Ferrocenyl triazole amino acid (L-leucine methyl ester (2, 5), L-phenylalanine methyl ester (3, 7), L-alanine methyl ester (4), L-valine tert-butyl ester (6), L-proline methyl ester (8)) and peptide derivatives ([Leu 5 ]-enkephalin (9, 10)) were prepared by Cu(I)-catalyzed [3+2] cycloaddition of azidoferrocene and 1,1′-diazidoferrocene with the corresponding alkyne-modified amino acids and peptide. A purity of >95% for the peptide conjugates was confirmed by HPLC. All new compounds were comprehensively characterized by elemental analysis, mass spectrometry (FAB and ESI-MS, including high-resolution MS), IR, and multinuclear 1D and 2D NMR spectroscopy. Solution structures were studied by circular dichroism (CD) and NMR spectroscopy, showing that compounds 5, 6, and 7 form intramolecular hydrogen bonds (IHBs) in noncoordinating solvents. Electrochemical studies show reversible processes of the redox couple Fc 0 /Fc + (Fc ) ferrocenyl) for compounds 2-9, whereas compound 10 exhibits an irreversible oxidation. A good correlation between the diffusion coefficients as determined by electrochemical methods and the molecular weight was established.

Chemotherapy resistance is a major challenge in ovarian cancer (OvCa). Thus, novel treatment combinations are highly warranted. However, many promising drug candidates tested in two-dimensional (2D) cell culture have not proved successful in the clinic. For this reason, we analyzed our drug combination not only in monolayers but also in three-dimensional (3D) tumor spheroids. One potential therapeutic target for OvCa is A disintegrin and metalloprotease 17 (ADAM17). ADAM17 can be activated by chemotherapeutics, which leads to enhanced tumor growth due to concomitant substrate cleavage. Therefore, blocking ADAM17 during chemotherapy may overcome resistance. Here, we tested the effect of the ADAM17 inhibitor GW280264X in combination with cisplatin on ovarian cancer cells in 2D and 3D. In 2D, the effect on five cell lines was analyzed with two readouts. Three of these cell lines formed dense aggregates or spheroids (HEY, SKOV-3, and OVCAR-8) in 3D and the treatment effect was analyzed with a multicontent readout (cytotoxicity, viability, and caspase3/7 activation). We tested the combined therapy on tumor spheroids derived from primary patient cells. In 2D, we found a significant reduction in the half minimal (50%) inhibitory concentration (IC50) value of the combined treatment (GW280264X plus cisplatin) in comparison with cisplatin monotherapy in all five cell lines with both 2D readout assays (viability and caspase activation). In contrast, the combined treatment only showed an IC50 reduction in HEY and OVCAR-8 3D tumor spheroid models using caspase3/7 activity or CelltoxTM Green as the readout. Finally, we found an improved effect of GW280264X with cisplatin in tumor spheroids derived from patient samples. In summary, we demonstrate that ADAM17 inhibition is a promising treatment strategy in ovarian cancer.

Adaptive sequential k-means (ASK) analysis of acoustic emission (AE) data was used to analyze the sources of AE during compression of three AZ31 magnesium samples with different initial texture. The results were compared to the classical hit-based approach. Observation of the deformed microstructure shows that the ASK analysis can distinguish very well between the signal originating in deformation twinning and dislocation slip. Moreover, together with microstructural analysis, the ASK algorithm revealed another source of AE for one of the samples, which was shown to be the double twinning.