Palladium(ii) complexes with thiosemicarbazones derived from pyrene as topoisomerase IB inhibitors

New palladium complexes with thiosemicarbazonate ligands derived from pyrene exhibit potent antiproliferative activity against A2780 and cisplatin-resistant A2780Cis human ovarian cancer cells, which is dependent on substituent groups of the thiosemicarbazone ligands. Cellular accumulation and distribution studies confirmed that palladium enters the cell nucleus. DNA and topoisomerase IB studies show that one complex is a potent TopIB inhibitor, with selectivity for cancer versus normal cells

Determination of the aggregate binding site of amyloid protofibrils using electron capture dissociation tandem mass spectrometry

Amyloid fibril formation is a hallmark in a range of human diseases. Analysis of the molecular details of amyloid aggregation, however, is limited by the difficulties in solubilizing, separating, and identifying the aggregated biomolecules. Additional labeling or protein modification is required in many current analytical techniques in order to provide molecular details of amyloid protein aggregation, but these modifications may result in protein structure disruption. Herein, ultrahigh resolution mass spectrometry (MS) with electron capture dissociation tandem MS (ECD MS/MS) has been applied to monitor the formation of early oligomers of human islet amyloid polypeptide (hIAPP), which aggregate rapidly in the pancreas of type II diabetes (T2D) patients. ECD MS/MS results show the aggregation region of the early oligomers is at the Ser-28/Ser-29 residue of a hIAPP unit and at the Asn-35 residue of another hIAPP unit near the C-terminus in the gas phase. These data contribute to the understanding of the binding site between hIAPP units which may help for specific target region therapeutic development in the future. Furthermore, MS has also been applied to quantify the amount of soluble amyloid protein remaining in the incubated solutions, which can be used to estimate the aggregation rate of amyloid protein during incubation (28 days). These data are further correlated with the results obtained using fluorescence spectroscopy and transmission electron microscopy (TEM) to generate a general overview of amyloid protein aggregation. The methods demonstrated in this article not only explore the aggregation site of hIAPP down to an amino acid residue level, but are also applicable to many amyloid protein aggregation studies

X-ray fluorescence imaging of single human cancer cells reveals that the N-heterocyclic ligands of iodinated analogues of ruthenium anticancer drugs remain coordinated after cellular uptake

Analogues of KP1019 containing iodinated indazole ligands were prepared to investigate the biological fate of the Ru-N-heterocycle bond in this class of anticancer agents. The new complexes, 5-iodoindazolium trans-tetrachloridobis(5-iodoindazole)ruthen(III)ate (1) and 5-iodoindazolium trans-tetrachlorido(dimethyl sulfoxide)(5-iodoindazole)ruthen(III)ate (3), were characterized by elemental analysis, mass spectrometry and UV-vis spectrophotometry. Tetramethylammonium salts of these complexes (2 and 4) were synthesized and characterized in a similar manner. Half-maximum inhibitory concentrations of 2 and 4 with regard to A549 cells at 24 h were determined on the basis of the dose-response curves derived from real-time cell adhesion impedance measurements and were shown to be in the same range as those determined for KP1019 and NAMI-A using the same method. X-ray fluorescence imaging of single cultured A549 cells treated with 2 or 4 showed that, in both cases, the distribution of ruthenium and iodine was identical, indicating that the Ru-N bonds in the anionic complexes remained intact after incubation in culture medium and subsequent cellular uptake and processing.Sumy Antony, Jade B. Aitken, Stefan Vogt, Barry Lai, Tracey Brown, Leone Spiccia, Hugh H. Harri