Development of Bimetallic Titanocene-Ruthenium-Arene Complexes As Anticancer Agents: Relationships between Structural and Biological Properties

Fabio Edafe, Philippe Richard, Olivier Pierre Zava
American Chemical Society, 2010
Article

Résumé

A series of bimetallic titanium-ruthenium complexes of general formula (η5-C5H5)(μ-η5:κ1-C5H4(CR12)nPR2R3)TiCl2RuCl2 (n = 0, 1, 2 or 4; R1 = H or Me; R2 = H, Ph, or Cy; R3 = Ph or Cy) have been synthesized, including two novel compds. as well as two cationic derivs. of formula [(η5-C5H5)(μ-η5:κ1-C5H4(CH2)nPPh2)TiCl2] (η6-p-cymene)RuCl (n = 0 or 2). The solid state structure of two of these compds. was also established by x-ray crystallog. The complexes showed a cytotoxic effect on human ovarian cancer cells and were markedly more active than their Ti or Ru monometallic analogs titanocene dichloride and RAPTA-C, resp. Studies of cathepsin B inhibition, an enzyme involved in cancer progression, showed that enzyme inhibition by the bimetallic complexes is influenced by the length of the alkyl chain in between the metal centers. Complementary ESI-MS studies provided evidence for binding of a Ru(II) fragment to proteins.

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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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The discovery of the anticancer properties of cisplatin in 1965 heralded the development of metallopharmaceuticals and founded a revolution in cancer therapy. Platinum drugs are believed to induce cytotoxicity by cross-linking DNA, causing changes to the DNA structure that inhibit replication and protein synthesis. Many current inorganic drugs such as cisplatin and related compounds are successfully used in the treatment of many cancer types. However there are problems associated with their use, in particular, cisplatin is highly toxic, leading to side effects and limiting the dose that can be administered. Complexes based on other metals have been investigated for their possible application as antitumour drugs. One of the most promising metals is ruthenium, and a number of ruthenium complexes show high in vitro and in vivo antitumour activity and some compounds are currently undergoing clinical trials. Organometallic ruthenium(II)-arene PTA complexes (PTA = 1,3,5-triaza-7-phosphaadamantane) with the general formula, RuCl2(η6-arene)(PTA) abbreviated RAPTA, were developed as part of this PhD thesis. These new compounds were characterised and evaluated for their in vitro anticancer activity towards the TS/A mouse adenocarcinoma and the healthy HBL-100 human mammary cell lines. Selective activity of RAPTA compounds towards tumour cells was observed. The p-cymene and benzene compounds RAPTA-C and RAPTA-B respectively, were selected for in vivo evaluation of their anticancer and antimetastatic activity and they were shown to be able to reduce the growth of lung metastases in CBA mice bearing the MCa mammary carcinoma. Moreover, a pharmacokinetic study of RAPTA-C was carried out to examine the fate of the compound in vivo after administration. Extending the series of RAPTA anticancer drugs, novel structurally modified RAPTA compounds were developed exploiting different strategies for establishing structure-activity relationships. The efficacy on enhancing the activity, the uptake and the biomolecular interactions of the novel drugs was evaluated and the effectiveness was compared to the non-functionalised RAPTA series of complexes.

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On the influence of "arm-on, arm-off" processes on alkene hydrogenation catalysed by a rhodium triphos complex

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The influence of phosphane "arm-on, arm-off" assocn./dissocn. in rhodium catalyzed alkene hydrogenation using [Rh(COD)(k3-triphos)]PF6 {1, COD = cyclooctadiene, triphos = 1,1,1-tris(diphenylphosphanylmethyl)ethane} has been investigated by comparison of the activity of 1 to mixts. of the related diphosphane complex, [Rh(COD)(k2-dppp)]PF6 {2, dppp = 1,3-bis(diphenylphosphanyl)propane} and triphenylphosphane (THF, 50 °C, 1 bar H2). These investigations are supplemented by a demonstration of the k2-k3 fluxionally of the triphos coordination in 1 by reversible reaction with [RuCl2(p-cymene)]2 at room temp. in CH2Cl2. The product of this reaction, the bimetallic complex [(p-cymene)Cl2Ru{(PPh2CH2)CMe(CH2PPh2) 2}Rh(COD)]PF6, was isolated and fully characterized, including detn. of the solid-state structure by X-ray diffraction anal. Despite this evidence for facile arm-off dissocn. of the triphos ligand in 1, complex 2, with or without triphenylphosphane, was found to be more efficient for the hydrogenation of styrene and cyclohexene. Notably, use of triphenylphosphane together with 2 was found to have beneficial effects - increasing the rate of styrene hydrogenation (in some cases) and helping to stabilize the metal center during cyclohexene hydrogenation. These observations are supported by mercury poisoning expts. and reactivity expts. with 2 in medium pressure sapphire NMR tubes.

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