Acid–base properties of an antivirally active acyclic nucleoside phosphonate: (<i>S</i>)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (HPMPA)

Blindauer, Claudia A.; Holý, Antonı́n; Sigel, Astrid; Operschall, Bert P.; Griesser, Rolf; Sigel, Helmut

doi:10.1039/d2nj00543c

Cited by 3 publications

(2 citation statements)

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“…The basicity of the adenine nitrogens decreases in the order N1 > N7 > N3, like it was observed for adenosine [177]. The micro acidity constant for + H•N7(HPMPA)N1 was estimated to be pk N7−N1 H•N7−N1 ca 3.5; the acid-base properties of PMEA are expected to be similar [181,182]. The metal ion-coordinating properties of HPMPA have also been studied [183], and it is interesting to compare these with those of (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC); note, the cytosine residue does not affect complex stability [184].…”

Section: Discussionmentioning

confidence: 60%

“…An important representative is (S)-9-[3-hydroxy-2-(phosphonomethoxy) propyl]adenine (HPMPA), which is active against a range of DNA viruses [180]. The acidbase properties of this compound have recently been studied in detail [181]. The basicity of the adenine nitrogens decreases in the order N1 > N7 > N3, like it was observed for adenosine [177].…”

Section: Discussionmentioning

confidence: 99%

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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 Among such derivatives are acyclic nucleoside phosphonates (ANPs), where the sugar moiety has been replaced by an aliphatic chain (often also containing an ether oxygen atom) and the phosphate group has been replaced by a phosphonate carrying a carbon–phosphorus bond to make the compounds less hydrolysis-sensitive.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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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

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

Sigel

2022

Molecules

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Metal‐Free, Light‐Mediated, Site‐Specific, Radical C6−H Alkylation of Purines with Alcohols Intervened by Oxalates without Catalysts

Liu

Tian

et al. 2023

Eur J Org Chem

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Herein, we report the development of a radical deoxyfunctionalization strategy for the direct CÀ H alkylation of purines and purine nucleosides with alcohols (1°, 2°, 3°) intervened by oxalates under 12 W blue LED irradiation. The reaction shows high regioselectivity at C6À H position of purine and is suitable for N9-, N7-substitued purines. The process accommodates purines and alcohols to deliver a wide range of products (31 examples) in 41-91 % yields, which avoids transition metal catalysts and organometallic reagents, and is not sensitive to moisture and air. Besides, the mild protocol displays broad functional groups tolerance and is easily up scalable to gram scale and can be used for late-stage CÀ H alkylation of purine to synthesize pharmaceutical 6-cyclopentyl nebularine with anti-CEM activity or natural d-menthol modification.

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Light, metal‐free regioselectiveC⁶‐Halkylation of purines and purine nucleosides with alcohols

Liu

Sun

Tian

et al. 2023

Journal of Heterocyclic Chem

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A metal‐, light‐free radical alkylation reaction of purines and nucleosides has been achieved with readily available alcohols (1°, 2°, 3°) as the alkyl radical sources enabled by oxalates, which does not need any catalysts, N2 protection, and protecting groups. Although there are three potential active C(sp2)H bonds and four interferential nitrogen atoms in the purine motif, the reaction still shows excellent regioselectivity at C6H position and does not face multialkylation problem. Besides, this approach shows broad functional groups tolerance and is scalable to the gram level, which can be applied to late‐stage CH alkylation of purine to synthesize 6‐cyclopentyl nebularine with anti‐CEM activity, thus demonstrating its utility.

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Acid–base properties of an antivirally active acyclic nucleoside phosphonate: (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (HPMPA)

Abstract: Protonation equilibria for the parent compound of three highly potent antivirals have been studied by 1H NMR spectroscopy.

Cited by 3 publications

References 60 publications

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

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

Metal‐Free, Light‐Mediated, Site‐Specific, Radical C6−H Alkylation of Purines with Alcohols Intervened by Oxalates without Catalysts

Light, metal‐free regioselectiveC⁶‐Halkylation of purines and purine nucleosides with alcohols

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Acid–base properties of an antivirally active acyclic nucleoside phosphonate: (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (HPMPA)

Abstract: Protonation equilibria for the parent compound of three highly potent antivirals have been studied by 1H NMR spectroscopy.

Cited by 3 publications

References 60 publications

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

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

Metal‐Free, Light‐Mediated, Site‐Specific, Radical C6−H Alkylation of Purines with Alcohols Intervened by Oxalates without Catalysts

Light, metal‐free regioselectiveC6‐Halkylation of purines and purine nucleosides with alcohols

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Product

Resources

About

Light, metal‐free regioselectiveC⁶‐Halkylation of purines and purine nucleosides with alcohols