Designing organometallic compounds for catalysis and therapy

Bioorganometallic chemistry is a rapidly developing area of research. In recent years organometallic compounds have provided a rich platform for the design of effective catalysts, e.g. for olefin metathesis and transfer hydrogenation. Electronic and steric effects are used to control both the thermodynamics and kinetics of ligand substitution and redox reactions of metal ions, especially Ru II. Can similar features be incorporated into the design of targeted organometallic drugs? Such complexes offer potential for novel mechanisms of drug action through incorporation of outer-sphere recognition of targets and controlled activation features based on ligand substitution as well as metal- and ligand-based redox processes. We focus here on η 6-arene, η 5-cyclopentadienyl sandwich and half-sandwich complexes of Fe II, Ru II, Os II and Ir III with promising activity towards cancer, malaria, and other conditions. © 2012 The Royal Society of Chemistry

Conjugation of a Ru(II) Arene Complex to Neomycin or to Guanidinoneomycin Leads to Compounds with Differential Cytotoxicities and Accumulation between Cancer and Normal Cells

A straightforward methodology for the synthesis of conjugates between a cytotoxic organometallic ruthenium(II) complex and amino- and guanidinoglycosides, as potential RNA-targeted anticancer compounds, is described. Under microwave irradiation, the imidazole ligand incorporated on the aminoglycoside moiety (neamine or neomycin) was found to replace one triphenylphosphine ligand from the ruthenium precursor [(η6-p-cym)RuCl(PPh3)2]+, allowing the assembly of the target conjugates. The guanidinylated analogue was easily prepared from the neomycin-ruthenium conjugate by reaction with N,N′-di-Boc-N″-triflylguanidine, a powerful guanidinylating reagent that was compatible with the integrity of the metal complex. All conjugates were purified by semipreparative high-performance liquid chromatography (HPLC) and characterized by electrospray ionization (ESI) and matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) and NMR spectroscopy. The cytotoxicity of the compounds was tested in MCF-7 (breast) and DU-145 (prostate) human cancer cells, as well as in the normal HEK293 (Human Embryonic Kidney) cell line, revealing a dependence on the nature of the glycoside moiety and the type of cell (cancer or healthy). Indeed, the neomycin-ruthenium conjugate (2) displayed moderate antiproliferative activity in both cancer cell lines (IC50 ≈ 80 μM), whereas the neamine conjugate (4) was inactive (IC50 ≈ 200 μM). However, the guanidinylated analogue of the neomycin-ruthenium conjugate (3) required much lower concentrations than the parent conjugate for equal effect (IC50 = 7.17 μM in DU-145 and IC50 = 11.33 μM in MCF-7). Although the same ranking in antiproliferative activity was found in the nontumorigenic cell line (3 2 > 4), IC50 values indicate that aminoglycoside-containing conjugates are about 2-fold more cytotoxic in normal cells (e.g., IC50 = 49.4 μM for 2) than in cancer cells, whereas an opposite tendency was found with the guanidinylated conjugate, since its cytotoxicity in the normal cell line (IC50 = 12.75 μM for 3) was similar or even lower than that found in MCF-7 and DU-145 cancer cell lines, respectively. Cell uptake studies performed by ICP-MS with conjugates 2 and 3 revealed that guanidinylation of the neomycin moiety had a positive effect on accumulation (about 3-fold higher in DU-145 and 4-fold higher in HEK293), which correlates well with the higher antiproliferative activity of 3. Interestingly, despite the slightly higher accumulation in the normal cell than in the cancer cell line (about 1.4-fold), guanidinoneomycin-ruthenium conjugate (3) was more cytotoxic to cancer cells (about 1.8-fold), whereas the opposite tendency applied for neomycin-ruthenium conjugate (2). Such differences in cytotoxic activity and cellular accumulation between cancer and normal cells open the way to the creation of more selective, less toxic anticancer metallodrugs by conjugating cytotoxic metal-based complexes such as ruthenium(II) arene derivatives to guanidinoglycosides

Social innovations as a basis for sustainable development of the industrial region

The aim of the work is to study the relationship between the sustainable development of an industrial region and social innovations. The paper highlights its features high-quality economic growth, the pace of socio-economic development, lean manufacturing, the introduction of high technologies, ensuring economic security, social innovations, considering the studied theoretical ideas about the essence and content of sustainable development of the industrial region. The author’s interpretation of the economic content of the concept of “social innovations» is justified. They represent qualitative changes in the areas of continuous reproduction of human and social capital to eliminate contradictions in economic interests and improve personal and public well-being. The features of social innovations (anthropocentrism, strategic nature, inertia, specificity, synergy, creativity, high degree of risk), reflecting their qualitative certainty, are revealed. The author argues that social innovations are a multi-faceted and rather complex economic category, the content of which should be considered through its types and forms of implementation. Using the example of an industrial region, the Lipetsk region, the authors studied such types of social innovations as the social contract and social entrepreneurship. As a result of the research, it is established that the social contract can be one of the sources of social entrepreneurship, which in turn determines the reproductive function of social innovations. Also, social innovations are an effective tool for improving the level of personal and public well-being by reducing contradictions in society and reducing social tension

The formation of state capitalism models in the oil industry: Russia and the world

In modern conditions, issues related to the effectiveness of the regulation of the oil industry by the state are becoming increasingly important. In January 2018, the World Economic Forum was held in Davos, at which, in particular, the impact of the growth of protectionist trends in the global trade in hydrocarbons and the impact of climate change on the planet on the export of hydrocarbons was noted. As a result of the forum, the key ways of adjusting the policy of states in the relevant area were identified. At the same time, a significant number of states are already seeing the process of changing state regulation of the industry. Given the current crisis situation associated with the coronavirus pandemic, an increasing number of private enterprises are coming under state control, which gives rise to new discussions about the renaissance of the so-called state capitalism.. In this article, the authors examined country specific features, as well as various concepts of the formation and development of state capitalism in the oil industry

Valuable Insight into the Anticancer Activity of the Platinum-Histone Deacetylase Inhibitor Conjugate, <i>cis</i>-[Pt(NH₃)₂malSAHA_–2H)]

<i>cis</i>-[Pt^II(NH₃)₂(malSAHA_–2H)], a cisplatin adduct conjugated to a potent histone deacetylase inhibitor (HDACi), suberoylanilide hydroxamic acid (SAHA), was previously developed as a potential anticancer agent. This Pt–HDACi conjugate was demonstrated to have comparable cytotoxicity to cisplatin against A2780 ovarian cancer cells but significantly reduced cytotoxicity against a representative normal cell line, NHDF. Thus, with a view to (i) understanding more deeply the effects that may play an important role in the biological (pharmacological) properties of this new conjugate against cancer cells and (ii) developing the next generation of Pt–HDACi conjugates, the cytotoxicity, DNA binding, cellular accumulation and HDAC inhibitory activity of <i>cis</i>-[Pt^II(NH₃)₂(malSAHA_–2H)] were investigated and are reported herein. <i>cis</i>-[Pt^II(NH₃)₂(malSAHA_–2H)] was found to have marginally lower cytotoxicity against a panel of cancer cell lines as compared to cisplatin and SAHA. <i>cis</i>-[Pt^II(NH₃)₂(malSAHA_–2H)] was also found to accumulate better in cancer cells but bind DNA less readily as compared to cisplatin. DNA binding experiments indicated that c<i>is</i>-[Pt^II(NH₃)₂(malSAHA_–2H)] bound DNA more effectively in cellulo as compared to in cell-free media. Activation of the Pt–HDACi conjugate was therefore investigated. The binding of c<i>is</i>-[Pt^II(NH₃)₂(malSAHA_–2H)] to DNA was found to be enhanced by the presence of thiol-containing molecules such as glutathione and thiourea, and activation occurred in cytosolic but not nuclear extract of human cancer cells. The activity of <i>cis</i>-[Pt­(NH₃)₂(malSAHA_–2H)] as a HDAC inhibitor was also examined; the conjugate exhibited no inhibition of HDAC activity in CH1 cells. In light of these results, novel Pt–HDACi conjugates are currently being developed, with particular emphasis, through subtle structural modifications, on enhancing the rate of DNA binding and enhancing HDAC inhibitory activity

Organometallic half-sandwich iridium anticancer complexes

The low-spin 5d6 IrIII organometallic half-sandwich complexes [(η5-Cpx)Ir(XY)Cl]0/+, Cpx = Cp*, tetramethyl(phenyl)cyclopentadienyl (Cpxph), or tetramethyl(biphenyl)cyclopentadienyl (Cpxbiph), XY = 1,10-phenanthroline (4−6), 2,2′-bipyridine (7−9), ethylenediamine (10 and 11), or picolinate (12−14), hydrolyze rapidly. Complexes with N,N-chelating ligands readily form adducts with 9-ethylguanine but not 9-ethyladenine; picolinate complexes bind to both purines. Cytotoxic potency toward A2780 human ovarian cancer cells increases with phenyl substitution on Cp*: Cpxbiph > Cpxph > Cp*; Cpxbiph complexes 6 and 9 have submicromolar activity. Guanine residues are preferential binding sites for 4−6 on plasmid DNA. Hydrophobicity (log P), cell and nucleus accumulation of Ir correlate with cytotoxicity, 6 > 5 > 4; they distribute similarly within cells. The ability to displace DNA intercalator ethidium bromide from DNA correlates with cytotoxicity and viscosity of Ir−DNA adducts. The hydrophobicity and intercalative ability of Cpxph and Cpxbiph make a major contribution to the anticancer potency of their IrIII complexes

Differences in the cellular response and signaling pathways between cisplatin and monodentate organometallic Ru(II) antitumor complexes containing a terphenyl ligand

The new monofunctional Ru(II)-arene complex [(η6-arene)Ru(II)(en)Cl]+, where en = 1,2-diaminoethane and the arene is para-terphenyl (complex 1) exhibits promising cytotoxic effects in human tumor cells including those resistant to conventional cisplatin (J. Med. Chem.2008, 51, 5310). The present study is focused on the cellular pharmacology of 1 to elucidate more deeply the mechanisms underlying its antitumor effects. We have identified several cellular mechanisms induced by 1 in human ovarian carcinoma cells, including inhibition of DNA synthesis, overexpression and activation of p53, expression of proapoptotic proteins p21WAF1 and Bax, G0/G1 arrest, and nuclear fragmentation as a result of apoptotic, and, to a much lower extent, also necrotic processes. Thus, 1 inhibits growth of the cancer cells through induction of apoptotic cell death and G0/G1 cell cycle arrest. Further investigations have shown that 1 induces apoptosis by regulating the expression of Bcl-2 family proteins. There were significant differences in cellular responses to the treatment with 1 and with conventional cisplatin, particularly in the kinetics and the extent of these responses. In addition, the distinct p53 activation profile of 1 compared with cisplatin provides an explanation for the activity of this ruthenium drug against cisplatin-resistant cells. Hence complex 1 may provide an alternative therapy in patients with acquired cisplatin resistance, particularly with respect to its very low mutagenicity and different mode of action compared to platinum antitumor drugs in clinical use