Ingo Ott

Organometallic Anticancer Compounds

The quest for alternative drugs to the well-known cisplatin and its derivatives, which are still used in more than 50% of the treatment regimes for patients suffering from cancer, is highly needed.1,2 Despite their tremendous success, these platinum compounds suffer from two main disadvantages: they are inefficient against platinum-resistant tumors, and they have severe side effects such as nephrotoxicity. The latter drawback is the consequence of the fact that the ultimate target of these drugs is ubiquitous: It is generally accepted that Pt anticancer drugs target DNA, which is present in all cells.3,4 Furthermore, as a consequence of its particular chemical structure, cisplatin in particular offers little possibility for rational improvements to increase its tumor specificity and thereby reduce undesired side effects. In this context, organometallic compounds, which are defined as metal complexes containing at least one direct, covalent metal−carbon bond, have recently been found to be promising anticancer drug candidates. Organometallics have a great structural variety (ranging from linear to octahedral and even beyond), have far more diverse stereochemistry than organic compounds (for an octahedral complex with six different ligands, 30 stereoisomers exist!), and by rational ligand design, provide control over key kinetic properties (such as hydrolysis rate of ligands). Furthermore, they are kinetically stable, usually uncharged, and relatively lipophilic and their metal atom is in a low oxidation state. Because of these fundamental differences compared to “classical coordination metal complexes”, organometallics offer ample opportunities in the design of novel classes of medicinal compounds, potentially with new metal-specific modes of action. Interestingly, all the typical classes of organometallics such as metallocenes, half-sandwich, carbene-, CO-, or π-ligands, which have been widely used for catalysis or biosensing purposes, have now also found application in medicinal chemistry (see Figure ​Figure11 for an overview of these typical classes of organometallics). Figure 1 Summary of the typical classes of organometallic compounds used in medicinal chemistry. In this Perspective, we report on the recent advances in the discovery of organometallics with proven antiproliferative activity. We are emphasizing those compounds where efforts have been made to identify their molecular target and mode of action by biochemical or cell biology studies. This Perspective covers more classes of compounds and in more detail than a recent tutorial review by Hartinger and Dyson.(5) Furthermore, whereas recent reviews and book contributions attest to the rapid development of bioorganometallic chemistry in general,6,7 this Perspective focuses on their potential application as anticancer chemotherapeutics. Another very recent review article categorizes inorganic anticancer drug candidates by their modes of action.(8) It should be mentioned that a full description of all currently investigated types of compounds is hardly possible anymore in a concise review. For example, a particularly promising class of organometallic anticancer compounds, namely, radiolabeled organometallics, has been omitted for space limitations. Recent developments of such compounds have been reviewed in detail by Alberto.(9)

Benzimidazol-2-ylidene gold(I) complexes are thioredoxin reductase inhibitors with multiple antitumor properties.

Gold(I) complexes such as auranofin have been used for decades to treat symptoms of rheumatoid arthritis and have also demonstrated a considerable potential as new anticancer drugs. The enzyme thioredoxin reductase (TrxR) is considered as the most relevant molecular target for these species. The here investigated gold(I) complexes with benzimidazole derived N-heterocyclic carbene (NHC) ligands represent a promising class of gold coordination compounds with a good stability against the thiol glutathione. TrxR was selectively inhibited by in comparison to the closely related enzyme glutathione reductase, and all complexes triggered significant antiproliferative effects in cultured tumor cells. More detailed studies on a selected complex revealed a distinct pharmacodynamic profile including the high increase of reactive oxygen species formation, apoptosis induction, strong effects on cellular metabolism (related to cell surface properties, respiration, and glycolysis), inhibition of mitochondrial respiration and activity against resistant cell lines.

Cellular Uptake, Cytotoxicity, and Metabolic Profiling of Human Cancer Cells Treated with Ruthenium(II) Polypyridyl Complexes [Ru(bpy)2(N-N)]Cl2 with N-N = bpy, phen, dpq, dppz, and dppn

A series of five ruthenium(II) polypyridyl complexes [Ru(bpy)2(NN)]Cl2 was tested against human HT‐29 and MCF‐7 cancer cell lines. Cellular uptake efficiency and cytotoxicity were found to increase with the size of the aromatic surface area of the NN ligand. The most active compound carrying the dppn ligand exhibits a low micromolar IC50 value against both cell lines comparable to that of cisplatin under similar conditions. Continuous measurement of oxygen consumption, extracellular acidification rate, and impedance of the cell layer with a chip‐based sensor system upon exposure to the complexes showed only small changes for the first two parameters throughout the series. A significant and irreversible decrease in impedance was, however, found for the dppn compound. This suggests that its biological activity is related to modifications in cell morphology or cell–cell and cell–matrix contacts.

Comparative in vitro evaluation of N-heterocyclic carbene gold(I) complexes of the benzimidazolylidene type.

Gold(I) complexes with a 1,3-diethylbenzimidazol-2-ylidene N-heterocyclic carbene (NHC) ligand of the type NHC-Au-L (L=-Cl, -NHC, or -PPh3) were comparatively evaluated as thioredoxin reductase (TrxR) inhibitors and antimitochondrial anticancer agents. Different effects were noted in various biochemical assays (e.g., inhibition of TrxR, cellular and mitochondrial uptake, or effects on mitochondrial membrane potential), and this was related to properties of the complexes such as bond dissociation energies and overall charge. Remarkable antiproliferative effects, a strong induction of apoptosis, and enhancement of reactive oxygen species (ROS) formation as well as other effects on tumor cell metabolism confirmed the promising potential of the complexes as novel anticancer chemotherapeutics.

On the Biological Properties of Alkynyl Phosphine Gold(I) Complexes

Gold complexes have a long tradition in the treatment of the symptoms of rheumatoid arthritis. 2] Therapeutically used drugs include mainly gold(I) thiolates (e.g. aurothiomalate and auranofin), which belong to the group of diseasemodifying antirheumatic drugs (DMARDs) that are used to slow down or stop the progression of this severe and disabling rheumatic disorder. Interestingly, in vitro studies on cultured tumor cells have also indicated the considerable potential of this class of metallodrugs for tumor chemotherapy, and thioredoxin reductase is one of the enzymes identified as a critical target. Intensified research on the development of gold antitumor drugs has led to many active species such as gold(I) complexes with phosphine, thiolate, chloride, and carbene ligands as well as gold(III) derivatives. 10–12] However, a major issue in the development of new bioactive gold complexes is the preparation of complexes that show suitable stability under physiological conditions. Gold complexes with alkynyl ligands, which are widely used because of their catalytic and luminescent properties, might display reasonably stable coordinative bonds. In fact, recent initial reports on the bioactivity of alkynyl gold complexes indicate that this type of organometallic complex offers opportunities for the development of new chemotherapeutics against cancer and infectious diseases. Despite these prospectives, only three studies on the biological potential of alkynyl gold complexes have been reported so far. Here, we present the outcome of a pilot study aimed at establishing the biological profile of alkynyl phosphine gold(I) complexes. Our study shows that the critical target enzyme thioredoxin reductase can be efficiently and selectively inhibited and that cysteine and selenocysteine residues are presumably the sites of molecular interaction with the enzyme. Moreover, we quantified the cellular uptake of the complexes, established their effects on tumor cell metabolism and mitochondrial respiration, and investigated their antiangiogenic properties in zebrafish embryos. A series of six alkynyl gold(I) complexes (1–6, see Figure 1) was prepared by reacting the respective alkynes with chloro(triphenylphosphine)gold(I). The structures were confirmed by H, C, P NMR, and IR spectroscopy and

Modulation of the Biological Properties of Aspirin by Formation of a Bioorganometallic Derivative

Despite recent advances in modern tumor therapy the development of effective drugs remain a challenge for medicinal chemists. The demand for innovative agents triggers interest in novel chemical strategies and new concepts for modern drug design. The vast majority of drugs used to date are purely “organic” compounds. However, stimulated by the tremendous success of the inorganic compound cisplatin in modern tumor therapy, interest in the development of other metal complexes has been rapidly growing. Bioorganometallic chemistry is a novel emerging field in medicinal chemistry, which aims at probing the biological (and therapeutic) potential of organometallic compounds. As a result of their different coordination geometries, chemical properties, and reactivities, metal complexes offer a wide spectrum of functional groups more or less unexplored in modern drug design and development. The hexacarbonyldicobalt moiety Co2(CO)6 bound to an alkyne, is one such functional group, for which promising results on medical applications have been reported. For example, Co2(CO)6 derivatives of antiepileptic drugs (e.g. carbamazepine) were used as diagnostic tools in the so-called carbonyl metallo immuno assay (CMIA), and complexes with fructopyranose, nucleoside, and neuropeptide ligands displayed interesting bioactivities. We have recently reported on alkyne hexacarbonyldicobalt species with promising antiproliferative properties. Interestingly, the cell growth inhibitory activity of the complexes depended strongly on the chemical structure of the alkyne ligand. Weakly active and inactive derivatives showed that the cobalt cluster does not cause general (unspecific) cytotoxic effects. In further studies the Co2(CO)6 complex of the aspirin (o-acetylsalicylic acid, ASS) derivative prop-2-ynyl-2-acetoxybenzoate (Co-ASS) emerged as a lead compound for this class of antiproliferative agents.

Preclinical and Clinical Studies on the Use of Platinum Complexes for Breast Cancer Treatment

As platinum compounds display high antitumoral efficacy against several breast cancer cell lines in-vitro they may be an interesting option for future clinical therapy of this disease. On the preclinical stage hormonally active and tissue selective platinum anticancer drugs have been investigated. Clinical trials on established platinum drugs (mainly cisplatin and carboplatin) showed that they can be efficient cytostatics for breast cancer therapy, if patients are carefully selected and suitable combination regimens (e.g. including taxanes) are administered. This review covers the latest findings about new platinum complexes in preclinical studies on the use against breast cancer as well as the outcome of the most relevant clinical trials.

Naphthalimide gold(I) phosphine complexes as anticancer metallodrugs

Gold(I) phosphine complexes exhibit promising properties for anticancer drug development. Here we report on a series of gold(I) phosphine complexes containing a naphthalimide ligand. Strong antiproliferative effects were observed in MCF-7 breast cancer cells as well as in HT-29 colon carcinoma cells. The cellular and nuclear gold levels were increased compared to analogues, in which the naphthalimide ligand was replaced by a chloro ligand. Compound 4a was selected for more detailed biochemical and biological studies, which revealed solvent dependent fluorescence emission, uptake of the compound into the organelles of tumor cells as well as antiangiogenic effects concerning angiogenesis and tumor-induced angiogenesis in vivo. Antiangiogenic properties of 4a were observed in two different zebrafish angiogenesis models, including a tumor-cell induced neovascularization assay.

A spontaneous gold(I)-azide alkyne cycloaddition reaction yields gold-peptide bioconjugates which overcome cisplatin resistance in a p53-mutant cancer cell line

Solid-phase peptide synthesis (SPPS) is a versatile technique for the assembly of small to medium size peptides, that can help in the delivery of bound metal complexes to certain cellular compartments, for example in cancer cells. This work shows a new route to gold-peptide bioconjugates via a non-catalyzed [3 + 2] cycloaddition reaction of gold azides with alkynyl peptides. Gold(I) tetrapeptide conjugates with a mitochondria-targeting sequence were synthesized and display prolonged stability in the presence of thiol-containing biological media. Their antiproliferative potency against selected cancer cells (2–50 μM) corresponds to the lipophilicity of the conjugates. The cellular uptake of Au, determined by atomic absorption spectroscopy (AAS), shows that high initial uptake equals strong cytotoxicity. Respiration and acidification rates react immediately upon treatment with the Au-peptide conjugates, and a terminal breakdown of essential cellular functions is complete within ca. 12 h at most, as observed by online monitoring of the cancer cell metabolism in a microfluidic biosensor device (Bionas sensorchip system). The mode of action of these Au-peptide bioconjugates was elucidated by a variety of biochemical and cell biological experiments. First, a strong selective inhibition of the enzyme thioredoxin reductase (TrxR), a regulator of cellular redox processes, was found. In this context, elevated levels of reactive oxygen species (ROS) and strong effects on the respiration of isolated mouse liver mitochondria were found. These finally lead to cell death via apoptotic pathways, as indicated by flow cytometry, low mitochondrial membrane potential (MMP) and DNA fragmentation. Intriguingly, cisplatin-resistance in p53-mutant MDA-MB231 breast cancer cells could be overcome by the Au-peptide conjugates presented herein.

Sulfur-substituted naphthalimides as photoactivatable anticancer agents: DNA interaction, fluorescence imaging, and phototoxic effects in cultured tumor cells

A series of sulfur-substituted naphthalimides (1-5) was prepared and investigated as antitumor drugs. Initial DNA interaction studies (by the fluorescence quenching method, UV/vis and CD spectroscopy, thermal denaturation, topoisomerase Western blot analysis, and DNA photocleavage experiments) expectedly suggested the DNA and topoisomerase as main targets of the agents. Fluorescence spectroscopic and microscopic experiments indicated a significant sensitivity of the emission intensities of 3 and 5 to the cellular environment and confirmed the cellular uptake and biodistribution into cell compartments for 1-3 and 5. A comparative evaluation of the antiproliferative effects under different experimental setups (concerning drug exposure period and an additional short-time UV irradiation) revealed significant phototoxic effects for the environmentally sensitive compounds 3 and 5 and strongly suggested the further development of sulfur-substituted naphthalimides for potential use in photodynamic tumor therapy.