Helmut Sigel

University of Zurich, Zürich, ZH, Switzerland

Are you Helmut Sigel?

Claim your profile

Publications (315)898.99 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The acidity constants of 3-fold protonated 9-[2-(phosphonomethoxy)ethyl]-2-amino-6-dimethylaminopurine, H3(PME2A6DMAP)+ are considered, and the stability constants of the M(H;PME2A6DMAP)+ and M(PME2A6DMAP) complexes with M2+ = Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+ or Cd2+ have been determined by potentiometric pH titrations in aqueous solution (25°C; I = 0.1 M, NaNO3). It is concluded that in the M(H;PME2A6DMAP)+ species, the proton is at the phosphonate group and that also the metal ion is coordinated (mainly in an outersphere manner) at this site. There is no indication that the purine residue participates in a significant extent in M2+ binding in the M(H;PME2A6DMAP)+ species. This contrasts, e.g., with the corresponding complexes formed by the parent compound 9-[2-(phosphonomethoxy)ethyl]adenine, that is, M(H;PMEA)+, where M2+ is mainly coordinated at the adenine residue. The application of previously determined straight-line plots of log versus for simple phosph(on)ate ligands, R-PO , where R represents a residue that does not affect metal ion binding, proves that all the M(PME2A6DMAP) complexes have larger stabilities than is expected for a sole phosphonate coordination of M2+. Comparison with previous results obtained for M(PME-R) complexes, where R is a non-coordinating residue of the (phosphonomethoxy)ethane chain, allows the conclusion that the increased stability of all the M(PME2A6DMAP) complexes is due to the formation of 5-membered chelates involving the ether-oxygen atom of the –CH2–O–CH2–PO residue: The formation degrees of these M(PME2A6DMAP)cl/O chelates, which occur in intramolecular equilibria for the mentioned metal ions, vary between about 20% (Sr2+, Ba2+) and 50% (Zn2+, Cd2+), going up to 67% (Cu2+) in the maximum. Any M2+ interaction with N3 or N7 of the purine moiety, as it occurs in M(PMEA) complexes, is suppressed by the (C2)NH2 and (C6)N(CH3)2 substituents, respectively. This observation, together with the previously determined stacking properties, offers an explanation why PME2A6DMAP2– has remarkable therapeutic effects.
    Canadian Journal of Chemistry 08/2014; · 0.96 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aromatic-ring stacking is pronounced among the noncovalent interactions occurring in biosystems and therefore some pertinent features regarding nucleobase residues are summarized. Self-stacking decreases in the series adenine > guanine > hypoxanthine > cytosine ~ uracil. This contrasts with the stability of binary (phen)(N) adducts formed by 1,10-phenanthroline (phen) and a nucleobase residue (N), which is largely independent of the type of purine residue involved, including (N1)H-deprotonated guanine. Furthermore, the association constant for (phen)(A)(0/4-) is rather independent of the type and charge of the adenine derivative (A) considered, be it adenosine or one of its nucleotides, including adenosine 5'-triphosphate (ATP(4-)). The same holds for the corresponding adducts of 2,2'-bipyridine (bpy), although owing to the smaller size of the aromatic-ring system of bpy, the (bpy)(A)(0/4-) adducts are less stable; the same applies correspondingly to the adducts formed with pyrimidines. In accord herewith, [M(bpy)](adenosine)(2+) adducts (M(2+) is Co(2+), Ni(2+), or Cu(2+)) show the same stability as the (bpy)(A)(0/4-) ones. The formation of an ionic bridge between -NH3 (+) and -PO3 (2-), as provided by tryptophan [H(Trp)(±)] and adenosine 5'-monophosphate (AMP(2-)), facilitates recognition and stabilizes the indole-purine stack in [H(Trp)](AMP)(2-). Such indole-purine stacks also occur in nature. Similarly, the formation of a metal ion bridge as occurs, e.g., between Cu(2+) coordinated to phen and the phosphonate group of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA(2-)) dramatically favors the intramolecular stack in Cu(phen)(PMEA). The consequences of such interactions for biosystems are discussed, especially emphasizing that the energies involved in such isomeric equilibria are small, allowing Nature to shift such equilibria easily.
    European Journal of Biochemistry 01/2014; · 3.42 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Stability constants of the ternary Cu(Arm)(H;PMEC)+ and Cu(Arm)(PMEC) complexes {PMEC2– = dianion of 1-[2-(phosphonomethoxy)ethyl]cytosine, Arm = 2, 2′-bipyridine (Bpy) or 1, 10-phenanthroline (Phen)} were measured by potentiometric pH titrations (aq. sol.; 25 °C; I = 0.1 M, NaNO3) and compared with those of Cu(Arm)(H;PMEA)+ and Cu(Arm)(PMEA) {PMEA2– = dianion of 9-[2-(phosphonomethoxy)ethyl]adenine}, and related species. The basicity of the terminal phosphonate group is similar in PMEC2– and PMEA2–. Stability-constant comparisons reveal, that in the monoprotonated ternary Cu(Arm)(H;PMEC)+ complexes H+ is at the phosphonate group, that the ether oxygen atom of the –CH2–O–CH2–P(O)–2(OH) residue participates, next to the P(O)–2(OH) group, in Cu(Arm)2+ coordination, and that π–π stacking between the aromatic rings of Cu(Arm)2+ and the pyrimidine moiety is important. The Cu(Arm)(PMEC) complexes are considerably more stable than the corresponding Cu(Arm)(R–PO3) species, where R–PO2–3 is a phosph(on)ate with a group R unable to interact intramolecularly. The stability enhancements are mainly attributed to intramolecular stacks and, to a smaller extent, to the formation of five-membered chelates involving the ether oxygen atom of the –CH2–O–CH2–P(O)2–3 residue of PMEC2–. Analysis of the intramolecular equilibria reveals that ca. 10 % of the isomeric ternary complexes exist with Cu(Arm)2+ solely coordinated to the phosphonate group, ca. 25 % as a five-membered chelate involving the ether oxygen, and ca. 65 % with an intramolecular π–π stack between the pyrimidine moiety of PMEC2– and the rings of Bpy or Phen. For a given Cu(Arm)2+ the stacking intensity increases from PMEC2– to PMEA2–. It seems feasible that the reduced stacking intensity of PMEC2–, together with a different hydrogen bonding pattern, leads to a different orientation of the cytosine residue (compared to the adenine moiety) in the active site of the nucleic acid polymerases, thus resulting in a reduced antiviral activity of PMEC compared to PMEA.
    Zeitschrift für anorganische Chemie 07/2013; 639(8‐9). · 1.16 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The intrinsic acid-base properties of the hexa-2'-deoxynucleoside pentaphosphate, d(ApGpGpCpCpT) [=(A1⋅G2⋅G3⋅C4⋅C5⋅T6)=(HNPP)(5-) ] have been determined by (1) H NMR shift experiments. The pKa values of the individual sites of the adenosine (A), guanosine (G), cytidine (C), and thymidine (T) residues were measured in water under single-strand conditions (i.e., 10 % D2 O, 47 °C, I=0.1 M, NaClO4 ). These results quantify the release of H(+) from the two (N7)H(+) (G⋅G), the two (N3)H(+) (C⋅C), and the (N1)H(+) (A) units, as well as from the two (N1)H (G⋅G) and the (N3)H (T) sites. Based on measurements with 2'-deoxynucleosides at 25 °C and 47 °C, they were transferred to pKa values valid in water at 25 °C and I=0.1 M. Intramolecular stacks between the nucleobases A1 and G2 as well as most likely also between G2 and G3 are formed. For HNPP three pKa clusters occur, that is those encompassing the pKa values of 2.44, 2.97, and 3.71 of G2(N7)H(+) , G3(N7)H(+) , and A1(N1)H(+) , respectively, with overlapping buffer regions. The tautomer populations were estimated, giving for the release of a single proton from five-fold protonated H5 (HNPP)(±) , the tautomers (G2)N7, (G3)N7, and (A1)N1 with formation degrees of about 74, 22, and 4 %, respectively. Tautomer distributions reveal pathways for proton-donating as well as for proton-accepting reactions both being expected to be fast and to occur practically at no "cost". The eight pKa values for H5 (HNPP)(±) are compared with data for nucleosides and nucleotides, revealing that the nucleoside residues are in part affected very differently by their neighbors. In addition, the intrinsic acidity constants for the RNA derivative r(A1⋅G2⋅G3⋅ C4⋅C5⋅U6), where U=uridine, were calculated. Finally, the effect of metal ions on the pKa values of nucleobase sites is briefly discussed because in this way deprotonation reactions can easily be shifted to the physiological pH range.
    Chemistry - A European Journal 04/2013; · 5.93 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cadmium(II), commonly classified as a relatively soft metal ion, prefers indeed aromatic-nitrogen sites (e.g., N7 of purines) over oxygen sites (like sugar-hydroxyl groups). However, matters are not that simple, though it is true that the affinity of Cd(2+) towards ribose-hydroxyl groups is very small; yet, a correct orientation brought about by a suitable primary binding site and a reduced solvent polarity, as it is expected to occur in a folded nucleic acid, may facilitate metal ion-hydroxyl group binding very effectively. Cd(2+) prefers the guanine(N7) over the adenine(N7), mainly because of the steric hindrance of the (C6)NH(2) group in the adenine residue. This Cd(2+)-(N7) interaction in a guanine moiety leads to a significant acidification of the (N1)H meaning that the deprotonation reaction occurs now in the physiological pH range. N3 of the cytosine residue, together with the neighboring (C2)O, is also a remarkable Cd(2+) binding site, though replacement of (C2)O by (C2)S enhances the affinity towards Cd(2+) dramatically, giving in addition rise to the deprotonation of the (C4)NH(2) group. The phosphodiester bridge is only a weak binding site but the affinity increases further from the mono- to the di- and the triphosphate. The same also holds for the corresponding nucleotides. Complex stability of the pyrimidine-nucleotides is solely determined by the coordination tendency of the phosphate group(s), whereas in the case of purine-nucleotides macrochelate formation takes place by the interaction of the phosphate-coordinated Cd(2+) with N7. The extents of the formation degrees of these chelates are summarized and the effect of a non-bridging sulfur atom in a thiophosphate group (versus a normal phosphate group) is considered. Mixed ligand complexes containing a nucleotide and a further mono- or bidentate ligand are covered and it is concluded that in these species N7 is released from the coordination sphere of Cd(2+). In the case that the other ligand contains an aromatic residue (e.g., 2,2'-bipyridine or the indole ring of tryptophanate) intramolecular stack formation takes place. With buffers like Tris or Bistris mixed ligand complexes are formed. Cd(2+) coordination to dinucleotides and to dinucleoside monophosphates provides some insights regarding the interaction between Cd(2+) and nucleic acids. Cd(2+) binding to oligonucleotides follows the principles of coordination to its units. The available crystal studies reveal that N7 of purines is the prominent binding site followed by phosphate oxygens and other heteroatoms in nucleic acids. Due to its high thiophilicity, Cd(2+) is regularly used in so-called thiorescue experiments, which lead to the identification of a direct involvement of divalent metal ions in ribozyme catalysis.
    Metal ions in life sciences. 01/2013; 11:191-274.
  • Source
    [Show abstract] [Hide abstract]
    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. · 1.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The role that the amino group plays in the metal ion (M2+) binding properties of the adenine residue is of great relevance because this residue occurs widely in nature. It is the aim of this review to evaluate this role. We consider first several 9-methylpurine derivatives with amino and methyl substituents at various positions: the data indicate that substituents at C6 inhibit M2+ binding at both, the N1 and N7 sites. To separate these effects we use (i) o-amino(methyl)pyridines as models for the pyrimidine part of the adenine residue, i.e., for N1, and (ii) benzimidazole derivatives regarding the properties of N7. The inhibiting effects of ortho-amino and ortho-methyl groups on N1 of pyridines are identical, which agrees with the fact that such an amino group has no basic properties at all. This is different with 1-methyl-4-aminobenzimidazole (MABI) (9-methyl-1,3-dideazaadenine) and 1,4-dimethylbenzimidazole (DMBI) (6,9-dimethyl-1,3-dideazapurine) because the amino group in MABI still has some basic properties and thus, its steric inhibition is somewhat smaller than that of the methyl group in DMBI. It is suggested that the methyl group in DMBI mimics the steric effects of (C6)NH2 upon (N7)-M2+ coordination in the adenine residue. The evaluation of the N1 versus N7 dichotomy for 2,9-dimethylpurine, 2-amino-9-methylpurine, and 6-amino-9-methylpurine (9-methyladenine) reveals that the (N7)-M2+ isomer dominates. It is further suggested that the (C6)NH2 adenine group may act as a proton donor and the O atom of a coordinated water molecule as acceptor. The metal ion-binding properties of the two acyclic nucleotide analogues 9-[(2-phosphonomethoxy)ethyl]adenine (PMEA) and 9-[(2-phosphonomethoxy)ethyl]-2-aminopurine (PME2AP), which are structural isomers due to the shift of the (C6)NH2 group in PMEA to the C2 site in PME2AP, fit into the indicated coordination patterns. In the monoprotonated species M(H;PMEA)+ and M(H;PME2AP)+ the proton is located at the phosphonate group and M2+ at N7. However, the M(H;PME2AP)+ complexes are considerably more stable than the M(H;PMEA)+ ones: indeed, the steric effect on N1 is the same in both types of complexes, but the one on N7 has disappeared in M(H;PME2AP)+. Furthermore, there is evidence that the (N7)-coordinated M2+ interacts with the P(O)2(OH)− group in an outersphere manner leading to practically identical formation degrees of the macrochelates formed with Mn2+, Co2+, Ni2+, Cu2+ or Zn2+ [on average 65 ± 15% (3σ)]. The coordination chemistry of PMEA2− and PME2AP2− differs for the 3d ions as well, whereas for the alkaline earth ions, which are primarily coordinated (like all other M2+) to the phosphonate group, 5-membered chelates form involving the ether O of the –CH2CH2–O–CH2–PO32− residue. In contrast, Co2+, Ni2+, and Cu2+ form with PMEA2− a further isomer, which involves next to the ether O also N3; macrochelates involving N7 and the phosphonate-coordinated M2+ are minority species, but for Ni2+ and Cu2+ they occur and formation degrees of all four isomers could be determined. In the M(PME2AP) complexes a N3 interaction practically does not occur; macrochelate formation of the phosphonate-coordinated M2+ with N7, which is the dominating species for Co2+, Ni2+, Cu2+ or Zn2+ is important here. The possible interrelations between M2+ coordination and the antiviral activity of the two acyclic nucleotide analogues, PMEA being especially active, are discussed shortly.
    Coordination Chemistry Reviews 01/2012; 256(s 1–2):260–278. · 11.02 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Adenosine (Ado) can accept three protons, at N1, N3, and N7, to give H(3) (Ado)(3+) , and thus has three macro acidity constants. Unfortunately, these constants do not reflect the real basicity of the N sites due to internal repulsions, for example, between (N1)H(+) and (N7)H(+). However, these macroconstants are still needed for the evaluations and the first two are taken from our own earlier work, that is, pK(H)(H(3))((Ado)) = -4.02 and pK(H)(H(2))((Ado)) = -1.53; the third one was re-measured as pK(H)(H)((Ado)) = 3.64 ± 0.02 (25 °C; I=0.5 M, NaNO(3)), because it is the main basis for evaluating the intrinsic basicities of N7 and N3. Previously, contradicting results had been published for the micro acidity constant of the (N7)H(+) site; this constant has now been determined in an unequivocal manner, and that of the (N3)H(+) site was obtained for the first time. The micro acidity constants, which describe the release of a proton from an (N)H(+) site under conditions for which the other nitrogen atoms are free and do not carry a proton, decrease in the order pk(N7-N1)(N7(Ado)N1·H)) = 3.63 ± 0.02 > pk(N7-N1)(H·N7(Ado)N1) = 2.15 ± 0.15 > pk(N3-N1,N7)(H·N3(Ado)N1,N7) =1.5 ± 0.3, reflecting the decreasing basicity of the various nitrogen atoms, that is, N1>N7>N3. Application of the above-mentioned microconstants allows one to calculate the percentages (formation degrees) of the tautomers formed for monoprotonated adenosine, H(Ado)(+) , in aqueous solution; the results are 96.1, 3.2, and 0.7% for N7(Ado)N1·H(+), (+)H·N7(Ado)N1, and (+)H·N3(Ado)N1,N7, respectively. These results are in excellent agreement with theoretical DFT calculations. Evidently, H(Ado)(+) exists to the largest part as N7(Ado)N1·H(+) having the proton located at N1; the two other tautomers are minority species, but they still form. These results are not only meaningful for adenosine itself, but are also of relevance for nucleic acids and adenine nucleotides, as they help to understand their metal ion-binding properties; these aspects are briefly discussed.
    Chemistry - A European Journal 05/2011; 17(29):8156-64. · 5.93 Impact Factor
  • Chemical Reviews 05/2011; 111(8):4964-5003. · 41.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: With a view on protein-nucleic acid interactions in the presence of metal ions we studied the "simple" mixed-ligand model systems containing histamine (Ha), the metal ions Ni(2+), Cu(2+), or Zn(2+) (M(2+)), and the nucleotides adenosine 5'-triphosphate (ATP(4-)) or uridine 5'-triphosphate (UTP(4-)), which will both be referred to as nucleoside 5'-triphosphate (NTP(4-)). The stability constants of the ternary M(NTP)(Ha)(2-) complexes were determined in aqueous solution by potentiometric pH titrations. We show for both ternary-complex types, M(ATP)(Ha)(2-) and M(UTP)(Ha)(2-), that intramolecular stacking between the nucleobase and the imidazole residue occurs and that the stacking intensity is approximately the same for a given M(2+) in both types of complexes: The formation degree of the intramolecular stacks is estimated to be 20 to 50%. Consequently, in protein-nucleic acid interactions imidazole-nucleobase stacks may well be of relevance. Furthermore, the well-known formation of macrochelates in binary M(2+) complexes of purine nucleotides, that is, the phosphate-coordinated M(2+) interacts with N7, is confirmed for the M(ATP)(2-) complexes. It is concluded that upon formation of the mixed-ligand complexes the M(2+)-N7 bond is broken and the energy needed for this process corresponds to the stability differences determined for the M(UTP)(Ha)(2-) and M(ATP)(Ha)(2-) complexes. It is, therefore, possible to calculate from these stability differences of the ternary complexes the formation degrees of the binary macrochelates: The closed forms amount to (65±10)%, (75±8)%, and (31±14) % for Ni(ATP)(2-), Cu(ATP)(2-), and Zn(ATP)(2-), respectively, and these percentages agree excellently with previous results obtained by different methods, confirming thus the internal validity of the data and the arguments used in the evaluation processes. Based on the overall results it is suggested that M(ATP)(2-) species, when bound to an enzyme, may exist in a closed macrochelated form only, if no enzyme groups coordinate directly to the metal ion.
    Chemistry - A European Journal 04/2011; 17(19):5393-403. · 5.93 Impact Factor
  • Metal ions in life sciences. 01/2011; 9:v-vi.
  • Metal ions in life sciences. 01/2011; 8:vii-viii.
  • Metal ions in life sciences. 01/2011; 9:vii-ix.
  • [Show abstract] [Hide abstract]
    ABSTRACT: The acidity constants of 3-fold protonated 9-[(2-phosphonomethoxy)ethyl]-2-aminopurine, H(3)(PME2AP)(+), and the stability constants of the M(H;PME2AP)(+) and M(PME2AP) complexes with M(2+) = Ca(2+), Mg(2+), Mn(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+) or Cd(2+) have been determined by potentiometric pH titrations in aqueous solution (25 degrees C; I = 0.1 M, NaNO(3)). It is concluded that in the M(H;PME2AP)(+) species, the proton is at the phosphonate group and the metal ion at N7 of the purine residue. This "open" form allows macrochelate formation of M(2+) with the monoprotonated phosphonate residue. The formation degree of this macrochelate amounts on average to 64 +/- 13% (3sigma) for those metal ions for which an evaluation was possible (Mn(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+)). The identity of this formation degree indicates that the M(2+)/P(O)(2)(-)(OH) interaction occurs in an outersphere manner. The application of previously determined straight-line plots of log K(M)(M(R-PO(3)))versus pK(H)(H(R-PO(3))) for simple phosph(on)ate ligands, R-PO(3)(2-), where R represents a residue that does not affect metal ion binding, proves that all the M(PME2AP) complexes have larger stabilities than is expected for a sole phosphonate coordination of M(2+). Combination with previous results allows the following conclusions: (i) The increased stability of the M(PME2AP) complexes of Ca(2+), Mg(2+) and Mn(2+) is due to the formation of 5-membered chelates involving the ether-oxygen atom of the -CH(2)-O-CH(2)-PO(3)(2-) residue; the formation degrees of these M(PME2AP)(cl/O) chelates for the mentioned metal ions vary between about 25% (Ca(2+)) to 40% (Mn(2+)). (ii) For the M(PME2AP) complexes of Co(2+), Ni(2+), Cu(2+), Zn(2+) or Cd(2+) next to the mentioned 5-membered chelates a further isomer is formed, namely a macrochelate involving N7, M(PME2AP)(cl/N7). The formation degrees of these macrochelates vary between about 30% (Cd(2+)) and 85% (Ni(2+)). (iii) The most remarkable observation of this study is that the shift of the NH(2) group from C6 to C2 facilitates very significantly macrochelate formation of a PO(3)(2-)-coordinated M(2+) with N7 due to the removal of steric hindrance in the M(PME2AP) complexes. However, any M(2+) interaction with N3 is completely suppressed, thus leading to significantly different coordination patterns than those observed previously with the antivirally active PMEA(2-) species.
    Dalton Transactions 07/2010; 39(27):6344-54. · 4.10 Impact Factor
  • Roland K O Sigel, Helmut Sigel
    [Show abstract] [Hide abstract]
    ABSTRACT: The three-dimensional architecture and function of nucleic acids strongly depend on the presence of metal ions, among other factors. Given the negative charge of the phosphate-sugar backbone, positively charged species, mostly metal ions, are necessary for compensation. However, these ions also allow and induce folding of complicated RNA structures. Furthermore, metal ions bind to specific sites, stabilizing local motifs and positioning themselves correctly to aid (or even enable) a catalytic mechanism, as, for example, in ribozymes. Many nucleic acids thereby exhibit large differences in folding and activity depending not only on the concentration but also on the kind of metal ion involved. As a consequence, understanding the role of metal ions in nucleic acids requires knowing not only the exact positioning and coordination sphere of each specifically bound metal ion but also its intrinsic site affinity. However, the quantification of metal ion affinities toward certain sites in a single-stranded (though folded) nucleic acid is a demanding task, and few experimental data exist. In this Account, we present a new tool for estimating the binding affinity of a given metal ion, based on its ligating sites within the nucleic acid. To this end, we have summarized the available affinity constants of Mg(2+), Ca(2+), Mn(2+), Cu(2+), Zn(2+), Cd(2+), and Pb(2+) for binding to nucleobase residues, as well as to mono- and dinucleotides. We have also estimated for these ions the stability constants for coordinating the phosphodiester bridge. In this way, stability increments for each ligand site are obtained, and a clear selectivity of the ligating atoms, as well as their discrimination by different metal ions, can thus be recognized. On the basis of these data, we propose a concept that allows one to estimate the intrinsic stabilities of nucleic acid-binding pockets for these metal ions. For example, the presence of a phosphate group has a much larger influence on the overall affinity of Mg(2+), Ca(2+), or Mn(2+) compared with, for example, that of Cd(2+) or Zn(2+). In the case of Cd(2+) and Zn(2+), the guanine N7 position is the strongest intrinsic binding site. By adding up the individual increments like building blocks, one derives an estimate not only for the overall stability of a given coordination sphere but also for the most stable complex if an excess of ligating atoms is available in a binding pocket saturating the coordination sphere of the metal ion. Hence, this empirical concept of adding up known intrinsic stabilities, like building blocks, to an estimated overall stability will help in understanding the accelerating or inhibiting effects of different metal ions in ribozymes and DNAzymes.
    Accounts of Chemical Research 03/2010; 43(7):974-84. · 20.83 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2010; 32(28).
  • Helmut Sigel
    [Show abstract] [Hide abstract]
    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2010; 30(34).
  • [Show abstract] [Hide abstract]
    ABSTRACT: The four acidity constants of threefold protonated xanthosine 5'-monophosphate, H(3)(XMP)(+), reveal that in the physiological pH range around 7.5 (X - H x MP)(3-) strongly dominates and not XMP(2-) as commonly given in textbooks and often applied in research papers. Therefore, this nucleotide, which participates in many metabolic processes, should be addressed as xanthosinate 5'-monophosphate as is stated in this critical review. Micro acidity constant schemes allow quantification of intrinsic site basicities. In 9-methylxanthine nucleobase deprotonation occurs to more than 99% at (N3)H, whereas for xanthosine it is estimated that about 30% are (N1)H deprotonated and for (X - H x MP)(3-) it is suggested that (N1)H deprotonation is further favored, especially in macrochelates where the phosphate-coordinated M(2+) interacts with N7. The formation degree of these macrochelates in the (X - H x MP x M)(-) species of Co(2+), Ni(2+), Cu(2+), Zn(2+) or Cd(2+) amounts to 90% or more. In the monoprotonated (M x X - H x MP x H)(+/-) complexes, M(2+) is located at the N7/[(C6)O] unit as the primary binding site and it forms macrochelates with the P(O)(2)(OH)(-) group to about 65% for nearly all metal ions considered (i.e., including Ba(2+), Sr(2+), Ca(2+), Mg(2+)); this indicates outer-sphere binding to P(O)(2)(OH)(-). Finally, a new method quantifying the chelate effect is applied to the M(X - H x MP)(-) species, stabilities and structures of mixed-ligand complexes are considered, and the stability constants for several M(X - H x DP)(2-) and M(X - H x TP)(3-) complexes are estimated (112 references).
    Chemical Society Reviews 09/2009; 38(8):2465-94. · 24.89 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The stability constants of the mixed-ligand complexes formed between Cu(Arm)2+, where Arm=2,2′-bipyridine (Bpy) or 1,10-phenanthroline (Phen), and the monoanion or the dianion of 9-[2-(phosphonomethoxy)ethyl]-2-aminopurine (PME2AP), a structural isomer of the antivirally active 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA), were determined by potentiometric pH titrations in aqueous solution at 25°C and I=0.1M (NaNO3). Detailed stability constant comparisons reveal that in the monoprotonated ternary Cu(Arm)(H;PME2AP)+ complexes the proton is at the phosphonate group and that stacking between Cu(Arm)2+ and H(PME2AP)− plays a significant role. The ternary Cu(Arm)(PME2AP) complexes are considerably more stable than the corresponding Cu(Arm)(R–PO3) species, where R–PO32- represents a phosph(on)ate ligand with a group R that is unable to participate in any kind of interaction within the complexes. The increased stability is attributed to intramolecular stack formation in the Cu(Arm)(PME2AP) complexes and also, to a smaller extent, to the formation of 5-membered chelates involving the ether–oxygen present in the –CH2–O–CH2–PO32- residue of PME2AP2−. This latter interaction was previously quantified by studying ternary Cu(Arm)(PME) complexes (PME2−=dianion of (phosphonomethoxy)ethane), which can form the 5-membered chelates but where no intramolecular ligand–ligand stacking is possible. Application of these results allows a quantitative analysis of the intramolecular equilibria involving three structurally different Cu(Arm)(PME2AP) species; e.g., about 5% of the Cu(Bpy)(PME2AP) system exist with the metal ion solely coordinated to the phosphonate group, 15% as a 5-membered chelate involving the ether–oxygen atom of the –CH2–O–CH2–PO32-residue, and 80% with an intramolecular π–π stack between the purine moiety of PME2AP2− and the aromatic rings of Bpy. Finally, comparison of the stacking properties of PME2AP2− and PMEA2− in their ternary complexes reveals that stacking is somewhat more pronounced in the Cu(Arm)(PMEA) than in the Cu(Arm)(PME2AP) species. Speculatively, this reduced stacking intensity, together with a different hydrogen-bonding pattern, could well lead to a different positioning of the 2-aminopurine moiety (compared to the adenine residue) in the active site cavity of nucleic acid polymerases and thus be responsible for the reduced antiviral activity of PME2AP compared with that of PMEA.
    Inorganica Chimica Acta 02/2009; 362(3):799-810. · 1.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The stability constants of the 1 : 1 complexes formed between Cu(Arm), where Arm = 2,2′-bipyridine or 1,10-phenanthroline, and guanosine 5′-diphosphate (GDP) or its monoprotonated form H(GDP) were determined by potentiometric pH titrations in water and in water containing 30 or 50% (v/v) 1,4-dioxane (25°C; I = 0.1 M, NaNO3). The stability of the binary Cu(GDP) complex is enhanced due to macrochelate formation of the diphosphate-coordinated Cu with N7 of the guanine residue as previously shown. In Cu(Arm)(GDP) the N7 is released from Cu and the stability enhancement of more than one log unit in aqueous solution is clearly attributable to intramolecular stack formation between the aromatic rings of Arm and the guanine moiety. Indeed, stacked isomers occur to more than 90% in equilibrium with open unstacked forms. Surprisingly, the same formation degrees of the stacks are observed for Cu(Arm)(dGMP) complexes, where dGMP = 2′-deoxyguanosine 5′-monophosphate, despite the fact that the overall stability of the latter species is by about 2.7 log units lower. In 1,4-dioxane–water mixtures stack formation is drastically reduced, probably due to hydrophobic solvation of the aromatic rings by the ethylene bridges of 1,4-dioxane. The relevance of these results regarding biological systems is indicated. †This study is dedicated to Professor Dr Alfredo Mederos on the occasion of his retirement from the University of La Laguna (Spain) with the very best wishes for all of his future endeavors.‡This is part 70 of the series Ternary Complexes in Solution; for parts 69 and 68 see 14 and 15, respectively.
    Journal of Coordination Chemistry 01/2009; 62(1):23-39. · 1.80 Impact Factor

Publication Stats

2k Citations
898.99 Total Impact Points

Institutions

  • 2004–2013
    • University of Zurich
      • Institut für Anorganische Chemie
      Zürich, ZH, Switzerland
    • Technische Universität Dortmund
      • Faculty of Chemistry
      Dortmund, North Rhine-Westphalia, Germany
  • 2003–2013
    • University of Granada
      • Department of Inorganic Chemistry
      Granata, Andalusia, Spain
  • 1964–2013
    • Universität Basel
      • • Department of Chemistry
      • • Department of Bioinorganic Chemistry
      Basel, BS, Switzerland
  • 2008
    • Wroclaw Medical University
      • Department of Inorganic Chemistry
      Wrocław, Lower Silesian Voivodeship, Poland
  • 2007
    • Nagoya University
      • Graduate School of Science
      Nagoya-shi, Aichi-ken, Japan
  • 1981
    • University of Virginia
      • Department of Chemistry
      Charlottesville, VA, United States
  • 1970–1978
    • Cornell University
      • Department of Nutritional Sciences
      Ithaca, NY, United States
  • 1975
    • Ithaca College
      • Department of Chemistry
      Ithaca, New York, United States