Alexander E. Egger

KP1019, A New Redox‐Active Anticancer Agent – Preclinical Development and Results of a Clinical Phase I Study in Tumor Patients

The promising drug candidate indazolium trans‐[tetrachlorobis(1H‐indazole)ruthenate(III)] (KP1019) is the second Ru‐based anticancer agent to enter clinical trials. In this review, which is an update of a paper from 2006 (Hartinger et al., J. Inorg. Biochem. 2006, 100, 891–904), the experimental evidence for the proposed mode of action of this coordination compound is discussed, including transport into the cell via the transferrin cycle and activation by reduction. The results of the early clinical development of KP1019 are summarized in which five out of six evaluated patients experienced disease stabilization with no severe side effects.

Transferring the concept of multinuclearity to ruthenium complexes for improvement of anticancer activity.

Multinuclear platinum anticancer complexes are a proven option to overcome resistance of established anticancer compounds. Transferring this concept to ruthenium complexes led to the synthesis of dinuclear Ru(II)-arene compounds containing a bis(pyridinone)alkane ligand linker. A pronounced influence of the spacer length on the in vitro anticancer activity was found, which is correlated to the lipophilicity of the complexes. IC(50) values in the same dimension as for established platinum drugs were found in human tumor cell lines. No cross-resistance to oxoplatin, a cisplatin prodrug, was observed for the most active complex in three resistant cell lines; in fact, a 10-fold reversal of sensitivity in two of the oxoplatin-resistant lines was found. (Bio)analytical characterization of the representative examples showed that the ruthenium complexes hydrolyze rapidly, forming predominantly diaqua species that exhibit affinity toward transferrin and DNA, indicating that both proteins and nucleobases are potential targets.

Development of an experimental protocol for uptake studies of metal compounds in adherent tumor cells

Cellular uptake is being widely investigated in the context of diverse biological activities of metal compounds on the cellular level. However, the applied techniques differ considerably, and a validated methodology is not at hand. Therefore, we have varied numerous aspects of sample preparation of the human colon carcinoma cell line SW480 exposed in vitro to the tumor-inhibiting metal complexes cisplatin and indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(iii)] (KP1019) prior to analysis with ICP-MS, and the results were found to be tremendously influenced by adsorption to the culture dishes. Adsorption to culture plates increases linearly with the concentration of KP1019, depends on the protein content of the medium, the duration of contact to protein-containing medium prior to drug addition and the hydrophilicity/lipophilicity of the compound. For varying degrees of cell confluence, adsorption of Ru hardly differs from cell-free experiments. Desorption from the plates contributes to total Ru detected in dependence on the cell harvesting method. Desorption kinetics for lysis in HNO(3) and tetramethylammonium hydroxide (TMAH) are comparable, but TMAH is a more potent desorbant. Sample storage conditions prior to analysis influence significantly the recovery of analyte. Protocols using cell lysis in the culture plate without proper corrections run the risk of producing artefacts resulting from metal adsorption/desorption to an extent comparable with the actual cellular content. However, experimental protocols reported in the literature frequently do not contain information whether adsorption or blank correction were performed and should be regarded with caution, especially if lysis was performed directly in the culture dishes.

Nanoscalic silver possesses broad-spectrum antimicrobial activities and exhibits fewer toxicological side effects than silver sulfadiazine

UNLABELLED Silver has been used successfully for decades as an antibacterial agent and has become a standard treatment for burns and bacterial skin infections. Silver-containing creams, particularly silver sulfadiazine (SSD), possess effective activities against bacteria and fungi. However, there is serious concern that silver ions applied to denuded skin might be absorbed in significant amounts, thus introducing the risk of silver deposition, potentially leading to internal organ injury. In view of these facts we compared the percutaneous absorption and the antimicrobial potency of SSD with a new composition, nanoscalic silver (NSAg). In a murine model topical application of NSAg resulted in significantly lower percutaneous absorption and internal organ deposition compared to SSD. Strikingly, antimicrobial activity of NSAg used as a 0.1% formulation was comparable not only with 0.1% SSD against different bacterial strains including methicillin-resistant Staphylococcus aureus, but also against different yeast and dermatophyte species. FROM THE CLINICAL EDITOR Nanoscale silver (NSAg) was demonstrated to have significantly lower percutaneous absorption and less accumulation in multiple organs when applied to denuded skin. Its antimicrobial activity against MRSA was not only comparable to silver sulfadiazine, but the formulation was also effective against different yeast and dermatophyte species.

Metal−Arene Complexes with Indolo(3,2‑c)‑quinolines: Effects of Ruthenium vs Osmium and Modifications of the Lactam Unit on Intermolecular Interactions, Anticancer Activity, Cell Cycle, and Cellular Accumulation

Six novel ruthenium(II)– and osmium(II)–arene complexes with three modified indolo[3,2-c]quinolines have been synthesized in situ starting from 2-aminoindoloquinolines and 2-pyridinecarboxaldehyde in the presence of [M(p-cymene)Cl2]2 (M = Ru, Os) in ethanol. All complexes have been characterized by elemental analysis, spectroscopic techniques (1H, 13C NMR, IR, UV–vis), and ESI mass spectrometry, while four complexes were investigated by X-ray diffraction. The complexes have been tested for antiproliferative activity in vitro in A549 (non-small cell lung), SW480 (colon), and CH1 (ovarian) human cancer cell lines and showed IC50 values between 1.3 and >80 μM. The effects of Ru vs Os and modifications of the lactam unit on intermolecular interactions, antiproliferative activity, and cell cycle are reported. One ruthenium complex and its osmium analogue have been studied for anticancer activity in vivo applied both intraperitoneally and orally against the murine colon carcinoma model CT-26. Interestingly, the osmium(II) complex displayed significant growth-inhibitory activity in contrast to its ruthenium counterpart, providing stimuli for further investigation of this class of compounds as potential antitumor drugs.

High Resolution Mass Spectrometry for Studying the Interactions of Cisplatin with Oligonucleotides

Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) has been used to probe the interaction of the anticancer drug cisplatin with oligonucleotides. The binding kinetics, the nature of the adducts formed, and the location of the binding site within the specifically designed double-stranded DNA oligonucleotides, ds(GTATTGGCACGTA) and ds(GTACCGGTGTGTA), were determined by recording mass spectra over time and/or employing tandem mass spectrometry (MS/MS). The FT-ICR MS studies show that binding to DNA takes place via a [Pt(NH 3) 2Cl] (+) intermediate prior to formation of bifunctional [Pt(NH 3) 2] (2+) adducts. Tandem MS reveals that the major binding sites correspond to GG and GTG, the known preferred binding sites for cisplatin, and demonstrates the preference for binding to guanosine within the oligonucleotide. The obtained results are discussed and compared to published data obtained by other mass spectrometric techniques, NMR spectroscopy and X-ray crystallography.

Unsymmetric Mono- and Dinuclear Platinum(IV) Complexes Featuring an Ethylene Glycol Moiety: Synthesis, Characterization, and Biological Activity

Eight novel mononuclear and two dinuclear platinum(IV) complexes were synthesized and characterized by elemental analysis, one- and two-dimensional NMR spectroscopy, mass spectrometry, and reversed-phase HPLC (log k(w)) and in one case by X-ray diffraction. Cytotoxicity of the compounds was studied in three human cancer cell lines (CH1, SW480, and A549) by means of the MTT assay, featuring IC(50) values to the low micromolar range. Furthermore a selected set of compounds was investigated in additional cancer cell lines (P31 and P31/cis, A2780 and A2780/cis, SW1573, 2R120, and 2R160) with regard to their resistance patterns, offering a distinctly different scheme compared to cisplatin. To gain further insights into the mode of action, drug uptake, DNA synthesis inhibition, cell cycle effects, and induction of apoptosis were determined for two characteristic substances.

A Novel Cytotoxic Cerium Complex: Aquatrichloridobis(1,10-phenanthroline)cerium(III) (KP776). Synthesis, Characterization, Behavior in H2O, Binding towards Biomolecules, and Antiproliferative Activity

The lanthanide complex aquatrichloridobis(1,10‐phenanthroline)cerium(III) [Ce(phen)2(H2O)Cl3] (KP776) was fully characterized by elemental analysis, IR‐, and 1H‐ and 13C‐NMR spectroscopy, as well as TG/DTA measurements, and its behavior in H2O, important for the application as a chemotherapeutic, was studied. In addition, the binding of KP776 to nucleotides and single serum proteins was investigated by capillary electrophoresis, whereas binding to proteins in human plasma was observed by ICP‐MS. The compound shows promising anticancer properties in vitro: proliferation of human cancer cell lines is strongly inhibited with IC50 values in the very low micromolar range.

Hydrolysis and Cytotoxic Properties of Osmium(II)/(III)-DMSO-Azole Complexes. Short Communication

The antiproliferative properties of the osmium(II) complexes cis,fac‐[OsIICl2(DMSO)3(L)] and trans,cis,cis‐[OsIICl2(DMSO)2(L)2] (L=1H‐pyrazole, 1H‐imidazole) were studied in three human cancer cell lines, namely 41M (ovary), SK‐BR‐3 (breast), and SW480 (colon). Their activities were compared with those of osmium(III) and ruthenium(III) NAMI‐A type complexes on HT‐29 (colon) and SK‐BR‐3 cancer cell lines. While IC50 values of all the OsII complexes were found to be >1000 μM in all cell lines, Os and Ru‐NAMI‐A type complexes showed remarkable antiproliferative activity. The marginal in vitro cytotoxicity of the OsII compounds is presumably attributed to their resistance to hydrolysis. However, the Os‐NAMI‐A complexes, which are also kinetically stable in aqueous solution, showed reasonable antiproliferative activity in vitro when compared with the analogous Ru compounds and with the OsII‐DMSO‐azole species, indicating that hydrolysis might be not a prerequisite for the antitumor activity of Os‐NAMI‐A type complexes.

Water-Soluble Cationic Derivatives of Indirubin, the Active Anticancer Component from Indigo naturalis

To overcome the problem of poor aqueous solubility and bioavailability of indirubin‐3‐oximes, the compounds were modified by attaching a quaternary ammonium group at the oxime moiety. Exploring the prodrug concept, an oxime ester with acetyl‐l‐carnitine was prepared, and the rate of its hydrolysis was investigated to assess its suitability for clinical administration. In addition, the cytotoxic potency of new stable oxime ethers with a choline moiety and their influence on the cell cycle were tested in human cancer cell lines.