title: Investigation of the acid-base and electromigration properties of 5-azacytosine derivatives using capillary electrophoresis and density functional theory calculations.
abstract: Capillary electrophoresis (CE) and quantum mechanical density functional theory (DFT) were applied to the investigation of the acid-base and electromigration properties of important compounds: newly synthesized derivatives of 5-azacytosine - analogs of efficient antiviral drug cidofovir. These compounds exhibit a strong antiviral activity and they are considered as potential new antiviral agents. For their characterization and application, it is necessary to know their acid-base properties, particularly the acidity constants (pKa) of their ionogenic groups (the basic N3atom of the triazine ring and the acidic phosphonic acid group in the alkyl chain). First, the mixed acidity constants (pKamix) of these ionogenic groups and the ionic mobilities of these compounds were determined by nonlinear regression analysis of the pH dependence of their effective electrophoretic mobilities. Effective mobilities were measured by CE in a series of background electrolytes in a wide pH range (2.0-10.5), at constant ionic strength (25mM) and constant temperature (25°C). Subsequently, the pKamixvalues were recalculated to thermodynamic pKavalues using the Debye-Hückel theory. The thermodynamic pKavalue of the NH+moiety at the N3atom of the triazine ring was found to be in the range 2.82-3.30, whereas the pKaof the hydrogenphosphonate group reached values from 7.19 to 7.47, depending on the structure of the analyzed compounds. These experimentally determined pKavalues were in good agreement with those calculated by quantum mechanical DFT. In addition, DFT calculations revealed that from the four nitrogen atoms in the 5-azacytosine moiety, the N3atom of the triazine ring is preferentially protonated. Effective charges of analyzed compounds ranged from zero or close-to-zero values at pH 2 to -2 elementary charges at pH≥9. Ionic mobilities were in the range (-16.7 to -19.1)×10-9m2V-1s-1for univalent anions and in the interval (-26.9 to -30.3)×10-9m2V-1s-1for divalent anions.
authors.affiliation: The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 542/2, 166 10 Prague 6, Czechia.
authors.forename: Denisa
authors.initials: D
authors.lastname: Geffertová
authors.affiliation: The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 542/2, 166 10 Prague 6, Czechia; Department of Chemistry, Federal Urdu University of Arts, Science & Technology, Block #9, Gulshan-e-Iqbal, University Road, 75300 Karachi, Pakistan.
authors.forename: Syed Tahir
authors.initials: ST
authors.lastname: Ali
authors.affiliation: The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 542/2, 166 10 Prague 6, Czechia.
authors.forename: Veronika
authors.initials: V
authors.lastname: Šolínová
authors.affiliation: The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 542/2, 166 10 Prague 6, Czechia.
authors.forename: Marcela
authors.initials: M
authors.lastname: Krečmerová
authors.affiliation: The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 542/2, 166 10 Prague 6, Czechia.
authors.forename: Antonín
authors.initials: A
authors.lastname: Holý
authors.affiliation: The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 542/2, 166 10 Prague 6, Czechia. Electronic address: havlas@uochb.cas.cz.
authors.forename: Zdeněk
authors.initials: Z
authors.lastname: Havlas
authors.affiliation: The Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 542/2, 166 10 Prague 6, Czechia. Electronic address: kasicka@uochb.cas.cz.
authors.forename: Václav
authors.initials: V
authors.lastname: Kašička
mesh_terms: D000143:Acids / Q000737:chemistry*; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry; D004573:Electrolytes / Q000737:chemistry; D019075:Electrophoresis, Capillary; D006863:Hydrogen-Ion Concentration; D009994:Osmolar Concentration; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D000143:Acids; D004573:Electrolytes; C039854:5-azacytosine; D003596:Cytosine
keywords: 5-azacytosine; Acidity constant; Capillary electrophoresis; Density functional theory; Effective charge; Ionic mobility