ISBN: 978-83-60043-10-3 - eurobic9

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Eurobic9, 2-6 September, 2008, Wrocław, Poland P127. Metal-ion Mediated Hoogsteen-type Base Pairs Between the Natural Pyrimidine Bases and Artificial 1-deaza and 1, 3-dideazapurine Bases D.A. Megger, F.A. Polonius, J. Müller Inorganic Chemistry, Dortmund University of Technology, Otto-Hahn-Str. 6, 44227, Dortmund, Germany e-mail: dominik.megger@tu-dortmund.de In the past few years many new base pairs containing artificial nucleobases have been reported. Those base pairs are mediated by hydrogen bonding, metal-ion binding, hydrophobic interactions or a combination of these interactions. As had been reported earlier, the incorporation of 19 metal ions in a row was achieved in our group using 1-deazaadenine D as base complementary to a deprotonated thymine T.[1] In this case, Hoogsteen-type base pairs are formed by one hydrogen bond and two coordinative bonds (Fig. A). The aim of our current work is the investigation of the metal-ion binding properties of oligonucleotides containing the artificial nucleobases 1, 3-dideazaadenine dD and 1, 3-dideaza-6-nitropurine dN. The reason for choosing dD as an artificial nucleobase is on the one hand the easier accessibility of dD compared to D and on the other hand the formal substitution of the N3 atom by a CH-group. This defunctionalisation of the nucleobase allows metal-ion binding only via the Hoogsteen edge. In case of dN we intend to develop an artificial nucleobase that is able to form metal-ion mediated Hoogsteen-type base pairs with cytosine C (Fig. B). The results of UV- and CD-spectroscopic experiments with oligonucleotides containing the above mentioned nucleobases in absence and presence of several metal ions will be discussed. Additionally the pKa values of the nucleosides of D, dD and dN will be presented. References: [1] F.-A. Polonius, J. Müller, Angew. Chem. Int. Ed., 2007, 46, 5602-5604. _____________________________________________________________________ 246
Eurobic9, 2-6 September, 2008, Wrocław, Poland P128. Antimicrobial Activity of the Co(II), Zn(II) and Cd(II) Complexes with N-benzyloxycarbonyl-S-phenylalanine D. Mitić a , M. Milenković b , S. Milosavljević a , Z. Miodragović a , K. Anđelković a and Dj. Miodragović a a Faculty of Chemistry, University of Belgrade, Studentski trg 12-16, 11000 Belgrade, Serbia e-mail: dmiodrag@chem.bg.ac.yu b Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, Serbia There is a pressing need for new antifungal agents because of the fast development of resistance of microorganisms to the state-of-the-art drugs currently used to treat different fungal infections. For this reason, the elaboration of new types of antifungal agents is presently a very real task. A promising field for this search is metal-based drugs. Metal-based drugs have a different mode of action compared to the commonly used commercial polyene and azole antifungal drugs. Treatment of fungal cells with, for example, Cu(II) and Ag(I) complexes [1] resulted in a reduced amount of ergosterol in the cell membrane and a subsequent increase in its permeability. In spite of interesting biological activities, only a few complexes with N-Boc amino acids have been described. As N-benzyloxycarbonylglycine has favorable membrane penetration properties [2], in our previous paper the preparation of neutral complexes of this ligand with various metal ions was described [3]. The antimicrobial activity of the obtained metal complexes was also determined and it was established that among the investigated strains, the Zn(II) and Co(II) complexes were selective, acting only against the yeast Candida albicans. In a further investigation, the complex of Zn(II) with N-benzyloxycarbonyl-S-alanine was synthesized and was shown to possess the same selectivity against Candida albicans [4]. In this study, new complex compounds of Zn(II), Cd(II) and Co(II) with N-benzyloxycarbonyl-S-phenylalanine (1-3) were synthesized and characterized. As N-benzyloxycarbonyl-S-phenylalanine is more hydrophobic (and more lipophilic) than N-Boc-glycine and N-Boc-S-alanine, it was supposed that these complexes could have better antimicrobial activities than the previously investigated ones. MIC values obtained for complexes are lower than MIC values obtained for ligand and simple metal salts. The comparison of MIC value of complex 2 with MIC value of complex with N-Boc-gly indicates that substitution of N-Boc-gly with N-Boc-S-phe ligand resulted in a more than twelve fold increase in the anti-Candida activity, from 1.11 to 0.09 mM. The increase in activity was also observed for complexes 1 and 3 [5]. The increase in the lipophilicity of N-benzyloxycarbonyl–S-phenylalaninato ligand is probably the reason for the better penetration of the complexes with this ligand in comparison to the complexes with N-Boc-glycine or N-Boc-S-alanine. It is interesting to note that Hitherto investigated complexes with N-benzyloxycarbonyl-amino acids exhibited the best activity against the yeast Candida albicans of the until now investigated bacterial and fungal strains. Complex 2 has MIC value almost the same as that of the standard drug nystatin in the case of Candida albicans ATCC 24433. Acknowledgement: This investigation was supported by the Ministry of Science of the Republic of Serbia, Grant No. 142010. References: [1] D.M. Lambert, G.K.E. Scriba, J.H. Poupaert, P. Dumont, Eur. J. Pharm. Sci. 4, 159 (1996). [2] B.S. Creaven, D. A. Egan, D. Karcz, K. Kavanagh, M. McCann, M. Mahon, A. Noble, B. Thati, M. Walsh, J. Inorg. Biochem. 101, 1108 (2007). [3] D.U. Miodragović, D.M. Mitić, Z.M. Miodragović, G.A. Bogdanović, Ž.J. Vitnik, M. D. Vitorović, M.Đ. Radulović, B.J. Nastasijević, I.O. Juranić, K.K. Anđelković, Inorg. Chim. Acta 361, 86 (2008). [4] D.M. Mitić, Đ.U. Miodragović, D.M. Sladić, Ž.J. Vitnik, Z.M. Miodragović, K.K. Anđelković, M.Đ. Radulović, N.O. Juranić, J. Serb. Chem. Soc. (2008), in press. [5] D. Mitić, M. Milenković, S. Milosavljević, D. Gođevac, Z. Miodragović, K. Anđelković, Dj. Miodragović, submited for Eur. J. Med. Chem. _____________________________________________________________________ 247
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ISBN: 978-83-60043-10-3 - eurobic9

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