Claudia A. Blindauer

Publications (3)5.09 Total impact

• Source

  Available from: Raquel B. Gómez-Coca

  Article: Extent of Intramolecular π-Stacks in Aqueous Solution in Mixed-Ligand Copper(II) Complexes Formed by Heteroaromatic Amines and Several 2-Aminopurine Derivatives of the Antivirally Active Nucleotide Analog 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA).

  Raquel B Gómez-Coca, Claudia A Blindauer, Astrid Sigel, Bert P Operschall, Antonín Holý, Helmut Sigel
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  ABSTRACT: The acidity constants of twofold protonated, antivirally active, acyclic nucleoside phosphonates (ANPs), H(2) (PE)(±) , where PE(2-) =9-[2-(phosphonomethoxy)ethyl]adenine (PMEA(2-) ), 2-amino-9-[2-(phosphonomethoxy)ethyl]purine (PME2AP(2-) ), 2,6-diamino-9-[2-(phosphonomethoxy)ethyl]purine (PMEDAP(2-) ), or 2-amino-6-(dimethylamino)-9-[2-(phosphonomethoxy)ethyl]purine (PME(2A6DMAP)(2-) ), as well as the stability constants of the corresponding ternary Cu(Arm)(H;PE)(+) and Cu(Arm)(PE) complexes, where Arm=2,2'-bipyridine (bpy) or 1,10-phenanthroline (phen), are compared. The constants for the systems containing PE(2-) =PMEDAP(2-) and PME(2A6DMAP)(2-) have been determined now by potentiometric pH titrations in aqueous solution at I=0.1M (NaNO(3) ) and 25°; the corresponding results for the other ANPs were taken from our earlier work. The basicity of the terminal phosphonate group is very similar for all the ANP(2-) species, whereas the addition of a second amino substituent at the pyrimidine ring of the purine moiety significantly increases the basicity of the N(1) site. Detailed stability-constant comparisons reveal that, in the monoprotonated ternary Cu(Arm)(H;PE)(+) complexes, the proton is at the phosphonate group, that the ether O-atom of the CH(2) OCH(2) P(O)$\rm{{_{2}^{-}}}$(OH) residue participates, next to the P(O)$\rm{{_{2}^{-}}}$(OH) group, to some extent in Cu(Arm)(2+) coordination, and that ππ stacking between the aromatic rings of Cu(Arm)(2+) and the purine moiety is rather important, especially for the H⋅PMEDAP(-) and H⋅PME(2A6DMAP)(-) ligands. There are indications that ternary Cu(Arm)(2+) -bridged stacks as well as unbridged (binary) stacks are formed. The ternary Cu(Arm)(PE) complexes are considerably more stable than the corresponding Cu(Arm)(RPO(3) ) species, where RPO$\rm{{_{3}^{2-}}}$ represents a phosph(on)ate ligand with a group R that is unable to participate in any kind of intramolecular interaction within the complexes. The observed stability enhancements are mainly attributed to intramolecular-stack formation in the Cu(Arm)(PE) complexes and also, to a smaller extent, to the formation of five-membered chelates involving the ether O-atom present in the CH(2) OCH(2) PO$\rm{{_{3}^{2-}}}$ residue of the PE(2-) species. The quantitative analysis of the intramolecular equilibria involving three structurally different Cu(Arm)(PE) isomers shows that, e.g., ca. 1.5% of the Cu(phen)(PMEDAP) system exist with Cu(phen)(2+) solely coordinated to the phosphonate group, 4.5% as a five-membered chelate involving the ether O-atom of the CH(2) OCH(2) PO$\rm{{_{3}^{2-}}}$ residue, and 94% with an intramolecular ππ stack between the purine moiety of PMEDAP(2-) and the aromatic rings of phen. Comparison of the various formation degrees of the species formed reveals that, in the Cu(phen)(PE) complexes, intramolecular-stack formation is more pronounced than in the Cu(bpy)(PE) species. Within a given Cu(Arm)(2+) series the stacking intensity increases in the order PME2AP(2-) <PMEA(2-) <PMEDAP(2-) <PME(2A6DMAP)(2-) . One could speculate that the reduced stacking intensity of PME2AP(2-) , together with a different H-bonding pattern, could well lead to a different orientation of the 2-aminopurine moiety (compared to the adenine residue) in the active site of nucleic acid polymerases and thus be responsible for the reduced antiviral activity of PME2AP compared with that of PMEA and the other ANPs containing a 6-amino substituent.
  Chemistry & Biodiversity 09/2012; 9(9):2008-34. · 1.80 Impact Factor
• Article: Magnesium complexes of the antiviral 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) and of its 1-, 3-, and 7-deaza analogues in aqueous solution

  Claudia A. Blindauer, Antonín Holý, Hana Dvořáková, H. Sigel
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  ABSTRACT:  The stability constants of the 1 : 1 complexes formed between Mg2+ and the anions of the N1, N3, and N7 deaza derivatives of 9-[2-(phosphonomethoxy)ethyl]adenine (PA2–), i.e., of Mg(H;PA)+ and Mg(PA), were determined by potentiometric pH titration in aqueous solution (25  °C; I=0.1 M, NaNO3) and compared with previous results [Sigel H, et al. (1992) Helv Chim Acta 75 : 2634–2656], obtained under the same conditions, for the corresponding complexes of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA2–) and (phosphonomethoxy)ethane (PME2–). Based on the analysis of a microconstant scheme it is concluded that in the monoprotonated complexes, Mg(H;PA)+, Mg2+ is coordinated to a significant part at the nucleobase, H+ being at the phosphonate group. By making use of log K Mg Mg(R-PO3) versus pK H H(R-PO3) straight-line plots (also obtained previously; see above) for simple phosphonates and phosphate monoesters, it is shown that all the Mg(PA) complexes, including those with PMEA2– and PME2–, are more stable than expected on the basis of the basicity of the ―PO2– 3 group. This proves that, to some extent, five-membered chelates, Mg(PA)cl/O, involving the ether oxygen of the ―CH2―O―CH2―PO2– 3 chain are formed; their formation degree amounts to about 30–40% in equilibrium with the isomer having only a phosphonate-Mg2+ coordination. In the case of Mg(1-deaza-PMEA), probably a further isomer occurs in which also N3 of the nucleobase participates. The different properties between the Mg(PA) species and the Mg(AMP) complex are discussed.
  JBIC Journal of Biological Inorganic Chemistry 07/1998; 3(4):423-433. · 3.29 Impact Factor
• Article: Metal Ion-Binding Properties of the Nucleotide Analogue 1-[2-(Phosphonomethoxy)ethyl]cytosine (PMEC) in Aqueous Solution

  Claudia A. Blindauer, Antonín Holý, Helmut Sigel
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  ABSTRACT: The acidity constants of the twofold protonated nucleotide analogue 1-[2-(phosphonomethoxy)ethyl]cytosine, H₂(PMEC)^±, as well as the stability constants of the M(H;PMEC)⁺ and M(PMEC) complexes with the metal ions M²⁺ = Mg²⁺, Ca²⁺, Sr²⁺, Ba²⁺, Mn²⁺, Co²⁺, Ni²⁺, Cu²⁺, Zn²⁺, and Cd²⁺ have been determined by potentiometric pH titrations in aqueous solution at I = 0.1 M (NaNO₃) and 25 °C. Comparison with previous results for the nucleobase-free compound (phosphonomethoxy)ethane, PME, and the parent nucleotides cytidine 5'-monophosphate (CMP^2-) and 2'-deoxycytidine 5'-monophosphate (dCMP^2-) shows that the metal ion-binding properties of PMEC^2- resemble closely those of PME^2-: This means, the primary binding site is the phosphonate group and with all of the metal ions studied, 5-membered chelates involving the ether oxygen of the -CH₂-O-CH₂-PO₃^2- chain are formed. The position of the isomeric equilibria between these chelates and the "open" complexes, -PO₃^2-/M²⁺ is calculated; the degree of formation of the chelates is identical within the error limits for the M(PME) and M(PMEC) systems. Hence, like in M(CMP) and M(dCMP) no interaction occurs with the cytosine residue in the M(PMEC) complexes. However, the monoprotonated M(H;PMEC)⁺ as well as the M(H;CMP)⁺ and M(dCMP)⁺ species carry the metal ion predominantly at the nucleobase, while the proton is at the phosph(on)ate group. The coordinating properties of PMEC^2- and CMP^2- or dCMP^2- differ thus only with respect to the possible formation of the 5-membered chelates involving the ether oxygen in M(PMEC) species, a possibility which does not exist in the complexes of the parent nucleotides. Possible reasons why PMEC is devoid of a significant antiviral activity are shortly discussed.