CHIRAL SWITCHING CONTROL OF PHARMACEUTICAL SUBSTANCES

OLGA V. LEVITSKAYA; TATIANA V. PLETENEVA; DARIA A. GALKINA; NADEZDA A. KHODOROVICH; ELENA V. USPENSKAYA; ANTON V. SYROESHKIN

doi:10.22159/ijap.2024v16i3.50481

Authors

OLGA V. LEVITSKAYA Pharmaceutical and Toxicological Chemistry Department, RUDN University, 6 Miklukho-Maklaya St, Moscow-117198, Russian Federation
TATIANA V. PLETENEVA Pharmaceutical and Toxicological Chemistry Department, RUDN University, 6 Miklukho-Maklaya St, Moscow-117198, Russian Federation https://orcid.org/0000-0001-7297-980X
DARIA A. GALKINA Pharmaceutical and Toxicological Chemistry Department, RUDN University, 6 Miklukho-Maklaya St, Moscow-117198, Russian Federation https://orcid.org/0000-0002-0270-2888
NADEZDA A. KHODOROVICH Pharmaceutical and Toxicological Chemistry Department, RUDN University, 6 Miklukho-Maklaya St, Moscow-117198, Russian Federation https://orcid.org/0000-0002-1289-4545
ELENA V. USPENSKAYA Pharmaceutical and Toxicological Chemistry Department, RUDN University, 6 Miklukho-Maklaya St, Moscow-117198, Russian Federation
ANTON V. SYROESHKIN Pharmaceutical and Toxicological Chemistry Department, RUDN University, 6 Miklukho-Maklaya St, Moscow-117198, Russian Federation https://orcid.org/0009-0009-2197-8861

DOI:

https://doi.org/10.22159/ijap.2024v16i3.50481

Keywords:

Kinetic isotope effect, Deuterium/protium ratio, Chiral switching

Abstract

Objective: The aim of this study was to demonstrate that chiral switching should be recognized as a widespread phenomenon that extends beyond the production of pure enantiomeric drugs.

Methods: To investigate the optical activity of substances from various chemical classes, enantiomers of chiral compounds (Sigma-Aldrich, USA) were chosen: valine and its racemic form (D-valine, L-valine, and racemic valine with optical purity ≥ 99%), L-ascorbic acid (content ≥ 99%), carbohydrates (D-glucose, D-galactose, L-galactose, contents ≥ 99.5%). Solutions were prepared using deuterium-depleted water (DDW – "light" water, D/H=4 ppm), natural deionized high-ohmic water (BD, D/H=140 ppm), and heavy water (99.9% D₂O; Sigma-Aldrich). Optical activity was measured using the Atago POL-1/2 polarimeter.

Results: One of the components in the racemic medication mixture can act as an inert agent, exhibit toxicity, or undergo undesirable biotransformation mechanisms, resulting in the formation of products with unknown properties.It has been established that a change in the deuterium/protium (D/H) ratio in water leads to a change in the equilibrium and kinetic characteristics of optically active compounds across various chemical classes, such as amino acids, carboxylic acids, and carbohydrates. An inequality was observed in the absolute values of the optical rotation of the L- and D-isomers of valine and galactose, depending on the D/H isotope ratio. The impact of chiral water clusters on optical rotation accounts for the sudden shift in the specific rotation of dilute solutions (less than 0.5%) of L-ascorbic acid in water, based on the D/H ratio. The influence of the isotopic composition of water was confirmed by studying the temperature-dependent mutarotation kinetics of D-glucose and L- and D-galactose in Arrhenius coordinates.

The mutarotation process in natural high-resistivity water is characterized by an activation energy (E_a) of 40.8 ± 1.4 kJ mol^-1, while in deuterium-depleted water, E_a = 63.6 ± 3.5 kJ mol^-1. This results in a kinetic isotope effect for deuterium (KIED) of 1.6.

Conclusion: Methodological approaches have been developed to control chiral switching based on the isotopic composition of water in vivo and in vitro. The study of changes in the optical activity of hierarchical structures in the human body, the influence of solvent properties on the mechanisms of optical rotation, as well as the use of KIED values can be utilized to monitor various chiral transitions in vitro and living organisms.

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