Gerhard Kelter

Chemistry, antiproliferative properties, tumor selectivity, and molecular mechanisms of novel gold(III) compounds for cancer treatment: a systematic study

AbstractThe antiproliferative properties of a group of 13 structurally diverse gold(III) compounds, including six mononuclear gold(III) complexes, five dinuclear oxo-bridged gold(III) complexes, and two organogold(III) compounds, toward several human tumor cell lines were evaluated in vitro using a systematic screening strategy. Initially all compounds were tested against a panel of 12 human tumor cell lines, and the best performers were tested against a larger 36-cell-line panel. Very pronounced antiproliferative properties were highlighted in most cases, with cytotoxic potencies commonly falling in the low micromolar—and even nanomolar—range. Overall, good-to-excellent tumor selectivity was established for at least seven compounds, making them particularly attractive for further pharmacological evaluation. Compare analysis suggested that the observed antiproliferative effects are caused by a variety of molecular mechanisms, in most cases “DNA-independent,” and completely different from those of platinum drugs. Remarkably, some new biomolecular systems such as histone deacetylase, protein kinase C/staurosporine, mammalian target of rapamycin/rapamycin, and cyclin-dependent kinases were proposed for the first time as likely biochemical targets for the gold(III) species investigated. The results conclusively qualify gold(III) compounds as a promising class of cytotoxic agents, of outstanding interest for cancer treatment, while providing initial insight into their modes of action.Graphical AbstractA series of gold(III) compounds showed cytotoxic properties and tumor selectivity toward a panel of cancer cell lines. Compare analysis provided insight into their possible mechanisms of action.

In-vitro anti-tumor activity studies of bridged and unbridged benzyl-substituted titanocenes

The benzyl-substituted ansa-titanocenes [1,2-di(cyclopentadienyl)-1,2-di-(4-N,N-dimethylaminophenyl)ethanediyl] titanium dichloride (Titanocene X) and [1,2-di(cyclopentadienyl)-1,2-bis(m-dimethoxyphenyl)ethanediyl] titanium dichloride (Titanocene Z), and the benzyl-substituted unbridged titanocene bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) were tested on the growth of a wide variety of tumor cells in vitro on a panel of 36 human tumor cell lines containing 14 different tumor types investigated in a cellular proliferation assay. Titanocene Y with a mean IC50 value of 65.8×10−6 mol/l over the full panel of 36 cancer cell lines reaches the activity of cisplatin with 14.7×10−6 mol/l within a factor of 4, whereas Titanocene X and Z show significantly less cytotoxic activity. Titanocene Y is most effective on pleura mesothelioma, and uterine and renal cell cancer, where the IC50 values are comparable or significantly better than for cisplatin. In particular, in the case of renal cell cancer and pleura mesothelioma there is an obvious lack of chemotherapeutic reagents, which might be filled by Titanocene Y, where a very promising cytotoxic effect in comparison with cisplatin could be shown.

Role of transferrin receptor and the ABC transporters ABCB6 and ABCB7 for resistance and differentiation of tumor cells towards artesunate.

The anti-malarial artesunate also exerts profound anti-cancer activity. The susceptibility of tumor cells to artesunate can be enhanced by ferrous iron. The transferrin receptor (TfR) is involved in iron uptake by internalization of transferrin and is over-expressed in rapidly growing tumors. The ATP-binding cassette (ABC) transporters ABCB6 and ABCB7 are also involved in iron homeostasis. To investigate whether these proteins play a role for sensitivity towards artesunate, Oncotests 36 cell line panel was treated with artesunate or artesunate plus iron(II) glycine sulfate (Ferrosanol®). The majority of cell lines showed increased inhibition rates, for the combination of artesunate plus iron(II) glycine sulfate compared to artesunate alone. However, in 11 out of the 36 cell lines the combination treatment was not superior. Cell lines with high TfR expression significantly correlated with high degrees of modulation indicating that high TfR expressing tumor cells would be more efficiently inhibited by this combination treatment than low TfR expressing ones. Furthermore, we found a significant relationship between cellular response to artesunate and TfR expression in 55 cell lines of the National Cancer Institute (NCI), USA. A significant correlation was also found for ABCB6, but not for ABCB7 in the NCI panel. Artesunate treatment of human CCRF-CEM leukemia and MCF7 breast cancer cells induced ABCB6 expression but repressed ABCB7 expression. Finally, artesunate inhibited proliferation and differentiation of mouse erythroleukemia (MEL) cells. Down-regulation of ABCB6 by antisense oligonucleotides inhibited differentiation of MEL cells indicating that artesunate and ABCB6 may cooperate. In conclusion, our results indicate that ferrous iron improves the activity of artesunate in some but not all tumor cell lines. Several factors involved in iron homeostasis such as TfR and ABCB6 may contribute to this effect.

Antitumor Activity of Bis-Indole Derivatives

This paper reports the synthesis of compounds formed by two indole systems separated by a heterocycle (pyridine or piperazine). As a primary screening, the new compounds were submitted to the National Cancer Institute for evaluation of antitumor activity in the human cell line screen. The pyridine derivatives were far more active than the piperazine derivatives. For the study of the mechanism of action, the most active compounds were subjected to COMPARE analysis and to further biological tests including proteasome inhibition and inhibition of plasma membrane electron transport. The compound bearing the 5-methoxy-2-indolinone moiety was subjected to the first in vivo experiment (hollow fiber assay) and was active. It was therefore selected for the second in vivo experiment (human tumor xenograft in mice). In conclusion we demonstrated that this approach was successful, since some of the compounds described are much more active than the numerous, so far prepared and tested 3-indolylmethylene-2-indolinones.

[Au2(phen2Me)2(μ-O)2](PF6)2, a Novel Dinuclear Gold(III) Complex Showing Excellent Antiproliferative Properties

A novel dioxo-bridged dinuclear gold(III) complex with two 2,9-dimethylphenanthroline ligands was synthesized and thoroughly characterized. Its crystal structure was solved, and its solution behavior assessed. Remarkably, this compound revealed excellent antiproliferative properties in vitro against a wide panel of 36 cancer cell lines, combining a high cytotoxic potency to pronounced tumor selectivity. Very likely, these properties arise from an innovative mode of action (possibly involving histone deacetylase inhibition), as suggested by COMPARE analysis. In turn, electrospray ionization-mass spectrometry studies provided valuable insight into its molecular mechanisms of activation and of interaction with protein targets. Gold(III) reduction, dioxo bridge disruption, coordinative gold(I) binding to the protein, and concomitant release of the phenanthroline ligand were proposed to occur upon interaction with superoxide dismutase, used here as a model protein. Because of the reported results, this new gold(III) compound qualifies itself as an optimal candidate for further pharmacological testing.

Mansouramycins A-D, cytotoxic isoquinolinequinones from a marine streptomycete.

Chemical screening of the ethyl acetate extract from the marine-derived Streptomyces sp. isolate Mei37 resulted in five isoquinolinequinones, four new derivatives, mansouramycin A-D (1, 3-5), and the known 3-methyl-7-(methylamino)-5,8-isoquinolinedione (2). Their structures were elucidated by NMR and MS techniques and by comparison with related compounds. Cytotoxicity profiling of the mansouramycins in a panel of up to 36 tumor cell lines indicated significant cytotoxicity of several derivatives, with pronounced selectivity for non-small cell lung cancer, breast cancer, melanoma, and prostate cancer cells.

Synthesis and Antiproliferative Activity of 2,5-bis(3′-Indolyl)pyrroles, Analogues of the Marine Alkaloid Nortopsentin

2,5-bis(3′-Indolyl)pyrroles, analogues of the marine alkaloid nortopsentin, were conveniently prepared through a three step procedure in good overall yields. Derivatives 1a and 1b exhibited concentration-dependent antitumor activity towards a panel of 42 human tumor cell lines with mean IC50 values of 1.54 μM and 0.67 μM, respectively. Investigating human tumor xenografts in an ex-vivo clonogenic assay revealed selective antitumor activity, whereas sensitive tumor models were scattered among various tumor histotypes.

N-carboxamido-staurosporine and selina-4(14),7(11)-diene-8,9-diol, new metabolites from a marine Streptomyces sp.

In our screening of micro-organisms for novel bioactive natural products, a new staurosporinone, N-carboxamido-staurosporine (1c), and a new sesquiterpene, (5S,8S,9R,10S)-selina-4(14),7(11)-diene-8,9-diol (2a), were isolated from the culture broth of the marine-derived Streptomyces sp. QD518. Their structures were determined by spectroscopic methods and by comparison of the NMR data with those of structurally related known natural products, which were isolated from the same strain.

Epoxyphomalin A and B, Prenylated Polyketides with Potent Cytotoxicity from the Marine-Derived Fungus Phoma sp.

Chemical investigation of a strain of the marine-derived fungus Phoma sp. has led to the discovery of epoxyphomalin A (1) and B (2), two new prenylated polyketides with unusual structural features. Epoxyphomalin A (1) showed superior cytotoxicity at nanomolar concentrations toward 12 of a panel of 36 human tumor cell lines. In COMPARE analyses, the observed cytotoxic selectivity pattern of 1 did not correlate with those of reference anticancer agents with known mechanisms of action.

Apralactone A and a New Stereochemical Class of Curvularins from the Marine Fungus Curvularia sp.

Chemical investigations of the cytotoxic extract of the marine-derived fungus Curvularia sp. (strain no. 768), isolated from the red alga Acanthophora spicifera, yielded the novel macrolide apralactone A (1), as well as the antipodes of curvularin macrolides 2-7. Compound 8, a dimeric curvularin was recognised as an artefact. The structures of 1-8 were elucidated by interpretation of their spectroscopic data (1D and 2D NMR, CD, MS, UV and IR). Apralactone A (1) is a 14-membered phenyl acetic acid macrolactone, and the first such compound with a 4-chromanone substructure. Compounds 1, 2, 4, 5 and 6 were found to be cytotoxic towards human tumor cell lines with mean IC50 values in the range of 1.25 to 30.06 µM.