Nonsteroidal Anti-inflammatory-Organometallic Anticancer Compounds

Compounds that combine metal-based drugs with covalently linked targeted organic agents have been shown, in some instances, to exhibit superior anticancer properties compared to the individual counterparts. Within this framework, we prepared a series of organometallic ruthenium(II)- and osmium(II)-p-cymene complexes modified with the nonsteroidal anti-inflammatory drugs (NSAIDs) indomethacin and diclofenac. The NSAIDs are attached to the organometallic moieties via monodentate (pyridine/phosphine) or bidentate (bipyridine) ligands, affording piano-stool Ru(II) and Os(II) arene complexes of general formula [M(eta(6)-p-cymene)Cl-2(N)], where N is a pyridine-based ligand, {2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indo1-3-yl) acetoxy) ethyl-3-(pyridin-3-yl)propanoate} or {2-(2-(24(2,6-dichlorophenyl)amino)-phenyl)acetoxy)ethyl-3-(pyridin-3-71)propanoate}, [M(eta(6)-p-cymene)Cl-2(P)], where P is a phosphine ligand, {2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yOacetoxy)ethyl-(diphenylpho sphanyl) benzo ate} or {2- (2- (2-((2,6-dichlorophenyl) amino)phenyl) acetoxy) ethyl-4-(diphenylphosphanyl)-benzoate, and [M(eta(6)-p-cymene)Cl(N,N')][Cl], where N,N' is a bipyridine-based ligand, (4'-methyl-[2,2'-bipyridin]-4-yOmethyl-2-(1-(4-chlorob enzoyl)-5-methoxy-2-methyl-1H-in dol-3-yl) acetate), (4'-methyl- [2,2'-bipyridin]-4-yl) methyl-2-(2-((2,6-dichlorophenyl) amino)phenyl) acetate), (bis (2- (2- (1- (4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indo1-3-71)acetoxy)-ethyl)[2,2'-bipyridine]-5,5'-dicarboxylate), or (bis(2-(2-(24(2,6-dichlorophenyl)amino)phenyl)acetoxy)ethyl)[2,2'-bipyridine]-5,5'-dicarboxylate). The antiproliferative properties of the complexes were assessed in human ovarian cancer cells (A2780 and A2780cisR, the latter being resistant to cisplatin) and nontumorigenic human embryonic kidney (HEK-293) cells. Some of the complexes are considerably more cytotoxic than the original drugs and also display significant cancer cell selectivity.

Varying the metal to ethacrynic acid ratio in ruthenium(ii)/osmium(ii)-p-cymene conjugates

Catherine Marie Amélie Clavel, Paul Joseph Dyson, Emilia Paunescu, Mylène Soudani

Following the identification of a ruthenium(II)-arene complex with an ethacrynic acid-modified imidazole ligand, which inhibits glutathione transferase (GST) and is cytotoxic to chemo-resistant cancer cells, a series of structurally related ruthenium(II)- and osmium(II)-p-cymene compounds have been prepared. In these complexes the ethacrynic acid is linked to the metals via appropriately modified pyridine ligands. The influence of the metal center and the metal:ethacrynic acid ratio on the cytotoxicity of the compounds was evaluated with the derivatives with one metal center and two ethacrynic acid moieties being the most potent against chemo-resistant A2780cisR cells (human ovarian cancer cells with acquired resistance to cisplatin). Moreover, compared to a complex with an ethacrynic acid-modified imidazole ligand (RAIMID-EA, Figure 2), these complexes display a significant degree of cancer cell specificity.

Elsevier2017

Structure-activity relationships for ruthenium(II)-arene drugs

Claudine Scolaro

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.

EPFL2007

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

Fabio Edafe, Philippe Richard, Olivier Pierre Zava

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.

American Chemical Society2010

Structure-activity relationships for ruthenium(II)-arene drugs

Claudine Scolaro

EPFL2007