Partners and International Organizations
(English)
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A, B, CZ, DK, FIN, F, D, GR, H, IRL, I, NL, N, PL, P, RO, SI, E, S, CH, GB
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Abstract
(English)
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Among the results obtained during the period of this report (01.04.2000-30.04.2001) the following ones may be emphasized: (i) In the ternary complexes (diethylenetriamine)Pt(PMEA-N1) and (diethylenetriamine)Pt(PMEA-N7) the (Dien)Pt2+ unit is coordinated either via N1 or via N7 to the adenine residue of the dianionic nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA2-); both ternary complexes are able to bind further metal ions like Mg2+, Ca2+ or Zn2+ at the phosphonate group of PMEA2- to give M[(Dien)Pt(PMEA-N1/N7)]2+ species despite the positively charged (Dien)Pt2+ at the nucleobase. This observation is meaningful regarding the properties of the antitumor drug Cisplatin, cis-(NH3)2PtCl2, which is believed to exert its biological action by binding of cis-(NH3)2Pt2+ to the N7 sites of the purine residues in DNA, because it shows that a phosph(on)ate site of a nucleotide unit may still bind metal ions, the decrease in stability being small. (ii) By studying the extent of intramolecular stack formation in the mixed ligand complexes Cu(Arm)(PA), where Arm = 2,2'-bipyridine or 1,10-phenanthroline and PA2- = PMEA2-, 3'-deoxa-PMEA2- or adenosine 5'-monophosphate (AMP2-), it is shown that the stacking properties of AMP2- and its analogues are quite alike; this similarity contrasts with previous results obtained for binary complexes in which the properties of the antivirally acitve PMEA2- differ significantly from those of 3'-deoxa-PMEA2- or AMP2-. (iii) Studies with Pb2+ revealed that its affinity towards the various constituents of single-stranded nucleic acids decreases in the following series: guanine-N7(O6) >Ž~ cytosine-N3(O2) >Ž~ R'OP(O)-/2OR (phosphate-diester bridge) >Ž~ adenine > uracil ~ thymine. This observation is of relevance for leadzymes, i.e. for ribozymes which require Pb2+ for catalytic activity, but also for other metal ions like Zn2+ because for these the same stability order is expected. Furthermore, it was shown that the replacement of an O by an S atom in a phosphate group enhances the affinity of this group for Pb2+ and Zn2+, but not for Mg2+; these results are of relevance for corresponding thiooligonucleotides which are of potential interest in antisense therapy.
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