Tina Riedel

Fighting Cancer with Transition Metal Complexes: From Naked DNA to Protein and Chromatin Targeting Strategies

Many transition metal complexes have unique physicochemical properties that can be efficiently exploited in medicinal chemistry for cancer treatment. Traditionally, double‐stranded DNA has been assumed to be the main binding target; however, recent studies have shown that nucleosomal DNA as well as proteins can act as dominant molecular binding partners. This has raised new questions about the molecular determinants that govern DNA versus protein binding selectivity, and has offered new ways to rationalize their biological activity and possible side effects. To address these questions, molecular simulations at an atomistic level of detail have been used to complement, support, and rationalize experimental data. Herein we review some relevant studies—focused on platinum and ruthenium compounds—to illustrate the power of state‐of‐the‐art molecular simulation techniques and to demonstrate how the interplay between molecular simulations and experiments can make important contributions to elucidating the target preferences of some promising transition metal anticancer agents. This contribution aims at providing relevant information that may help in the rational design of novel drug‐discovery strategies.

Synthesis and Antiproliferative Activity of New Ruthenium Complexes with Ethacrynic-Acid-Modified Pyridine and Triphenylphosphine Ligands

Pyridine- and phosphine-based ligands modified with ethacrynic acid (a broad acting glutathione transferase inhibitor) were prepared and coordinated to ruthenium(II)-arene complexes and to a ruthenium(III) NAMI-A type complex. All the compounds (ligands and complexes) were fully characterized by analytical and spectroscopic methods and, in one case, by single-crystal X-ray diffraction. The in vitro anticancer activity of the compounds was studied, with the compounds displaying moderate cytotoxicity toward the human ovarian cancer cell lines. All the complexes led to similar levels of residual GST activity in the different cell lines, irrespective of the stability of the Ru-ligand bond.

New Class of Half-Sandwich Ruthenium(II) Arene Complexes Bearing the Water-Soluble CAP Ligand as an in Vitro Anticancer Agent

Ruthenium(II) arene complexes of 1,4,7-triaza-9-phosphatricyclo[5.3.2.1]tridecane (CAP) were obtained. Cytotoxicity studies against cancer cell lines reveal higher activity than the corresponding PTA analogues and, in comparison to the effects on noncancerous cells, the complexes are endowed with a reasonable degree of cancer cell selectivity.

Cytotoxic Half-Sandwich Rh(III) and Ir(III) β-Diketonates

A series of half-sandwich pentamethylcyclopentadienyl rhodium(III) and iridium(III) complexes [Cp*M(DBM/HDB/AVB)Cl] and [Cp*M(DBM/HDB/AVB)(PTA)][SO3CF3], where Cp* = pentamethylcyclopentadienyl, the proligands DBMH = dibenzoylmethane, HDBH = o-hydroxydibenzoylmethane, AVBH = avobenzone, and PTA = 1,3,5-triaza-7-phosphaadamantane, is reported. All the complexes were characterized by IR, 1H and 13C NMR spectroscopy, electrospray ionization mass spectrometry, elemental analysis, and DFT calculations. Five of the complexes have also been characterized in the solid-state by X-ray crystallography. The cytotoxicity of the complexes has been evaluated against human ovarian A2780 and A2780cisR cell lines and, with the only exception of complexes 1 and 2 that display a negligible cytotoxicity, exhibit moderate cytotoxicity toward both cancer cell lines. However, the complexes do not show cancer cell selectivity with respect to human embryonic kidney HEK293 cells.

Regulating the anticancer properties of organometallic dendrimers using pyridylferrocene entities: synthesis, cytotoxicity and DNA binding studies

A new series of eight first- and second-generation heterometallic ferrocenyl-derived metal-arene metallodendrimers, containing ruthenium(ii)-p-cymene, ruthenium(ii)-hexamethylbenzene, rhodium(iii)-cyclopentadienyl or iridium(iii)-cyclopentadienyl moieties have been prepared. The metallodendrimers were synthesized by first reacting DAB-(NH2)n (where n = 4 or 8, DAB = diaminobutane) with salicylaldehyde, and then the Schiff-base dendritic ligands were reacted in a one-pot reaction with the appropriate [(η(6)-p-iPrC6H4Me)RuCl2]2, [(η(6)-C6Me6)RuCl2]2, [(η(5)-C5Me5)IrCl2]2 or [(η(5)-C5Me5)RhCl2]2 dimers, in the presence of 4-pyridylferrocene. Heterometallic binuclear analogues were prepared as models of the larger metallodendrimers. All complexes have been characterized using analytical and spectroscopic methods. The cytotoxicity of the heterometallic metallodendrimers and their binuclear analogues were evaluated against A2780 cisplatin-sensitive and A2780cisR cisplatin-resistant human ovarian cancer cell lines and against a non-tumorigenic HEK-293 human embryonic kidney cell line. The second generation Ru(ii)-η(6)-C6Me6 metallodendrimer is the most cytotoxic and selective compound. DNA binding experiments reveal that a possible mode-of-action of these compounds involves non-covalent interactions with DNA.

Nucleosome acidic patch-targeting binuclear ruthenium compounds induce aberrant chromatin condensation

The ‘acidic patch’ is a highly electronegative cleft on the histone H2A–H2B dimer in the nucleosome. It is a fundamental motif for protein binding and chromatin dynamics, but the cellular impact of targeting this potentially therapeutic site with exogenous molecules remains unclear. Here, we characterize a family of binuclear ruthenium compounds that selectively target the nucleosome acidic patch, generating intra-nucleosomal H2A-H2B cross-links as well as inter-nucleosomal cross-links. In contrast to cisplatin or the progenitor RAPTA-C anticancer drugs, the binuclear agents neither arrest specific cell cycle phases nor elicit DNA damage response, but rather induce an irreversible, anomalous state of condensed chromatin that ultimately results in apoptosis. In vitro, the compounds induce misfolding of chromatin fibre and block the binding of the regulator of chromatin condensation 1 (RCC1) acidic patch-binding protein. This family of chromatin-modifying molecules has potential for applications in drug development and as tools for chromatin research.Histone H2A–H2B dimers in nucleosomes contain an acidic patch, a highly electronegative cleft. Here, the authors characterize a family of binuclear ruthenium compounds that selectively target the acidic patch, generating intra-nucleosomal H2A-H2B cross-links as well as inter-nucleosomal cross-links.

Chemo-manipulation of tumor blood vessels by a metal-based anticancer complex enhances antitumor therapy

Human pleural mesothelioma is an incurable and chemoresistant cancer. Using a nude mouse xenograft model of human pleural mesothelioma, we show that RAPTA-T, a compound undergoing preclinical evaluation, enhances tumor vascular function by decreasing blood vessel tortuosity and dilation, while increasing the coverage of endothelial cells by pericytes and vessel perfusion within tumors. This in turn significantly reduces the interstitial fluid pressure and increases oxygenation in the tumor. Consequently, RAPTA-T pre-treatment followed by the application of cisplatin or liposomal cisplatin (Lipoplatin) leads to increased levels of the cytotoxin in the tumor and enhanced mesothelioma growth inhibition. We demonstrate that the vascular changes induced by RAPTA-T are related, in part, to the inhibition of poly-(ADP-ribose) polymerase 1 (PARP-1) which is associated to tumor vascular stabilization. These findings suggest novel therapeutic implications for RAPTA-T to create conditions for superior drug uptake and efficacy of approved cytotoxic anti-cancer drugs in malignant pleural mesothelioma and potentially other chemoresistant tumors.

Drug Repurposing Approach Identifies a Synergistic Drug Combination of an Antifungal Agent and an Experimental Organometallic Drug for Melanoma Treatment

By screening a drug library comprising FDA approved compounds, we discovered a potent interaction between the antifungal agent haloprogin and the experimental organometallic drug RAPTA-T, to synergistically induce cancer cell killing. The combination of these two small molecules, even at low doses, elicited an improved therapeutic response on tumor growth over either agent alone or the current treatment used in the clinic in the highly aggressive syngeneic B16F10 melanoma tumor model, where classical cytotoxic chemotherapeutic agents show little efficacy. The combination with the repurposed chemodrug haloprogin provides the basis for a new powerful treatment option for cutaneous melanoma. Importantly, because synergistic induction of tumor cell death is achieved with low individual drug doses, and cellular targets for RAPTA-T are different from those of classical chemotherapeutic drugs, a therapeutic strategy based on this approach could avoid toxicities and potentially resistance mechanisms, and could even inhibit metastatic progression.

Palladium(II)-Stabilized Pyridine-2-Diazotates: Synthesis, Structural Characterization, and Cytotoxicity Studies

Well-defined diazotates are scarce. Here we report the synthesis of unprecedented homoleptic palladium(II) diazotate complexes. The palladium(II)-mediated nitrosylation of 2-aminopyridines with NaNO2 results in the formation of metal-stabilized diazotates, which were found to be cytotoxic to human ovarian cancer cells.