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Quantification of isomeric equilibria formed by metal ion complexes of 8-[2-(phosphonomethoxy)ethyl]-8-azaadenine (8,8aPMEA) and 9-[2-(phosphonomethoxy)ethyl]-8-azaadenine (9,8aPMEA). Derivatives of the antiviral nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA)

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Abstract

The acidity constants of the two-fold protonated acyclic 9-[2-(phosphonomethoxy)ethyl]-8-azaadenine, H2(9,8aPMEA)±, and its 8-isomer, 8-[2-(phosphonomethoxy)ethyl]-8-azaadenine, H2(8,8aPMEA)±, both abbreviated as H2(PA)±, as well as the stability constants of their M(H;PA)+ and M(PA) complexes with the metal ions M2+=Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+ or Cd2+, have been determined by potentiometric pH titrations in aqueous solution at I=0.1 M (NaNO3) and 25 °C. Application of previously determined straight-line plots of log \( K_{{\text{M(R-PO}}_{\text{3}} {\text{)}}}^{\text{M}} \) versus \( {\text{p}}K_{{\text{H(R-PO}}_{\text{3}} {\text{)}}}^{\text{H}} \) for simple phosph(on)ate ligands, \( {\text{R-PO}}_3^{2-} \), where R represents a residue without an affinity for metal ions, proves that for all M(PA) complexes a larger stability is observed than is expected for a sole phosphonate coordination of the metal ion. This increased stability is attributed to the formation of five-membered chelates involving the ether oxygen present in the aliphatic residue (\( {\text{-CH}}_{\text{2}} {\text{-O-CH}}_{\text{2}} {\text{-PO}}_{\text{3}}^{{\text{2}}-} \)) of the ligands. The formation degrees of these chelates were calculated; they vary between about 13% for Ca(8,8aPMEA) and 71% for Cu(8,8aPMEA). The adenine residue has no influence on complex stability except in the Cu(9,8aPMEA) and Zn(9,8aPMEA) systems, where an additional stability increase attributable to the adenine residue is observed and equilibria between four different isomers exist. This means (1) an open isomer with a sole phosphonate coordination, M(PA)op, where PA2−=9,8aPMEA2−, (2) an isomer with a five-membered chelate involving the ether oxygen, M(PA)cl/O, (3) an isomer which contains five- and seven-membered chelates formed by coordination of the phosphonate group, the ether oxygen and the N3 site of the adenine residue, M(PA)cl/O/N3, and finally (4) a macrochelated isomer involving N7, M(PA)cl/N7. For Cu(9,8aPMEA) the formation degrees are 15, 30, 48 and 7% for Cu(PA)op, Cu(PA)cl/O, Cu(PA)cl/O/N3 and Cu(PA)cl/N7, respectively; this proves that the macrochelate involving N7 is a minority species. The situation for the Cu(PMEA) system, where PMEA2− represents the parent compound, i.e. the dianion of 9-[2-(phosphonomethoxy)ethyl]adenine, is quite similar. The relationship between the antiviral activity of acyclic nucleoside phosphonates and the structures of the various complexes is discussed and an explanation is offered why 9,8aPMEA is biologically active but 8,8aPMEA is not.

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Fig. 2

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Notes

  1. For further abbreviations see the legends to Figs. 1 and 2

  2. Species written without a charge either do not carry one or represent the species in general (i.e. independent of their protonation degree); which of the two possibilities applies is always clear from the context. In formulas like M(H;PA)+, the H+ and PA2− are separated by a semicolon to facilitate reading, yet they appear within the same parenthesis to indicate that the proton is at the ligand without defining its location

  3. Information regarding US FDA: (2002) Chem Rundschau (CH-4501 Solothurn, Switzerland) no. 19 (Oct 8), p 68

  4. Information regarding EMEA as downloaded from the World Wide Web in December 2003: http://www.emea.eu.int/humandocs/PDFs/EPAR/hepsera/610202en1.pdf

Abbreviations

(d)ATP4−:

(2′-deoxy)adenosine 5′-triphosphate

PMEA:

9-[2-(phosphonomethoxy)ethyl]adenine

8,8aPMEA:

8-[2-(phosphonomethoxy)ethyl]-8-azaadenine

9,8aPMEA:

9-[2-(phosphonomethoxy)ethyl]-8-azaadenine

I :

ionic strength

K a :

acidity constant

M2+:

divalent metal ion

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Acknowledgements

The competent technical assistance of Mrs Rita Baumbusch and Mrs Astrid Sigel in the preparation of this manuscript as well as stimulating discussions with members of the COST D20 programme are gratefully acknowledged. This study was supported by the Swiss National Science Foundation (H.S.) and the Programme of Targeted Projects (S4055109) of the Academy of Sciences of the Czech Republic (A.H.) as well as within the COST D20 programme by the Swiss Federal Office for Education and Science (H.S.) and the Ministry of Education of the Czech Republic (D20.002; A.H.). This study also received support from the University of Basel and it is further part of a research project (no 4055905) of the Institute of Organic Chemistry and Biochemistry (IOCB) in Prague.

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Authors and Affiliations

  1. Department of Chemistry, Inorganic Chemistry, University of Basel, Spitalstrasse 51, 4056 , Basel, Switzerland

    Raquel B. Gómez-Coca, Larisa E. Kapinos & Helmut Sigel

  2. Institute of Organic Chemistry and Biochemistry, Academy of Sciences, 16610 , Prague, Czech Republic

    Antonín Holý

  3. Inorganic Chemistry Department, Faculty of Chemistry, University of Seville, 41071 , Seville, Spain

    Rosario A. Vilaplana & Francisco González-Vílchez

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  1. Raquel B. Gómez-Coca
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  2. Larisa E. Kapinos
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  4. Rosario A. Vilaplana
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  6. Helmut Sigel
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Correspondence to Helmut Sigel.

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Gómez-Coca, R.B., Kapinos, L.E., Holý, A. et al. Quantification of isomeric equilibria formed by metal ion complexes of 8-[2-(phosphonomethoxy)ethyl]-8-azaadenine (8,8aPMEA) and 9-[2-(phosphonomethoxy)ethyl]-8-azaadenine (9,8aPMEA). Derivatives of the antiviral nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA). J Biol Inorg Chem 9, 961–972 (2004). https://doi.org/10.1007/s00775-004-0591-7

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