Arene ruthenium dichloro complexes containing isonicotinic ester ligands: Synthesis, molecular structure and cytotoxicity

Paul Joseph Dyson, Olivier Pierre Zava
Elsevier, 2013
Article

A series of p-cymene ruthenium dichloro complexes containing isonicotinic ester ligands, [(arene) RuCl2NC5H4-4-COO-C6H4-p-O-(CH2)(n)-CH3] (n = 1: 1, n = 3: 2, n = 5: 3, n = 7:4, n = 9: 5, n = 11: 6, n = 13: 7, n = 15: 8), were prepared from p-cymene ruthenium dichloro dimer and the corresponding isonicotinic ester ligand. The single-crystal X-ray analysis of 1 shows the molecule to adopt the usual pseudo-tetrahedral piano-stool geometry, the isonicotinic ester ligand being coordinated through the nitrogen atom. The cytotoxicity of all complexes and of the free ligands was studied towards human ovarian cancer cells; high activities were observed only for n = 9 (presenting a chain with ten carbon atoms), both as far as the free ligands and the complexes are concerned. Based on this result, a new isonicotinic ester ligand with a C-10 substituent containing a terminal alcohol function, NC5H4-4-COO-C6H4-p-O-(CH2)(10)-OH, was synthesized by a four-step method, and arene ruthenium complexes thereof, [(arene)RuCl2NC5H4-4-COO-C6H4-p-O-(CH2)(10)-OH] (arene = C6H6: 9a, arene = p-MeC6H4Pri: 9b, arene = C6Me6: 9c) were prepared. The complexes 9a and 9b show indeed remarkable anticancer activities, the IC50 values for human ovarian cancer cells being in the submicromolar range. The highest cytotoxicity was observed for complex 9b, with IC50 values of 0.18 mu M for A2780 and 3.04 mu M for the cisplatin-resistant mutant A2780cisR. (C) 2012 Elsevier B.V. All rights reserved.

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Paul Joseph Dyson, Olivier Pierre Zava
Elsevier, 2013
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https://infoscience.epfl.ch/record/189229?ln=fr

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Synthesis, structural characterization and cytotoxicity of bimetallic chlorogold(I) phosphine complexes employing functionalized phosphinoferrocene carboxamides

Paul Joseph Dyson, Tina Riedel

Gold( I) phosphine complexes of the general formula [AuCl(Ph(2)PfcCONHY-kappa P)], where Y is CH2CO2Me (7), CH2CONH2 (8), CH2CH2OH (9), CH(CH2OH)(2) (10), C(CH2OH)(3) (11), and CH2SO3(HNEt3) (12), and fc is ferrocene-1,1'-diyl, were prepared from [AuCl(tht)] (tht = tetrahydrothiophene) and the appropriate phosphinoferrocene carboxamides (1-6). The compounds were characterized by spectroscopic and analytical methods, and the molecular structures of 7 and 9 were determined by single-crystal X-ray crystallography. Complexes 7-12 exerted antiproliferative activity against the human ovarian cancer cells in vitro. The IC50 values ranged ca. 0.3-3.7 mu M for the A2780 cell line, and 3.1-20 mu M for the cisplatin resistant cell line A2780R, with complex 7 being the most cytotoxic against both cell types. IC50 values for the non-tumorigenic human embryonic kidney (HEK) cells, serving as a measure of a general toxicity, were found in roughly similar ranges, i.e. 0.9-6.8 mu M. (c) 2013 Elsevier B.V. All rights reserved.

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New Zn(II) complexes with N2S2 Schiff base ligands. Experimental and theoretical studies of the role of Zn(II) in disulfide thiolate-exchange

Maryam Bagheri, Kurt Schenk

Described are the synthesis and characterization of two, potentially tetradentate, N2S2 Schiff-base ligands, containing a disulfide bond, N,N'-bis(3-phenylprop-2-en-l-ylidene)-2,2'-disulfanediyldianiline (L-1) and N,N'-bis(3,3-diphenylprop-2-en-1-ylidene)-2,2'-disulfanediyldianiline (L-2), and their reaction with Zn2+. Surprisingly, both L-1 and L-2 undergo reductive disulfide bond scission upon reaction with Zn2+ in alcoholic media to give, under alcohol oxidation, the respective Zn(NS)2 complexes Zn(L-3)(2) (1) and Zn(L-4)(2) (2), where the L-3 and L-4 are the respective bidentate thiolate-imine anions. The ligands L-1 and L-2 and the complexes I and 2 have been characterized spectroscopically, and the crystal and molecular structures of the two complexes have been determined by single crystal X-ray diffraction. The coordination geometry around Zn(II) centers in both complexes is a distorted tetrahedron. In addition, DFT calculations (B3LYP/LANL2DZ/6-311++G(d,p)) support the structure of I. Cyclic voltammetric studies demonstrate that Zn(II) shifts the reduction potential of the disulfide ligands L-1 and L-2 to less negative values thus making them more susceptible to reductive cleavage of the disulfide bond. The results of semi-empirical PM6 calculations offer key insight into the nature of the transition state for this reaction. (C) 2014 Elsevier Ltd. All rights reserved.

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Arene Osmium Complexes with Ethacrynic Acid-Modified Ligands: Synthesis, Characterization, and Evaluation of Intracellular Glutathione S-Transferase Inhibition and Antiproliferative Activity

Paul Joseph Dyson, Emilia Paunescu, Tina Riedel

Four arene osmium complexes were prepared containing derivatives of ethacrynic acid, a potent inhibitor of glutathione Stransferases, either by direct coordination or via N- or P-donor ligands. The complexes were characterized by spectroscopic and analytical methods and, for Os(eta(6)-p-cymene)(acetylacetonato)(2-(2,3-dichloro-4(2-ethylenebutanoyephenoxy)acetato) and Os(eta(6)-p-cymene)Cl-2(2-(2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetoxy)ethyl nicotinato), by single-crystal X-ray diffraction. The cytotoxicity of the complexes toward human ovarian cancer cells and nontumorous human embryonic kidney cells was investigated, and two of the complexes, for which ruthenium analogues are known, helped to delineate the influence of the metal ion. Inhibition studies of intracellular glutathione S-transferases (GSTs, detoxification enzymes implicated in drug resistance) indicate that the observed cytotoxicity of the complexes involves GST inhibition, as well as other targets following dissociation of the ethacrynic acid group from the osmium(II) ion.

American Chemical Society2016

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