Sanam Movassaghi

Anticancer activity of Ru- and Os(arene) compounds of a maleimide-functionalized bioactive pyridinecarbothioamide ligand

With the aim of increasing the accumulation of Ru anticancer agents in the tumor, a targeted delivery strategy based on a maleimide anchor for the biological vector human serum albumin (HSA) was developed. A group of piano stool Ru- and Os(η6-arene) complexes carrying a maleimide-functionalized N-phenyl-2-pyridinecarbothioamide (PCA) ligand was designed allowing for covalent conjugation to biological thiols. The complexes were characterized by NMR spectroscopy, ESI-MS, elemental analysis and single-crystal X-ray diffraction analysis. The compounds were shown to undergo halido/aqua ligand exchange reactions in aqueous solution, depending mainly on the metal center and the nature of the halide. In vitro cytotoxicity studies revealed low potency which is explained by the observed high reactivity of the maleimide to the thiol of l-cysteine (Cys), while the metal center itself shows little affinity to amino acids of the model protein lysozyme.

Anticancer Ru( η 6 - p -cymene) complexes of 2-pyridinecarbothioamides: A structure–activity relationship study

Ru(II) and Os(II) complexes of 2-pyridinecarbothioamide ligands were introduced as orally administrable anticancer agents (S.M. Meier, M. Hanif, Z. Adhireksan, V. Pichler, M. Novak, E. Jirkovsky, M.A. Jakupec, V.B. Arion, C.A. Davey, B.K. Keppler, C.G. Hartinger, Chem. Sci., 2013, 4, 1837-1846). In order to identify structure-activity relationships, a series of N-phenyl substituted pyridine-2-carbothiamides (PCAs) were obtained by systematically varying the substituents at the phenyl ring. The PCAs were then converted to their corresponding RuII(η6-p-cymene) complexes and characterized spectroscopically and by X-ray diffraction as well as in terms of stability in water and HCl. The cytotoxic activity of the PCA ligands and their respective organoruthenium compounds was evaluated in a panel of cell lines (HCT116, H460, SiHa and SW480). The lipophilic PCAs 1-4 showed cytotoxicity in the low micromolar range and 6 was the most potent compound of the series with an IC50 value of 1.1μM against HCT116 colon cancer cells. These observations were correlated with calculated octanol/water partition coefficient (clogP) data and quantitative estimated druglikeness. A similar trend as for the PCAs was found in their Ru complexes, where the complexes with more lipophilic ligands proved to be more cytotoxic in all tested cell lines. In general, the PCAs and their organoruthenium derivatives demonstrated excellent drug-likeness and cytotoxicity with IC50 values in the low micromolar range, making them interesting candidates for further development as orally active anticancer agents.

Analysis of ruthenium anticancer agents by MEEKC-UV and MEEKC–ICP-MS: Impact of structural motifs on lipophilicity and biological activity

We present here the first comprehensive study on the lipophilicity of ruthenium anticancer agents encompassing compounds with broad structural diversity, ranging from octahedral RuIII(azole) through to RuII(arene) complexes. MEEKC was used to determine the capacity factors of the Ru complexes, and after a complex peak was unambiguously assigned using MEEKC–ICP‐MS, the results were validated through comparison with the log P determined by octanol/water partitioning experiments. Correlation of the two data sets demonstrated a close relationship despite the limited structural overlap of the compounds studied. The capacity factors found by MEEKC allowed for the clustering of complexes based on their structure and this could be used to rationalize the observed cytotoxicity in the human colon carcinoma HCT116 cell line. It was demonstrated that rather than modification of the mono‐ or bidentate coordinated ligands much tighter control over a complexes lipophilic properties could be achieved through modification of the Ru(arene) ligand, with minimal detriment to cytotoxicity. This demonstrates the flexibility and potential of the Ru piano‐stool scaffold. MEEKC proved to be a highly efficient means of screening the anticancer potential of preclinical ruthenium complex candidates for their lipophilic properties and correlate them with their biological activity and structural properties.

A Bioactive l-Phenylalanine-Derived Arene in Multitargeted Organoruthenium Compounds: Impact on the Antiproliferative Activity and Mode of Action

RuII(η6-arene) compounds carrying bioactive flavonol ligands have shown promising anticancer activity against tumor cells via a multitargeting mode of action, i.e., through interaction with DNA and inhibition of topoisomerase IIα. By introducing a novel arene ligand based on the amino acid l-phenylalanine (Phe), we aimed to alter the pharmacological properties of the complexes. We report here a series of novel RuII(η6-arene)Cl complexes with different substituents on the phenyl ring of the flavonol which should maintain the multitargeting capability of the parent η6- p-cymene (cym) complexes. Studies with selected examples revealed stability in aqueous solution after quickly forming aqua complexes but rapid decomposition in pure DMSO. The reactions with protein and DNA models proceeded quickly and resulted in cleavage of the flavonol or adduct formation, respectively. The compounds were found to be cytotoxic with significant antiproliferative activity in cancer cells with IC50 values in the low μM range, while not following the same trends as observed for the cym analogues. Notably, the cellular accumulation of the new derivatives was significantly higher than for their respective cym complexes, and they induced DNA damage in a manner similar to that of cisplatin but to a lesser extent.