SOLUTION PROPERTIES OF ANTIVIRAL ADENINE-NUCLEOTIDE ANALOGS - THE ACID-BASE PROPERTIES OF 9-[2-(PHOSPHONOMETHOXY)ETHYL]ADENINE (PMEA) AND OF ITS N1, N3 AND N7 DEAZA DERIVATIVES IN AQUEOUS-SOLUTION

The pD dependence of the H-1 NMR chemical shifts of the aromatic and a liphatic hydrogens of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) and of its 1-, 3- and 7-deaza derivatives have been measured in D2O at 25 degrees C (I = 0.1 mol dm(-3), NaNO3; at pD < 1 I increases to 0.3 mol dm(-3)) in order to determine the sites of protonation as well as the acidity constants, The most basic site in all these PMEAs (= PM) is t he phosphonate group, -PO32-, followed by N1 in PMEA, 3- and 7-deaza-P MEA. In 1-deaza-PMEA the formation of H2PM+/- occurs by protonation of N3. Further protonation in strongly acidic medium is possible with al l four PMEAs. All acidity constants measured in D2O have been transfor med to H2O as solvent: pK(H4PM)(H) similar or equal to 0 is due to dep rotonation of H+(N7), where appropriate; pK(H1PM)(H) similar or equal to 1.1 to 1.3 is due to -P(O)(OH)(2); pK(H2PM)(H) similar or equal to 4.1 to 6.6 is due to H+(N1) or H+(N3); and pK(HPM)(H) similar or equal to 6.9 to 7.8 is due to -P(O)(2)(OH)(-). Determination of pK(H2PM)(H) and pK(HPM)(H) by potentiometric pH titrations in water (H2O; I=0.1 m ol dm(-3), NaNO3; 25 degrees C) give the same results. As in various i nstances the buffer regions of two successive equilibria are overlappi ng, a micro acidity constant scheme has been developed and the constan ts for the various sites calculated; it is concluded, e.g. that about 80% of the H(7-deaza-PMEA)(-) species carry the proton at the phosphon ate residue and 20% at N1. The H-1 NMR data indicate that the PMEAs in the form PM2- occur to some extent in an orientation similar to the a nti conformation of 5'-AMP(2-); i.e. the phosph(on)ate group is close to H8. For H(3-deaza-PMEA)(-) the monoprotonated phosphonate group is in the vicinity of H2 in a hydrophobic region and it is suggested that this is the reason for the relatively high pK(a) value of about 7.8 c ompared with pK(a) similar or equal to 6.9 to 7.0 for HPM- of the othe r PMEAs. Finally, the acid-base properties of the PMEAs are compared w ith those of 5'-AMP and of tubercidin 5'-monophosphate (= 7-deaza-5'-A MP).