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

Making Functionality More General

The definition for the notion of a "function" is not cast in stone, but depends upon what we adopt as types in our language. With partial equivalence relations (pers) as types in a relational language, we show that the functional relations are precisely those satisfying the simple equation f = f o fu o f, where "o" and "u" are respectively the composition and converse operators for relations. This article forms part of "A calculational theory of pers as types"

Dimensionnement d’un imageur grand champ et haute résolution angulaire pour la détection de menaces à longue portée

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On the Constancy of the Diameter of the Sun during the Rising Phase of Solar Cycle 24

International audienceThe potential relationship between solar activity and changes in solar diameter remains the subject of debate and requires both models and measurements with sufficient precision over long periods of time. Using the PICARD instruments, we carried out precise measurements of variations in solar diameter during the rising phase of solar cycle 24. From new correction methods we found changes in PICARD space telescope solar radius amplitudes that were less than ±20 mas (i.e. ±14.5 km) for the years 2010–2011. Moreover, PICARD ground-based telescope solar radius amplitudes are smaller than ±50 mas from 2011 to 2014. Our observations could not find any direct link between solar activity and significant fluctuations in solar radius, considering that the variations, if they exist, are included within this range of values. Further, the contribution of solar radius fluctuations is low with regard to variations in total solar irradiance. Indeed, we find a small variation of the solar radius from space measurements with a typical periodicity of 129.5 days, with ±6.5 mas variation

Design of an αZ Wide-field and High Angular Resolution Imaging System in the Visible Spectrum

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