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

. 2022 Apr 19;27(9):2625. doi: 10.3390/molecules27092625

Table of Contents

1. Some General Considerations

2. Why Is the Antiviral PMEApp⁴⁻ a Better Substrate for Nucleic Acid Polymerases than (2’-Deoxy)Adenosine 5′-Triphosphate (dATP⁴⁻/ATP⁴⁻)?

3. Modelling the Interactions of Metal Ions with the Ether Oxygen of PMEA²⁻

4. The N3 versus N7 Metal Ion-Binding Mode in Acyclic Nucleoside Phosphonates (ANPs) Containing a Purine Moiety

4.1. The Metal Ion-Coordinating Properties of 9-[2-(Phosphonomethoxy)ethyl]-2-aminopurine (PME2AP)

4.2. The Metal Ion-Coordinating Properties of 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA)

4.3. The Metal Ion-Coordinating Properties of 9-[2-(Phosphonomethoxy)ethyl]-2,6-diaminopurine (PMEDAP)

5. The Various Inhibiting Substituents in 9-[2-(Phosphonomethoxy)ethyl]-2-amino-6-dimethylaminopurine (PME2A6DMAP) Lead to PME-Like Metal Ion-Binding Properties

6. Mechanistic Considerations on the Metal Ion-Promoted Dephosphorylation of ATP

6.1. Effects of Increasing Amounts of Metal Ions on the Dephosphorylation Rate

6.2. Oligo Formation and the Effect of Self-Association on the Dephosphorylation Rate

6.3. Promotion of ATP Hydrolysis by AMP and PMEA, and Inhibition of the Reactivity by Adenine-Altered AMP Relatives

6.4. Matrix-Assisted Self-Association and Its Significance for Cell Organelles with High ATP Concentrations

7. Solution Structures of Mixed-Ligand Complexes Containing ATP⁴⁻ and Related Ligands

7.1. Ligands Containing a Ribose Residue with a Phosphate Group

7.2. Acyclic Nucleoside Phosphonates. Cu(arm)(PMEA) as an Example with Intramolecular Stack Formation

8. The Effect of a Change in Solvent Polarity on the Stability and Structure of Binary and Ternary Complexes

8.1. The Dianion of (Phosphonomethoxy)ethane (PME²⁻) as an Example of a Polar O-Ligand. The Properties of Cu(PME) Are Largely as Expected

8.2. Nitrogen Donor Sites Are Especially Sensitive to Polarity Changes of the Solvent

8.3. Competing Solvent Effects on N- versus O-Sites in the Same Ligand and Its Bearing on Complex Stability

9. Discussion

10. Conclusions and Outlook

Abbreviations and Definitions

References