous target present in nearly all cells, is low. Nevertheless, DNA has remained the primary target for medicinal chemists developing metal-based anticancer drugs, although DNA has been essentially abandoned in favour of non-genomic targets by medicinal chemists developing organic drugs. A number of organometallic drugs that target proteins/enzymes have been developed and these compounds, based on ruthenium, osmium and gold, are described in this chapter. Targets include cathepsin B, thioredoxin reductases, multidrug resistance protein (Pgp), glutathione S-transferases and kinases. It is found that compounds that inhibit these various targets are active against metastatic tumours, or tumours that are resistant to classical DNA damaging agents such as cisplatin, and therefore offer considerable potential in clinical applications.

{(1R,2R,4R)-4-Methyl-1,2-cyclohexanediamine}oxalatoplatinum(II): A Novel Enantiomerically Pure Oxaliplatin Derivative Showing Improved Anticancer Activity in Vivo

Novel derivatives of the clinically established anticancer drug oxaliplatin were synthesized. Cytotoxicity of the compounds was studied in six human cancer cell lines by means of the MTT assay. Additionally, most promising complexes were also investigated in cisplatin- and oxaliplatin-resistant human cancer cell models. The therapeutic efficacy in vivo was studied in the murine L1210 leukemia model. Most remarkably, {(1R,2R,4R)-4-methyl-1,2-cyclohexanediamine}oxalatoplatinum(II), comprising an equatorial methyl substituent at position 4 of the cyclohexane ring, was as potent as oxaliplatin in vitro but distinctly more effective in the L1210 model in vivo at the optimal dose. The advantage observed in the in vivo situation was mainly based on a more favorable therapeutic index. The maximum tolerated dose of the novel analogue was higher than that of oxaliplatin and caused a greater increase in life span (>200% versus 152%), with more animals experiencing long-term survival (5/6 versus 2/6). These data support further (pre)clinical development of the methyl-substituted oxaliplatin analogue with improved anticancer activity.

Anthracene-tethered ruthenium(II) arene complexes as tools to visualize the cellular localization of putative organometallic anticancer compounds.

Anthracene derivatives of ruthenium(II) arene compounds with 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane (pta) or a sugar phosphite ligand, viz., 3,5,6-bicyclophosphite-1,2-O-isopropylidene-α-d-glucofuranoside, were prepared in order to evaluate their anticancer properties compared to the parent compounds and to use them as models for intracellular visualization by fluorescence microscopy. Similar IC(50) values were obtained in cell proliferation assays, and similar levels of uptake and accumulation were also established. The X-ray structure of [{Ru(η(6)-C(6)H(5)CH(2)NHCO-anthracene)Cl(2)(pta)] is also reported.

Synthesis and characterization of a new class of anti-angiogenic agents based on ruthenium clusters

New triruthenium-carbonyl clusters derivatized with glucose-modified bicyclophosphite ligands have been synthesized. These compounds were found to have cytostatic and cytotoxic activity and depending on the number of bicyclophosphite ligands, and could be tuned for either anti-cancer or specific anti-angiogenic activity. While some compounds had a broad cellular toxicity profile in several cell types others showed endothelial cell specific dose-dependent anti-proliferative and anti-migratory efficacy. A profound inhibition of angiogenesis was also observed in the in vivo chicken chorioallantoic membrane (CAM) model, and consequently, these new compounds have considerable potential in drug design, e.g. for the treatment of cancer.