Multiwavelength UV-Metric and pH-Metric Determination of the Dissociation Constants of the Hypoxia-inducible Factor Prolylhydroxylase Inhibitor Roxadustat

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216275%3A25310%2F18%3A39912886" target="_blank" >RIV/00216275:25310/18:39912886 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216275:25530/18:39912886

Výsledek na webu

<a href="http://dx.doi.org/10.1016/j.molliq.2018.07.076" target="_blank" >http://dx.doi.org/10.1016/j.molliq.2018.07.076</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.molliq.2018.07.076" target="_blank" >10.1016/j.molliq.2018.07.076</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Multiwavelength UV-Metric and pH-Metric Determination of the Dissociation Constants of the Hypoxia-inducible Factor Prolylhydroxylase Inhibitor Roxadustat

Popis výsledku v původním jazyce

UV-VIS spectra, molar absorption coefficients and protonation equilibriaRoxadustat is an orally bioavailable, hypoxiainducible factor prolyl hydroxylase inhibitor with potential anti-anemic activity. It is one of the Active Pharmacenutical Ingredients possessing acidic/basic functionalities their ionization state is controlled by solution pH and acid dissociation constants. Nonlinear regression of the pH-spectra with programs REACTLAB and SQUAD84 and of the pH-titration curve with ESAB determined four multiple consecutive dissociation constants with the protonation scheme. A sparingly soluble neutral molecule LH3 of Roxadustat was dissociated to the soluble anions LH2-, LH2- and L3- or protonated to the cation LH4+ in an aqueous medium. The graph of molar absorption coefficients of variously protonated species according to wavelength shows that the spectra of two anions LH2- and LH2-are nearly the same in colour. The Roxadustat spectrum exhibited five sharp isosbestic points related to the LH2-/L3- equilibrium. Four consecutive thermodynamic dissociation constants were estimated using UV-metric data pKTa1 = 3.60(04), pKTa2 = 5.62(14), pKTa3 = 7.66(16), pKTa4 = 9.08(02) at 25°C and pKTa1 = 3.60(04), pKTa2 = 5.73(10), pKTa3 = 7.52(10), pKTa4 = 8.99(02) at 37°C and using pH-metric data pKTa1 = 4.33(09), pKTa2 = 6.57(11), pKTa3 = 8.88(05), pKTa4 = 9.03(04) at 25°C and pKTa1 = 4.25(09), pKTa2 = 6.49(10), pKTa3 = 8.80(06), pKTa4 = 9.00(05) at 37°C The positive values of the enthalpy ΔH0 showed that the dissociation process is endothermic and the positive values of the Gibbs free energy ΔG0 at 25°C indicated that the dissociation process was not spontaneous, which also was confirmed by a negative value of the entropy ΔS0. Four macro-dissociation constants of Roxadustat and six protonation locations were predicted by MARVIN.

Název v anglickém jazyce

Multiwavelength UV-Metric and pH-Metric Determination of the Dissociation Constants of the Hypoxia-inducible Factor Prolylhydroxylase Inhibitor Roxadustat

Popis výsledku anglicky

UV-VIS spectra, molar absorption coefficients and protonation equilibriaRoxadustat is an orally bioavailable, hypoxiainducible factor prolyl hydroxylase inhibitor with potential anti-anemic activity. It is one of the Active Pharmacenutical Ingredients possessing acidic/basic functionalities their ionization state is controlled by solution pH and acid dissociation constants. Nonlinear regression of the pH-spectra with programs REACTLAB and SQUAD84 and of the pH-titration curve with ESAB determined four multiple consecutive dissociation constants with the protonation scheme. A sparingly soluble neutral molecule LH3 of Roxadustat was dissociated to the soluble anions LH2-, LH2- and L3- or protonated to the cation LH4+ in an aqueous medium. The graph of molar absorption coefficients of variously protonated species according to wavelength shows that the spectra of two anions LH2- and LH2-are nearly the same in colour. The Roxadustat spectrum exhibited five sharp isosbestic points related to the LH2-/L3- equilibrium. Four consecutive thermodynamic dissociation constants were estimated using UV-metric data pKTa1 = 3.60(04), pKTa2 = 5.62(14), pKTa3 = 7.66(16), pKTa4 = 9.08(02) at 25°C and pKTa1 = 3.60(04), pKTa2 = 5.73(10), pKTa3 = 7.52(10), pKTa4 = 8.99(02) at 37°C and using pH-metric data pKTa1 = 4.33(09), pKTa2 = 6.57(11), pKTa3 = 8.88(05), pKTa4 = 9.03(04) at 25°C and pKTa1 = 4.25(09), pKTa2 = 6.49(10), pKTa3 = 8.80(06), pKTa4 = 9.00(05) at 37°C The positive values of the enthalpy ΔH0 showed that the dissociation process is endothermic and the positive values of the Gibbs free energy ΔG0 at 25°C indicated that the dissociation process was not spontaneous, which also was confirmed by a negative value of the entropy ΔS0. Four macro-dissociation constants of Roxadustat and six protonation locations were predicted by MARVIN.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10406 - Analytical chemistry

Projekt

—

Návaznosti

S - Specificky vyzkum na vysokych skolach<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Molecular Liquids

ISSN

0167-7322

e-ISSN

—

Svazek periodika

268

Číslo periodika v rámci svazku

October

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

17

Strana od-do

386-402

Kód UT WoS článku

000447817400044

EID výsledku v databázi Scopus

2-s2.0-85050202365