Book of Abstracts - Ruhr-Universität Bochum

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OP-9 ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum Synthesis and Structure-Activity Relationship of Organometallic Derivatives of Curcumin as Anticancer Agents Anusch Arezki, Emilie Brulé,* and Gérard Jaouen Chimie ParisTech (ENSCP), Laboratoire Charles Friedel (UMR 7223), Organometallic Medicinal Chemistry Group 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France E-mail: anusch-arezki@chimie-paristech.fr Turmeric and especially its main and active constituent curcumin have traditionally been used as a food preservative, as well as a natural remedy in Ayurvedic and Chinese medicine for centuries. But it is only within the past few years that modern research has focused on curcumin's biological properties (antioxidant, anti-inflammatory...) and in particular on the extraordinary actions of curcumin in preventing and fighting cancer. Curcumin has at least a dozen separate ways of interfering with cancer progression, but at the same time preserving normal cells. 1 In our laboratory, we chose different curcuminoids as starting materials to lead to a novel class of bioorganometallic anticancer agents by covalently grafting different organometallic ligands to the curcuminoid skeleton. The synthesis of the new ferrocenyl molecules was primarily done by substitution of the central carbon of the curcuminoids, 2 which has shown to have a crucial influence on activity against some cancer cells. 3 The new complexes were tested in vitro on different cancer cell lines, such as prostate and skin (melanoma), and showed promising cytotoxic effects on all types. For some of the ferrocenyl-curcuminoid derivatives, enhanced cytotoxic activity was observed compared to the organic curcuminoid analogues, with up to a 3- and 4-fold improvement on prostate and melanoma cells, respectively. MeO HO OH O Curcumin OMe OH 25 MeO R 1 OH O R 2 R 2 R 1 : H, OH, OMe R 2 : H, OMe = organic linker Curcumin and ferrocenyl derivatives of several curcuminoids Due to encouraging results in vitro, the National Institute of Health of the United States is currently screening, in collaboration with the National Cancer Institute, one selected ferrocenyl curcuminoid on 60 different cancer cell lines (colon, lung, central nervous system,…). Primary single dose testing revealed a particular selectivity of the compound for certain types of cancer in vitro, which has led to more detailed investigations, presently ongoing. Acknowledgement to the Gottlieb-Daimler and Carl-Benz Foundation (Germany) and the Association pour la Recherche sur le Cancer (ARC) (France) for PhD funding. References 1. A. Goel, A. B. Kunnumakkara, B. B. Aggarwal, Biochem. Pharmacol. 2008, 75, 787-809. 2. A. Arezki, E. Brulé, G. Jaouen, Organometallics 2009, 28, 1606-1609. 3. L. Lin, Q. Shi, A. K. Nyarko, K. F. Bastow et al. J. Med. Chem. 2006, 49, 3963-3972. 4. P. Anand, A. B. Kunnumakkara, R. A. Newman, B. B. Aggarwal, Mol. Pharm. 2007, 4, 804-818. Fe OMe R 1
OP-10 ISBOMC `10 5.7 – 9.7. 2010 Ruhr-Universität Bochum Synthesis, characterization and antiproliferative activity of a series of Pt(IV) complexes: a QSAR approach to their cytotoxicity Domenico Osella, a Paola Gramatica, b Ester Papa, b Mara Luini, b Elena Monti, b Marzia B. Gariboldi, b Mauro Ravera, a Elisabetta Gabano, a and Luca Gaviglio a a University of Piemonte Orientale “A. Avogadro”, Department of Environmental and Life Sciences, Viale Michel 11, 15121, Alessandria, Italy. b Department of Structural and Functional Biology, University of Insubria, Via A. da Giussano 10, 21052 Busto Arsizio (VA), Italy. E-mail: domenico.osella@mfn.unipmn.it Octahedral Pt(IV) complexes are usually supposed to behave as antitumor pro-drugs: most of them can be reduced by the hypoxic environment of the tumour tissue to square planar Pt(II) via a two electron reduction and loss of axial ligands. Both axial and equatorial ligands play an important role in setting the redox potential into the biological window and modulating the lipophilicity of Pt(IV) complexes, whereas the two carrier groups (N-based) determine the antiproliferative potency of the drug. A large series of Pt(IV) complexes containing different ligands was synthesized, characterized and tested for in vitro antitumor activity against ovarian carcinoma, A2780, and colon adenocarcinoma, HCT116, cell lines. A quantitative structure-activity relationship (QSAR) analysis was performed on this series of Pt(IV) complexes to find a relationship among cytotoxicity (IC50), reduction peak potential (Ep), partition coefficient (log Po/w) and theoretical molecular descriptors. The whole set of descriptors was used as an input set for modeling, in order to identify different structural features of Pt(IV) complexes related to the in vitro cytotoxicity. In the resulting models, a lipophilic descriptor (i.e log Po/w or number of secondary sp 3 carbon atoms, nCs) plus an electronic descriptor (Ep, number of oxygen atoms, nO, or total polar surface area, TPSA(NO)) is necessary for the optimal modeling. This results support the general findings that the biological behavior of Pt(IV) complexes is related to their uptake, reduction, and structure of the corresponding Pt(II) metabolites. 26
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Sergey Abramkin Universität Wien,
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Prof. Dr. Toshikazu Hirao Osaka Uni
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Obiora Augustine Orakwue Hyqid Nige
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