4.6 Article

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

Journal

NEW JOURNAL OF CHEMISTRY
Volume 46, Issue 14, Pages 6484-6493

Publisher

ROYAL SOC CHEMISTRY
DOI: 10.1039/d2nj00543c

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Funding

  1. Departments of Chemistry of the University of Basel
  2. University of Warwick

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HPMPA is an antiviral substance with interesting acid-base behavior. By measuring the chemical shifts of the protons in HPMPA, the protonation sites and acidity constants were determined. The phosphonate group is the most basic site, followed by the N1 position of adenine. The basicity of the adenine nitrogens decreases in the order N1 > N7 > N3.
HPMPA is an acyclic nucleoside phosphonate analogue of AMP which displays antiviral properties. Therefore, its acid-base behavior as well as that of related compounds like PMEA, 9-[2-(phosphonomethoxy)ethyl]adenine, are for many reasons (e.g., binding to enzymes, coordination of metal ions) of general interest. HPMPA can accept two protons at the phosphonate and two more at the adenine residue, but not all acidity constants are accessible by potentiometric pH titrations. Therefore, we measured the chemical shifts of the nine non-exchangeable HPMPA protons by H-1 NMR in D2O in dependence on pD in the range from 1 to 12. The corresponding results allowed identifying the protonation sites and, transferred to aqueous solution, they gave also the acidity constants. The most basic site is the phosphonate group followed by N1 of adenine. The pK(a) values increase from ca. -0.27 [-N7(H)(+)] via 1.27 [-PO(OH)(2)] and 4.23 [-N1(H)(+)] to 6.86 [-PO(OH)(-)]. In the fully protonated species charge repulsion exists between N1(H)(+) and N7(H)(+); therefore, the affinity of N7 for H+ is not correctly reflected by the measured acidity constant (ca. -0.27). Needed is the intrinsic micro acidity constant which reflects the H+ affinity of N7 under conditions where N1 is unprotonated; we abbreviate this species as H+center dot N7(HPMPA)N1. The corresponding microconstant is estimated to be pk(H center dot N7-N1)(N7-N1) approximate to 3.5; the minor species H+center dot N7(HPMPA)N1 occurs with an estimated formation degree between about 5 to 20%. The basicity of the adenine nitrogens decreases in the order N1 > N7 > N3.

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