Helmut Sigel

Universität Basel, Bâle, Basel-City, Switzerland

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Publications (358)1552.44 Total impact

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    ABSTRACT: Potentiometric pH titrations and pD dependent (1)H NMR spectroscopy have been applied to study the acidification of the exocyclic amino group of adenine (A) model nucleobases (N9 position blocked by alkyl groups) when carrying trans-a2Pt(II) (with a=NH3 or CH3NH2) entities both at N1 and N7 positions. As demonstrated, in trinuclear complexes containing central A-Pt-A units, it depends on the connectivity pattern of the adenine bases (N7/N7 or N1/N1) and their rotamer states (head-head or head-tail), how large the acidifying effect is. Specifically, a series of trinuclear complexes with (A-N7)-Pt-(N7-A) and (A-N1)-Pt-(N1-A) cross-linking patterns and terminal 9-alkylguanine ligands (9MeGH, 9EtGH) have been analyzed in this respect, and it is shown that, for example, the 9MeA ligands in trans-,trans-,trans-[Pt(NH3)2(N7-9MeA-N1)2{Pt(NH3)2(9EtGH-N7)}2](ClO4)6·6H2O (4a) and trans-,trans-,trans-[Pt(NH3)2(N7-9EtA-N1)2{Pt(CH3NH2)2(9-MeGH-N7)}2](ClO4)6·3H2O (4b) are more acidic, by ca. 1.3units (first pKa), than the linkage isomer trans-,trans-,trans-[Pt(CH3NH2)2(N1-9MeA-N7)2{Pt(NH3)2(9MeGH-N7)}2](NO3)6·6.25H2O (1b). Overall, acidifications in these types of complexes amount to 7-9units, bringing the pKa values of such adenine ligands in the best case close to the physiological pH range. Comparison with pKa values of related trinuclear Pt(II) complexes having different co-ligands at the Pt ions, confirms this picture and supports our earlier proposal that the close proximity of the exocyclic amino groups in a head-head arrangement of (A-N7)-Pt-(N7-A), and the stabilization of the resulting N6H(-)⋯H2N6 unit, is key to this difference. Copyright © 2015 Elsevier Inc. All rights reserved.
    Journal of Inorganic Biochemistry 02/2015; 148. DOI:10.1016/j.jinorgbio.2015.02.004 · 3.44 Impact Factor
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    ABSTRACT: The acyclic nucleoside phosphonate (ANP2−) 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG) is anticancer and antivirally active. The acidity constants of the threefold protonated H3(PMEG)+ were determined by potentiometric pH titrations (aq. sol.; 25 °C; I = 0.1 M, NaNO3). Under the same conditions and by the same method, the stability constants of the binary Cu(H;PMEG)+ and Cu(PMEG) complexes as well as those of the ternary ones containing a heteroaromatic N ligand (Arm), that is, of Cu(Arm)(H;PMEG)+ and Cu(Arm)(PMEG), where Arm = 2,2′-bipyridine (Bpy) or 1,10-phenanthroline (Phen), were measured. The corresponding equilibrium constants, taken from our earlier work for the systems with 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) and 9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine (PMEDAP) as well as those for Cu(PME) and Cu(Arm)(PME), where PME2− = (phosphonomethoxy)ethane = (ethoxymethyl)phosphonate, were used for comparisons. These reveal that in the monoprotonated ternary Cu(Arm)(H;PE)+ complexes, the proton and Cu(Arm)2+ are at the phosphonate group; the ether oxygen of the –CH2–O–CH2–P(O)2−(OH) residue also participates to some extent in Cu(Arm)2+ coordination. Furthermore, the coordinated Cu(Arm)2+ forms a bridge with the purine moiety undergoing π–π stacking which is more pronounced with H·PMEDAP− than with H·PMEA−. Most intense is π stack formation (st) with the guanine residue of H·PMEG−; here the bridged form Cu(Arm)(H·PMEG)st+ occurs next to an open (op), unbridged (binary) stack, formulated as Cu(Arm)2+/(H·PMEG)op−. The unprotonated and neutral ternary Cu(Arm)(PE) 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 intramolecular interaction. The observed stability enhancements are mainly due to intramolecular stack formation (st) between the aromatic rings of Arm and the purine residue in the Cu(Arm)(PE) complexes and also, to a smaller extent, to the formation of five-membered chelates involving the ether oxygen of the –CH2–O–CH2–PO32− residue (cl/O) of the PE2− species. The quantitative analysis of the intramolecular equilibria reveals three structurally different Cu(Arm)(PE) isomers; e.g., of Cu(Phen)(PMEG) ca. 1.1% exist as Cu(Phen)(PMEG)op, 3.5% as Cu(Phen)(PMEG)cl/O, and 95% as Cu(Phen)(PMEG)st. Comparison of the various formation degrees reveals that within a given Cu(Arm)(PE) series the stacking tendency decreases in the order PMEG2− ⩾ PMEDAP2− > PMEA2−. Furthermore, stacking is more pronounced in the acyclic Cu(Arm)(PE) complexes compared with that in the Cu(Arm)(NMP) species, where NMP2− = corresponding parent (2′-deoxy)nucleoside 5′-monophosphate. Here is possibly one of the reasons for the biological activity of the ANPs. One is tempted to speculate that the pronounced stacking tendency of PMEG2−, together with a different H-bonding pattern, leads to enhanced binding in the active site of nucleic acid polymerases, thus being responsible for the pronounced anticancer and antiviral activity of PMEG.
    Polyhedron 02/2015; DOI:10.1016/j.poly.2015.02.022 · 2.01 Impact Factor
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    ABSTRACT: The acidity constants of protonated 9-[2-(phosphonomethoxy) ethyl]-2-amino-6-dimethylaminopurine (H-3(PME2A6DMAP)(+)) are considered, and the stability constants of the M(H;PME2A6DMAP)(+) and M(PME2A6DMAP) complexes (M2+ = Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, or Cd2+) were measured by potentiometric pH titrations in aqueous solution (25 degrees C; I = 0.1 mol/L, NaNO3). In the M(H;PME2A6DMAP)(+) species, H+ and M2+ (mainly outersphere) are at the phosphonate group; this is relevant for phosphoryl-diester bridges in nucleic acids because, in the present system, there is no indication for a M2+-purine binding. This contrasts, for example, with the complexes formed by 9-[2-(phosphonomethoxy) ethyl] adenine, M(H;PMEA)(+), where M2+ is mainly situated at the adenine residue. Application of log K-M(R-PO3)(M) vs center dot pK(H(R-PO3))(H) plots for simple phosph(on) ate ligands, R-PO32- (R being a residue that does not affect M2+ binding), proves that all M(PME2A6DMAP) complexes have larger stabilities than what would be expected for a M2+-phosphonate coordination. Comparisons with M(PME-R) complexes, where R is a noncoordinating residue of the (phosphonomethoxy) ethane chain, allow one to conclude that the increased stability is due to the formation of five-membered chelates involving the ether-oxygen of the -CH2-O-CH2-PO32- residue: the percentages of formation of these M(PME2A6DMAP)(cl/O) chelates, which occur in intramolecular equilibria, vary between 20% (Sr2+, Ba2+) and 50% (Zn2+, Cd2+), up to a maximum of 67% (Cu2+). Any M2+ interaction with N3 or N7 of the purine moiety, as in the parent M(PMEA) complexes, is suppressed by the (C2)NH2 and (C6)N(CH3)(2) substituents. This observation, together with the previously determined stacking properties, offers an explanation why PME2A6DMAP(2-) has remarkable therapeutic effects.
    Canadian Journal of Chemistry 08/2014; 92(8). DOI:10.1139/cjc-2014-0041 · 1.06 Impact Factor
  • Astrid Sigel · Bert P Operschall · Helmut Sigel
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    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; 19(4-5). DOI:10.1007/s00775-013-1082-5 · 2.54 Impact Factor
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    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). DOI:10.1002/zaac.201300095 · 1.16 Impact Factor
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    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 06/2013; 19(25). DOI:10.1002/chem.201203330 · 5.73 Impact Factor
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    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 02/2013; 11:191-274. DOI:10.1007/978-94-007-5179-8_8
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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. DOI:10.1002/cbdv.201200022 · 1.52 Impact Factor
  • Astrid Sigel · Bert P. Operschall · Helmut Sigel
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    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. DOI:10.1016/j.ccr.2011.06.030 · 12.24 Impact Factor
  • Astrid Sigel · Helmut Sigel · Roland K. O. Sigel
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    ABSTRACT: Noncovalent interactions play important roles in modern chemical research encompassing also bio-systems. Among these interactions aromatic-ring stacking is especially pronounced as, next to hydrogen bonding, hydrophobic and ionic interactions, it is crucial for the three-dimensional structure of nucleic acids (RNA, DNA) and proteins (enzymes). We have now measured by 1H-NMR shift experiments the stability of binary stacks formed between purine nucleosides or nucleotides (N) and the "indicator" ligand 1,10-phenanthroline (Phen), and we also reviewed the related literature. Surprisingly, we observe that the stability of the (Phen)(N) adducts is largely independent of the type of purine residue involved, including deprotonation, e.g., at (N1)H of a guanine moiety, and also of the location of the phosphate group at the ribosyl ring. This contrasts with the self-stacking tendency which decreases within the series adenosine > guanosine > inosine > cytidine - uridine. Interestingly, the formation of an ionic (+/-) or metal ion (M 2+) bridge stabilizes the formation of stacks as observed, e.g., in mixed ligand Cu 2+ complexes formed between Phen and adenosine 5′-monophosphate (5′-AMP 2-); yet, in these instances the position of the phosphate group at the ribosyl ring affects the stability of the stacks: It decreases in the order 2′-AMP 2- > 5′-AMP 2- > 3′-AMP 2- in the Cu(Phen)(AMP) complexes demonstrating a significant steric discrimination. The stability of stacks also depends on the size of the aromatic-ring systems involved; as one would expect, purines stack better than pyrimidines and Phen generally better than 2,2′-bipyridine. Results obtained with various mixed ligand metal ion complexes containing adenosine 5′-triphosphate (ATP 4-) and an amino acid anion (Aa -) lead to the conclusion: The recognition of the adenine residue by the amino acid side chain in M(ATP)(Aa) 3- complexes decreases in the series tryptophan (indole residue) > histidine (imidazole residue) > leucine (isopropyl residue) > alanine (methyl group). This type of selectivity is certainly of relevance for amino acid/protein interactions with nucleotides/nucleic acids. The addition of an organic solvent like 1,4-dioxane reduces the solvent polarity and decreases the stability of binary stacks like (Phen)(ATP) 4- dramatically; in contrast, intramolecular stacks, as present in Cu(Phen)(ATP) 2-, are much less affected. Because the "effective" dielectric constant or permittivity in the active site cavity of an enzyme or a ribozyme is lower than in bulk water, Nature has here a further tool to achieve selectivity. Here it needs to be noted that the involved changes in free energy (ΔG 0) are small; e.g., a formation degree of 20% of an intramolecuar stack in a mixed ligand complex corresponds only to about -0.6 kJ mol -1 allowing Nature to shift such equilibria easily.
    Journal- Indian Chemical Society 08/2011; 88(8):1093-1115. · 0.17 Impact Factor
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    ABSTRACT: Adenosine (Ado) can accept three protons, at N1, N3, and N7, to give H3(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, =−4.02 and =−1.53; the third one was re-measured as =3.64±0.02 (25 °C; I=0.5 M, NaNO3), 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 =3.63±0.02 > =2.15±0.15 > =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. DOI:10.1002/chem.201003544 · 5.73 Impact Factor
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    ABSTRACT: Studies have demonstrated that for monodentate primary binding sites the intensity of the hydroxyl-metal-ion interaction increases with the decreasing charge present in the coordinating atom. With regard to biological systems the observations made with hydroxyacetate are certainly of more relevance. Despite the negatively charged carboxylate group, which constitutes the primary binding site, still formation degrees of 71%, 75%, and 91% are reached for Mg((HOAc)cl +, Mn(HOAc)cl +, and Zn(HOAc)cl +, respectively. A further point that warrants emphasis is the observation that with N-hydroxyethylglycinate (HOGly -), which offers the bidentate glycinate-like unit as the primary binding site, participation of the hydroxyl group in metal-ion coordination increases dramatically, leading in general to formation degrees of above 99.5% for the M(HOGly) + species. It is hoped that the presented results initiate searches for metal-ion-hydroxyl group interactions in proteins, but especially in nucleic acids.
    Chemical Reviews 05/2011; 111(8):4964-5003. DOI:10.1021/cr100415s · 46.57 Impact Factor
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    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 05/2011; 17(19):5393-403. DOI:10.1002/chem.201001931 · 5.73 Impact Factor
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    Astrid Sigel · Helmut Sigel
    Monatshefte fuer Chemie/Chemical Monthly 04/2011; 142(4):323-324. DOI:10.1007/s00706-010-0437-7 · 1.22 Impact Factor
  • Astrid Sigel · Helmut Sigel · Roland K O Sigel
    Metal ions in life sciences 01/2011; 8:vii-viii.
  • Research Progress in Chemistry. Inorganic Chemistry. Reactions, Structures and Mechanisms., Edited by Harold H. Trimm, 01/2011: chapter 7. Nickel (11 ), Copper (11) and Zinc (11) Colllplexes of 183 9~[2~ ( Phosphonomerhoxy)ethyl l~8~az.aadeni n e (9,8aPMEA), (he 8~Az.a Deriv:uive of the Antiviral Nudeotide Analogue 9~[2~( Phosphonomethoxy)e rh y l ladenine (PMEA). Quanrification of Four I: pages 183-204; Apple Academic Press Inc.., ISBN: 978-1-926692-59-3
  • Astrid Sigel · Helmut Sigel · Roland K O Sigel
    Metal ions in life sciences 01/2011; 9:v-vi.
  • Astrid Sigel · Helmut Sigel · Roland K O Sigel
    Metal ions in life sciences 01/2011; 9:vii-ix. DOI:10.1039/9781849732512
  • Helmut Sigel
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    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 08/2010; 30(34). DOI:10.1002/chin.199934312

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  • 1964–2015
    • Universität Basel
      • • Department of Chemistry
      • • Department of Bioinorganic Chemistry
      Bâle, Basel-City, Switzerland
  • 2008
    • Lodz University of Technology
      Łódź, Łódź Voivodeship, Poland
  • 2007–2008
    • University of Zurich
      • Institut für Anorganische Chemie
      Zürich, Zurich, Switzerland
  • 1996–2000
    • Institute of Inorganic Chemistry
      Aussig, Ústecký, Czech Republic
  • 1994
    • University of Virginia
      • Department of Chemistry
      Charlottesville, Virginia, United States
  • 1993
    • Comenius University in Bratislava
      Presburg, Bratislavský, Slovakia
  • 1969–1972
    • Cornell University
      • Department of Nutritional Sciences
      Итак, New York, United States