Partners and International Organizations
(English)
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AT, BE, BG, CZ, DK, FI, FR, DE, EL, HU, IE, IL, IT, NL, NO, PL, RO, SI, ES, SE, CH, TR, UK
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Abstract
(English)
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During the time of this report (01.02.2005-23.02.2006) several significant results were obtained; the most pertinent ones follow: (i) Metal ion-binding studies of the dianion of 9-[2-(phosphonoethoxy)ethyl]adenine (PEEA2-) and comparison with previous results for the antivirally active nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA2-) reveals that 6-membered chelates involving the ether oxygen in the 'aliphatic' chain are considerably less stable than the corresponding 5-membered ones [Inorg. Chem. 44 (2005) 5104-5117]. Because it has been concluded that the metal ion-ether interaction is crucial for the formation of the reactive intermediate needed in the transfer of a nucleotidyl residue in the polymerase reaction [Chem. Soc. Rev. 34 (2005) 875-900], the mentioned observation offers an explanation why PMEA is a nucleotide analogue with excellent antiviral properties whereas its close relative PEEA is not. PMEA itself is now used in the form of its bis(pivaloyloxymethyl)ester as a drug in hepatitis B therapy. (ii) In nucleic acids metal ion-carbonyl oxygen interactions are expected to occur if support by a primary binding site is provided. This has now been proven to be the case in a study of (N3)-deprotonated uridine, thymidine, and related pyrimidine nucleosides [Proc. Nat. Acad. Sci. USA 102 (2005) 7459-7464]. Similar interactions are expected for the guanine residue, the acid-base properties of which were studied in the dinucleotide d(pGpG) [Org. Biomol. Chem. 4 (2006)]; the corresponding studies with metal ions are in progress. (iii) The coordination chemistry of the anticancer compound Cisplatin, i.e. of cis-(NH3)2PtCl2 or better of its reactive intermediate cis-(NH3)2Pt2+, has been extensively investigated. Much less is known about the inactive analogue Transplatin. We have now studied the complex trans,trans,trans-(NH3)2Pt(N7-µ-9-MeA-N1)2[(NH3)2Pt(9-EtG-N7)]6+2 , where 9-MeA = 9-methyladenine and 9-EtG = 9-ethylguanine, which contains a nucleobase quartett, and discovered to our surprise that one of the adenine (C6)NH2 groups is deprotonated with pKa = 7.1, i.e. in the physiological pH range [to be published]. The biological consequences of this low pKa value are not yet known, but it is certain that this low pKa is due to an intensive H bonding network in the mentioned complex.
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