Metal ion complexes of nucleoside phosphorothioates reflecting the ambivalent properties of lead(<scp>ii</scp>)

Sigel, Astrid; Operschall, Bert P.; Sigel, Roland K. O.; Sigel, Helmut

doi:10.1039/c7nj04989g

Cited by 6 publications

(2 citation statements)

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“…17E has been most thoroughly studied with Pb 2+ for its highest activity ,,, and with Mg 2+ for potential biomedical applications. ,, If Pb 2+ can play a general acid role, we might be able to probe this role by studying the pH–rate profile, and the fitted p K a value might be associated with the p K a of the Pb 2+ -bound water. For metal ions playing a Lewis acid role, such as Mg 2+ , the fitted p K a might be independent of the p K a of the metal ions (e.g., only related to the deprotonation of the 2′-OH nucleophile).…”

Section: Resultsmentioning

confidence: 99%

Probing Metal-Dependent Phosphate Binding for the Catalysis of the 17E DNAzyme

2021

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The RNA-cleaving 17E DNAzyme exhibits different levels of cleavage activity in the presence of various divalent metal ions, with Pb 2+ giving the fastest cleavage. In this study, the metal−phosphate interaction is probed to understand the trend of activity with different metal ions. For the first-row transition metals, the lowest activity shown by Ni 2+ correlates with the inhibition by the inorganic phosphate and its water ligand exchange rate, suggesting inner-sphere metal coordination. Cleavage activity with the two stereoisomers of the phosphorothioate-modified substrates, R p and S p , indicated that Mg 2+ , Mn 2+ , Fe 2+ , and Co 2+ had the highest S p :R p activity ratio of >900. Comparatively, the activity was much less affected using the thiophilic metals, including Pb 2+ , suggesting inner-sphere coordination. The pH−rate profiles showed that Pb 2+ was different than the rest of the metal ions in having a smaller slope and a similar fitted apparent pK a and the pK a of metal-bound water. Combining previous reports and our current results, we propose that Pb 2+ most likely plays the role of a general acid while the other metal ions are Lewis acid catalysts interacting with the scissile phosphate.

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Section: Resultsmentioning

confidence: 99%

Probing Metal-Dependent Phosphate Binding for the Catalysis of the 17E DNAzyme

2021

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“…As the virus uses the cellular machinery of the host for its own reproduction (for details see [22,30]), the transcription machinery including nucleotide derivatives of such compounds were also developed and studied in detail. Nucleotides were systematically altered at the nucleobase, at the sugar moiety, and at the phosphate group (e.g., thiophosphate [31][32][33]) with the aim of discovering compounds that inhibit the synthesis of viral DNA or RNA. Among early successful compounds were acyclic nucleoside phosphonates [30], which have the advantage that the phosphorus-carbon bond is not split by dephosphorylation enzymes and that they have no OH group available that allows the continuation of a growing nucleic acid chain-instead, the incorporation of such a derivative into the growing chain leads to its termination [34,35].…”

Section: Some General Considerationsmentioning

confidence: 99%

Coordination Chemistry of Nucleotides and Antivirally Active Acyclic Nucleoside Phosphonates, including Mechanistic Considerations

Sigel

2022

Molecules

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Considering that practically all reactions that involve nucleotides also involve metal ions, it is evident that the coordination chemistry of nucleotides and their derivatives is an essential corner stone of biological inorganic chemistry. Nucleotides are either directly or indirectly involved in all processes occurring in Nature. It is therefore no surprise that the constituents of nucleotides have been chemically altered—that is, at the nucleobase residue, the sugar moiety, and also at the phosphate group, often with the aim of discovering medically useful compounds. Among such derivatives are acyclic nucleoside phosphonates (ANPs), where the sugar moiety has been replaced by an aliphatic chain (often also containing an ether oxygen atom) and the phosphate group has been replaced by a phosphonate carrying a carbon–phosphorus bond to make the compounds less hydrolysis-sensitive. Several of these ANPs show antiviral activity, and some of them are nowadays used as drugs. The antiviral activity results from the incorporation of the ANPs into the growing nucleic acid chain—i.e., polymerases accept the ANPs as substrates, leading to chain termination because of the missing 3′-hydroxyl group. We have tried in this review to describe the coordination chemistry (mainly) of the adenine nucleotides AMP and ATP and whenever possible to compare it with that of the dianion of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA2− = adenine(N9)-CH2-CH2-O-CH2-PO32) [or its diphosphate (PMEApp4−)] as a representative of the ANPs. Why is PMEApp4− a better substrate for polymerases than ATP4−? There are three reasons: (i) PMEA2− with its anti-like conformation (like AMP2−) fits well into the active site of the enzyme. (ii) The phosphonate group has an enhanced metal ion affinity because of its increased basicity. (iii) The ether oxygen forms a 5-membered chelate with the neighboring phosphonate and favors thus coordination at the Pα group. Research on ANPs containing a purine residue revealed that the kind and position of the substituent at C2 or C6 has a significant influence on the biological activity. For example, the shift of the (C6)NH2 group in PMEA to the C2 position leads to 9-[2-(phosphonomethoxy)ethyl]-2-aminopurine (PME2AP), an isomer with only a moderate antiviral activity. Removal of (C6)NH2 favors N7 coordination, e.g., of Cu2+, whereas the ether O atom binding of Cu2+ in PMEA facilitates N3 coordination via adjacent 5- and 7-membered chelates, giving rise to a Cu(PMEA)cl/O/N3 isomer. If the metal ions (M2+) are M(α,β)-M(γ)-coordinated at a triphosphate chain, transphosphorylation occurs (kinases, etc.), whereas metal ion binding in a M(α)-M(β,γ)-type fashion is relevant for polymerases. It may be noted that with diphosphorylated PMEA, (PMEApp4−), the M(α)-M(β,γ) binding is favored because of the formation of the 5-membered chelate involving the ether O atom (see above). The self-association tendency of purines leads to the formation of dimeric [M2(ATP)]2(OH)− stacks, which occur in low concentration and where one half of the molecule undergoes the dephosphorylation reaction and the other half stabilizes the structure—i.e., acts as the “enzyme” by bridging the two ATPs. In accord herewith, one may enhance the reaction rate by adding AMP2− to the [Cu2(ATP)]2(OH)− solution, as this leads to the formation of mixed stacked Cu3(ATP)(AMP)(OH)− species, in which AMP2− takes over the structuring role, while the other “half” of the molecule undergoes dephosphorylation. It may be added that Cu3(ATP)(PMEA) or better Cu3(ATP)(PMEA)(OH)− is even a more reactive species than Cu3(ATP)(AMP)(OH)−. – The matrix-assisted self-association and its significance for cell organelles with high ATP concentrations is summarized and discussed, as is, e.g., the effect of tryptophanate (Trp−), which leads to the formation of intramolecular stacks in M(ATP)(Trp)3− complexes (formation degree about 75%). Furthermore, it is well-known that in the active-site cavities of enzymes the dielectric constant, compared with bulk water, is reduced; therefore, we have summarized and discussed the effect of a change in solvent polarity on the stability and structure of binary and ternary complexes: Opposite effects on charged O sites and neutral N sites are observed, and this leads to interesting insights.

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Phosphorothioate nucleic acids for probing metal binding, biosensing and nanotechnology

Saran

Huang

Liu

2021

Coordination Chemistry Reviews

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Metal ion complexes of nucleoside phosphorothioates reflecting the ambivalent properties of lead(ii)

Abstract: The lead(ii)-lone pair leads to ambivalency: hemidirected (distorted, non-spherical) coordination spheres result from electronegative O-coordination and holodirected (symmetric, spherical) ones from less electronegative S-coordination.

Cited by 6 publications

References 62 publications

Probing Metal-Dependent Phosphate Binding for the Catalysis of the 17E DNAzyme

Probing Metal-Dependent Phosphate Binding for the Catalysis of the 17E DNAzyme

Coordination Chemistry of Nucleotides and Antivirally Active Acyclic Nucleoside Phosphonates, including Mechanistic Considerations

Phosphorothioate nucleic acids for probing metal binding, biosensing and nanotechnology

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