Metals in medicine: metal-related diseases

P 20 Lipophilic platinum(II) complexes with dicarboxylates: in vitro antiproliferative activity as well as the mechanism of the suppression of tumour cells growth Kamil Hoffmann, Ewa Maj, Andrzej Wojtczak, Joanna Wietrzyk, Iwona Łakomska Bioinorganic Chemistry Research Group, Faculty of Chemistry, Nicolaus Copernicus University, Gagarina 7, 87-100 Toruń, Poland, hoffmann@doktorant.umk.pl; Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53-114 Wrocław, Poland; Faculty of Chemistry, Nicolaus Copernicus University, Gagarina 7, 87-100 Toruń, Poland Improving a therapeutic profile of existing platinum(II) complexes, combination of 5,7-diterbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp) as N-donor ligand and two types of leaving groups: malonate (mal) (1) as well as cyclobutane-1,1-dicarboxylate (CBDC) (2) were used. The complexes were characterized in depth by multinuclear magnetic resonance spectroscopy (H, C, N, Pt) and X-ray. The spectroscopical results indicate that the local geometry around the platinum(II) center approximates a square-planar arrangement with two monodentate nitrogen atom N3 of the dbtp and bidentate dicarboxylate. To estimate the permeability of [Pt(mal)(dbtp)2] and [Pt(CBDC)(dbtp)2] through the cell membrane, their partition coefficients were calculated using shake-flask method. Both complexes were much more lipophilic (log P = *2.0) than cisplatin (log P = 1.76) or carboplatin (log P = -1.48). Additionally, the therapeutic potential of the obtained Pt(II) compounds was examined using in vitro cytotoxicity experiments against two human cancer cell lines i.e.: cisplatin-resistance breast (T47D) and lung adenocarcinoma (A549). They exhibited improved cytotoxic activity against T47D cell line, suggesting ability to overcome cisplatin resistance mechanism in that tumour cell line. Furthermore, it ought to be highlighted that presented platinum-based prodrugs, resulted to be over 36-times more active than carboplatin against A549. Promising results encouraged to analyze also the influence of platinum(II) complexes on cell cycle and cell death (subG1) of A549 cell. It was demonstrated that (1,2) are capable of arresting the cell cycle at the G0/G1 phase, whilst cisplatin and carboplatin stopped the cells in G2/M stage, signifying the differences in the mechanism of the suppression of tumour cell growth. Finally, in the quest for low–toxic platinum drugs, the antiproliferative in vitro activity against normal mouse fibroblast cells (Balb/3T3). The title platinum (II) complexes were 1.5-fold less active than cisDDP, implying that they should be less toxic than the worldwide used cisplatin. Financial support by the National Science Center (DEC–2012/07/ N/ST5/00221) to K.H. is gratefully acknowledged. P 21 Visible light-induced annihilation of human tumour cells using novel platinum-porphyrin conjugates Anu Naik, Riccardo Rubbiani, Gilles Gasser, Bernhard Spingler Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland Despite the extended use of porphyrin complexes in PDT [1,2], tetraplatinated porphyrins have so far not been studied for their anticancer properties upon light irradiation [3]. This is in contrast to ruthenated tetrapyridyl porphyrin complexes [4]. We would like to report about the synthesis of novel tetraplatinated porphyrins as well as their photophysical characterization and in vitro light-induced anticancer properties [5]. The quantum yield of O2 (U) production upon light irradiation was found to be between 0.41 and 0.54. The dark and light toxicity against human cancerous and non-cancerous cell lines (MRC-5, HeLa, A2780 and CP70) was determined by the MTT assay. IC50 values were obtained after 4 h incubation, a washing step, followed by 15 min irradiation at either 420 nm (6.95 J cm) or 575 nm, (6.23 J cm) respectively. These platinum-porphyrin conjugates had only minor dark toxicity, however upon visible light irradiation, IC50 values down to 19 ± 4 nM could be observed. These values correspond to an excellent phototoxic index (PI = IC50 dark/IC50 light) of [5,000. After 4 h incubation in HeLa cells, incubation of a tetraplatinum-porphyrin conjugate led to a concentration of about 105 ng Pt in the nucleus per mg protein in the cell. Strikingly, the use of this conjugate increased the nuclear platinum content by more than 30-fold compared with cisplatin. This is obviously only partially a consequence of the porphyrin conjugate having 4 platinum centers versus one in cisplatin; the main reason being that the conjugate is a more efficient platinum importer into the cell nucleus than cisplatin. Taken together, all these favourable characteristics imply that tetraplatinated porphyrin complexes may be worth being explored as novel PDT anti-cancer agents in vivo. Financial support by the Forschungskredit (A.N.), the University of Zurich, the Swiss National Science Foundation (Professorship No. PP00P2_133568 to G.G) and the Novartis Jubilee Foundation (G.G and R.R) is gratefully acknowledged.