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Acid-base properties of an antivirally active acyclic nucleoside phosphonate: (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (HPMPA)
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SYSNO ASEP 0556558 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Acid-base properties of an antivirally active acyclic nucleoside phosphonate: (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (HPMPA) Author(s) Blindauer, C. A. (CH)
Holý, Antonín (UOCHB-X)
Sigel, A. (CH)
Operschall, B. P. (CH)
Griesser, R. (CH)
Sigel, H. (CH)Source Title New Journal of Chemistry. - : Royal Society of Chemistry - ISSN 1144-0546
Roč. 46, č. 14 (2022), s. 6484-6493Number of pages 10 s. Language eng - English Country GB - United Kingdom Keywords metal-ion complexes ; adenosine 5-monophosphate AMP ; nucleotide analogs OECD category Organic chemistry Method of publishing Open access Institutional support UOCHB-X - RVO:61388963 UT WOS 000769618200001 EID SCOPUS 85127711024 DOI 10.1039/d2nj00543c Annotation 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. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2023 Electronic address https://doi.org/10.1039/D2NJ00543C
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