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

• Published in: Molecules (Basel, Switzerland) Vol. 27; no. 9; p. 2625
• Main Authors: Sigel, Astrid, Sigel, Helmut, Sigel, Roland K O
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 19.04.2022; MDPI
• Subjects: 2-Aminopurine; acyclic nucleoside phosphonates; Adenine; Adenine - chemistry; Adenosine; Adenosine Monophosphate; Adenosine Triphosphate; Anions; Antiviral activity; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; antivirals; ATP; Basicity; Binding; Biological activity; cell organelles; Chelates; Chelating Agents - chemistry; Chemistry; competing solvent effects; complex stabilities; Conformation; Copper; Deoxyribonucleic acid; Dephosphorylation; Dielectric constant; DNA; Enzymes; Ethers; Hydroxyl groups; Ions; Isomers; Ligands; Metal ions; Metals - chemistry; Molecular chains; Nucleic acids; Nucleosides; Nucleotides; Nucleotides - chemistry; Organelles; Organophosphonates - chemistry; Oxygen; Phosphates; Phosphonates; Phosphorus; Polarity; Purines; Residues; Review; Self-association; Solvents; Stacks; Structural stability; Substrates; Sugars; isodesmic model; self-association; antivirals; complex stabilities; mechanistic considerations; solvent effects; polymerases; cell organelles; hydrolysis of ATP; 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA); nucleic acids; mixed ligand complexes; kinases; metal ion complexes; ternary complexes; dephosphorylation; polarity changes; competing solvent effects; nucleotide analogues; intramolecular equilibria; triphosphate coordination modes; acyclic nucleoside phosphonates
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27092625

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 Among such derivatives are acyclic nucleoside phosphonates (ANPs), where the sugar moiety has been replaced by an aliphatic chain (often also containing an ether oxygen atom) and the phosphate group has been replaced by a phosphonate carrying a carbon-phosphorus bond to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 (PMEA = adenine(N9)-CH -CH -O-CH -PO32) [or its diphosphate (PMEApp )] as a representative of the ANPs. Why is PMEApp a better substrate for polymerases than ATP ? There are three reasons: (i) PMEA with its -like conformation (like AMP ) 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 P 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)NH 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)NH favors N7 coordination, e.g., of Cu , whereas the ether O atom binding of Cu in PMEA facilitates N3 coordination via adjacent 5- and 7-membered chelates, giving rise to a Cu(PMEA) isomer. If the metal ions (M ) 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, (PMEApp ), 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 [M (ATP)] (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 AMP to the [Cu (ATP)] (OH) solution, as this leads to the formation of mixed stacked Cu (ATP)(AMP)(OH) species, in which AMP takes over the structuring role, while the other "half" of the molecule undergoes dephosphorylation. It may be added that Cu (ATP)(PMEA) or better Cu (ATP)(PMEA)(OH) is even a more reactive species than Cu (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) 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.