Original Article CHIRAL SWITCHING CONTROL OF PHARMACEUTICAL SUBSTANCES OLGA V. LEVITSKAYA , TATIANA V. PLETENEVA * , DARIA A. GALKINA , NADEZDA A. KHODOROVICH , ELENA V. USPENSKAYA , ANTON V. SYROESHKIN Pharmaceutical and Toxicological Chemistry Department, RUDN University, 6 Miklukho-Maklaya St, Moscow-117198, Russian Federation *Corresponding author: Tatiana V. Pleteneva; * Email: tvplet@mail.ru Received: 29 Jan 2024, Revised and Accepted: 16 Mar 2024 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 (Ea) of 40.8±1.4 kJ mol -1 , while in deuterium- depleted water, Ea = 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. Keywords: Kinetic isotope effect, Deuterium/protium ratio, Chiral switching © 2024 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/) DOI: https://dx.doi.org/10.22159/ijap.2024v16i3.50481 Journal homepage: https://innovareacademics.in/journals/index.php/ijap INTRODUCTION The renowned J.-B. Biot established the principles of dynamic stereochemistry [1], which explain various processes involving optically active compounds. The term "chiral switch" was first used to refer to the extraction of the active enantiomer from a racemate or mixture of diastereoisomers (epimers) patented as drugs [2]. Later, this term began to be used for the synthesis of new enantiomers of pharmaceutical substances that had not previously been used as drugs [3]. The stereochemical properties of drug enantiomers contribute to differences in pharmacokinetic and pharmacological profiles, as well as the ways they interact with chiral biological targets [4]. The use of a single pure enantiomer instead of a racemate improves the effectiveness and/or safety of treatment [5] and promotes the development of new drugs across various pharmacological classes [6]. The significance of chiral switching extends beyond the development and production of enantiopure drugs. This concept has significantly expanded in scope. Over the past decades, scientific knowledge has accumulated regarding the change in the chirality of drugs during biotransformation (stereoselective metabolism), leading to the formation of numerous optically active products with unknown properties [7, 8]. These degradation products can interact with the naturally occurring alternating hierarchical structures in the body [9]. Changes in the pharmacokinetic properties of chiral compounds are observed at molecular, cellular, and organismal levels (fig. 1). For example, deuterated drugs are new compounds in which protium (H) atoms are replaced by deuterium (D) atoms [10]. The kinetic isotope effect of deuterium (KIED) results in a reduction in the drug's dosage and toxicity and also prevents the epimerization of optically active substances. Dose-response diagrams for a unicellular organism demonstrate the importance of deuterium as an essential trace element. Deficiency or excess of this element can reduce the organism's vitality. The homeostasis area is tightly regulated by the ratio of deuterium to hydrogen at various temperatures [11]. Another example that highlights the significance of broadening the concept of "chiral switching" is the shift in the direction of optical rotation that occurs as hierarchical structures develop in living systems. This makes it possible to use chirality as a tool for the stratification of hierarchical systems in living organisms and non-living objects [12, 13]. Chiral switching occurs during the process of inducing chirality in achiral molecules and giant heterogeneous water clusters [14], facilitated by small optically active structures known as "sergeant- soldier" [15]. The accumulated experimental data necessitate the generalization and development of new approaches to control chiral switching based on the kinetic isotope effect of deuterium [16, 17]. Deuterium is one of the essential elements [18]. Its main role in living organisms and laboratory settings is to participate in chiral switching at different hierarchical levels within the body. The presence of deuterium (D) in a drug molecule or solvent, in various ratios with protium (H), enables the control of various types of chiral switching. The behavior of optically active compounds from various chemical classes (such as the amino acid valine, ascorbic acid, and carbohydrates like glucose and galactose) in waters with different deuterium/protium ratios is discussed. International Journal of Applied Pharmaceutics ISSN-0975-7058 Vol 16, Issue 3, 2024