DEUTERIUM AS A TOOL FOR CHANGING THE PROPERTIES OF PHARMACEUTICAL SUBSTANCES (REVIEW)
The review is devoted to the influence of the hydrogen isotope – deuterium on biological models of organisms and the biological activity of pharmaceutical substances.
The positions of the influence of deuterium on the properties of active pharmaceutical ingredients and excipients are examined from different perspectives. The first position reflects an increase in the kinetic isotope effect (KIE) in processes involving known pharmaceutical substances in aqueous solutions with a deuterium/protium ratio (D/H) below natural. For the first time, the dose-response diagram shows the identity of deuterium with essential trace elements, when a deficiency and excess of an element reduces the organism's vitality. Improved kinetic characteristics are demonstrated for the molecular and organism levels of different hierarchical gradations. In particular, they consist in the possibility of increasing the dissolution rate of substances by influencing the carbohydrate mutarotation processes and the optical activity of chiral substances, increased accumulation of essential elements in medicinal plants and other processes associated with a possible change in metabolic pathways in the cell and the organism as a whole.
The second considered position of the influence of deuterium is associated with the use of deuterated substances – new compounds or obtained by substitution of protium in known protium analogues. The KIE is presented, which is expressed in a decrease in the biotransformation rate as a result of deuteration, it allows predicting a rapid development of the new direction in the development of drugs. Having an identical therapeutic effect, deuterated analogs provide improved pharmacokinetic characteristics, such as reduced toxicity, blocked epimerization of optically active substances, and a change in the mechanisms of biotransformation. The obtained results make it possible to predict the mechanisms of the effect of deuterium on the biochemical transformations of pharmaceutical substances in the organism.
2. Anton Syroeshkin, Olga Levitskaya, Elena Uspenskaya, Tatiana Pleteneva Deuterium Depleted Water as an Adjuvant in Treatment of Cancer. Systematic Reviews in Pharmacy. 2019; 10 (1): 112-117. DOI: 10.5530/srp.2019.1.19.
3. Zoroddu MA, Aaseth J, Crisponi G, Medici S, Peana M, & Nurchi VM. The essential metals for humans: A brief overview. Journal of Inorganic Biochemistry. 2019. DOI: 10.1016/j.jinorgbio.2019.03.013.
4. Basov A, Fedulova L, Baryshev M, Dzhimak S. Deuterium-Depleted Water Influence on the Isotope 2H/1H Regulation in Body and Individual Adaptation. Nutrients. 2019;11:1903. doi:10.3390/nu11081903
5. Tracey Pirali, Marta Serafini, Sarah Cargnin, and Armando A. Genazzani Applications of Deuterium in Medicinal Chemistry. Journal of Medicinal Chemistry. 2019; 62(11): 5276-5297. DOI: 10.1021/acs.jmedchem.8b01808.
6. Roger D. Tung. Deuterium medicinal chemistry comes of age. Future Med. Chem. 2016; 8 (5): 491-494.
7. Syroeshkin A.V., Pleteneva T.V., Uspenskaya E.V., Zlatskiy I.A., Antipova N.A., Grebennikova T.V., Levitskaya O.V. D/H control of chemical kinetics in water solutions under low deuterium concentrations. Chemical Engineering Journal. 2019; 377:119827. DOI: 10.1016/j.cej.2018.08.213
8. Goncharuk VV, Syroeshkin AV, Zlatskiy IA, Uspenskaya EV, Orekhova AV, Levitskaya OV, Dobrovolskiy VI, Pleteneva TV. Quasi-chemical description of the kinetics of cell death Spirostomum ambiguum biosensor for biological activity of aqueous solutions. Journal of Water Chemistry and Technology. 2017; 39 (2): 97-102. DOI: 10.3103/S1063455X17020072.
9. Levitskaya OV, Syroeshkin AV, Pleteneva TV. Arrhenius kinetics as a bioactivity assessment criterion for drug substances and excipients. Pharmaceutical Chemistry Journal. 2016; 49 (11):779-781.
10. Titorovich OV., Lyulina EB, Pleteneva TV, Maksimova TV, Syroeshkin AV, Uspenskaya EV, Burdeinaya TN, Shandryuk GA. Reaction of an Antioxidant (Sodium Sulfite) with 3-Hydroxy-6-Methyl-2-Ethylpyridinium Salts. Pharmaceutical Chemistry Journal. 2015; 48 (12): 842-844.
11. Tsisanova ES, Uspenskaya EV, Pleteneva TV, Syroeshkin AV. Study of biological activity and D/H ratio of water with the aid of cellular biosensor spirostomum ambiguum. Trace elements in medicine. 2010; 11 (2): 8.
12. Syroeshkin AV., Pleteneva TV., Uspenskaya EV, Levitskaya OV, Tribot-laspiere MA, Zlatsky IA, Khodorovich NA, Nikifirova MV, Zaytseva SA. Polarimetric research of pharmaceutical substances in aqueous solutions with different water isotopologues ratio. International Journal of Applied Pharmaceutics. 2018; 10 (5): 20182.
13. Syroeshkin AV, Pleteneva TV, Uspenskaya EV, Levitskaya OV. Optical methods in studies of the chiral properties of drugs I. Valine in water with various deuterium contents. Vedomosti Scientific Center for Expertise in Medical Applications. 2016; 1: 25-29 (in Russ.)
14. Goncharuk VV, Lapshin VB, Burdeinaya TN, Pleteneva TV, Chernopyatko AS, Atamanenko ID, Ul’yantsev AS, Uspenskaya EV, Samsoni-Todorov AO, Taranov VV, Nikolaev GM, Kavitskaya AA, Romanyukina IYu, Prikhod’ko RV, Orekhova EA, Yaremenko VA, Kotel’chuk AS, Syroeshkin AV. Physicochemical Properties and Biological Activity of the Water Depleted of Heavy Isotopes. Journal of Water Chemistry and Technology. 2011; 33 (1): 15-25.
15. Somlyai G, Javaheri B, Davari H, Gyöngyi Z, Somlyai I, Tamaddon KA, Boros LG. Pre-clinical and clinical data confirm the anticancer effect of deuterium depletion. Biomacromol J. 2016; 2 (1): 1-7.
16. Krempels K, Somlyai I, Gyöngyi Z, Ember I, Balog K, Abonyi O, Somlyai GA. Retrospective study of survival in breast cancer patients undergoing deuterium depletion in addition to conventional therapies. J Cancer Res Ther. 2013; 1(8): 194-200.
17. Goncharuk VV, Syroeshkin AV, Pleteneva TV, Uspenskaya EV, Levitskaya OV, Tverdislov VA. On the possibility of chiral structure density submillimeter inhomogeneities existing in water. Journal of Water Chemistry and Technology. 2017: 39 (6): 319-324.
18. Elena V. Uspenskaya, Tatyana V. Pleteneva, Anton V. Syroeshkin, Ilaha V. Kazimova, Tatyana E. Elizarova, Artem I. Odnovorov. Role of stable hydrogen isotope variations in water for drug dissolution managing Curr. Issues Pharm. Med. Sci. 2020:33(2): 94-101. DOI: 10.2478/cipms-2020-0017
19. Zrelov OYu, Syroeshkin AV, Uspenskaya EV, Titorovich (Levitskaya) OV. Effect of water isotopic composition on galactose mutarotation kinetics. Pharmaceutical Chemistry Journal. 2015; 49 (6): 413-416.
20. Anton Syroeshkin, Maria Makarova, Tatiana Maksimova, Tatiana Pleteneva, Igor Zlatskiy. Development Of Zinc-Enriched Medicinal And Food Plants. SRP. 2020; 11 (10): 726-731. DOI: 10.31838/srp.2020.10.108
21. Halenova T, Zlatskiy I, Syroeshkin A, Maximova T, Pleteneva T. Deuterium-depleted water as adjuvant therapeutic agent for treatment of diet-induced obesity in rats. Molecules. 2020; 25: 23. DOI: 10.3390/molecules25010023.
22. Basov A, Fedulova L, Vasilevskaya E & Dzhimak S. Possible mechanisms of biological effects observed in living systems during 2H/1H isotope fractionation and deuterium interactions with other biogenic isotopes. Molecules. 24, 4101; 10.3390/molecules24224101 (2019)
23. Cisanova ES, Syroeshkin AV, Uspenskaya EV, Ul’yantsev AS, Pleteneva TV, Klimova EV, Berseneva EA. The study of biological activity and the ratio of deuterium/protium (D/H) in water using a cellular biosensor S. ambiguum. Studied in Russia. 2010; 46: 558-593.
24. Lewis GN. Biology of heavy water. Nature. 1934;133:620.
25. Lobyshev VN, Kalinichenko LP. Isotopic effects in biological systems. Moscow: Nauka, 1978 [in Russ].
26. Boros LG, D'Agostino DP, Katz HE. Submolecular regulation of cell transformation by deuterium depleting water exchange reactions in the tricarboxylic acid substrate cycle. Med Hypotheses. 2016;87:69-74.
27. Robins RJ, Remaud GS, Billault I. Natural mechanisms by which deuterium depletion occurs in specific positions in metabolites. Eur Chem Bull. 2012;1(1):39-40.
28. Cleland WW. The use of isotope effects to determine enzyme mechanisms. Journal of Biological Chemistry. 2003;278(52):51975-84.
29. Strekalova T, Evansa M, Chernopiatko A, CouchaY, Costa-Nunes J, et al. Deuterium content of water increases depression susceptibility: The potential role of a serotonin-related mechanism. Behavioural Brain Research. 2015;277:237-44.
30. C?rpini?an L, Petcu MD, Petrovici S, Chi? C, Ghi?e A, Zehan R. The Influence of deuterium depleted water on the hematocrit and the leukocyte formula in rats intoxicated with chromium. Scientific Papers: Animal Science and Biotechnologies. 2010;43(1):464-8.
31. Olariu L, Petcu M, Cuna S, Scurtu M, Tulcan C, Brudiu I. The role of deuterium depleted water (ddw) administration in blood deuterium concentration in Cr (VI) intoxicated rats. Lucr?ri Stiin?ifice Medicin? Veterinar?. 2010;43(2):193-6.
32. Hang M, Huynh V, Meyer TJ. Colossal kinetic isotope effects in proton-coupled electron transfer. PNAS. 2004;101(36):13138-41.doi.org/ 10.1073/pnas.0405086101
33. Syroeshkin AV, Antipova NV, Zlatska AV, Zlatskiy IA, Skylska MD, Grebennikova TV, Goncharuk VV. The effect of the deuterium depleted water on the biological activity of the eukaryotic cells. Journal of Trace Elements in Medicine and Biology. 2018; 50: 629-633.
34. Zlatskiy IA, Zlatska AV, Antipova NV, Syroeshkin AV. Effect of deuterium on the morpho-functional characteristics of normal and cancer cells in vitro. Trace Elements and Electrolytes. 2018; 35: 211-214. DOI: 10.5414/TEX0155410
35. Zlatskiy IA, Zlatska AV, Antipova NV, Dolenko SA, Gordiienko IM, Gubar OS, Vasyliev RG, Zubov DA, Novikova SN and Syroeshkin AV. Comparative Analysis of the Different Dyes' Potential to Assess Human Normal and Cancer Cell Viability in Vitro under Different D/H Ratios in a Culture Medium. Scientific World Journal. https://doi.org/10.1155/2020/2373021
36. Zlatska A, Vasyliev RG, Gordiienko IM et al. Effect of the deuterium on efficiency and type of adipogenic differentiation of human adipose-derived stem cells in vitro. Sci Rep 10, 5217 (2020). https://doi.org/10.1038/s41598-020-61983-3
37. Zlatskiy I, Pleteneva T, Skripnikov A, Grebennikova T, Maksimova T, Antipova N, Levitskaya O, Makarova M, Selivanenko I, Syroeshkin A. Dependence of Biocatalysis on D/H Ratio: Possible Fundamental Differences for High-Level Biological Taxons. Molecules 2020, 25, 4173. https://doi.org/10.3390/molecules25184173
38. Somlyai G, Jancsó G, Jákli G, Vass K, Barna B, Lakics V, Gaál T. Naturally occurring deuterium is essential for the normal growth rate of cells. FEBS Letters. 1993; 317 (1): 1-4.
39. Demmig-Adams B, Stewart JJ, Adams WW 3rd. Multiple feedbacks between chloroplast and whole plant in the context of plant adaptation and acclimation to the environment. Philos Trans R Soc Lond B Biol Sci. 2014;369(1640):20130244. Published 2014 Mar 3. doi:10.1098/rstb.2013.0244
40. Buchachenko AL, Kuznetsov DA. Mol. Biol. 2006. 40, N 1. – P. 9-15.
41. Maret W. The Metals in the biological periodic system of the elements: concepts and conjectures. International Journal of Molecular Sciences. 2016; 17 (1): 66. DOI: 10.3390/ijms17010066.
42. Dzhimak SS, Basov AA, Baryshev MG. Content of Deuterium in Biological fluids and organs: influence of deuterium depleted water on D/H gradient and the process of adaptation biochemistry. Biophysics and Molecular Biology. 2015;465:370-3.
43. Yavari K, & Kooshesh L. Deuterium depleted water inhibits the proliferation of human MCF7 breast cancer cell lines by inducing cell cycle arrest. Nutr. Cancer. 71, 1019-1029 (2019).
44. Z. Gyöngyi F, Budán I, Szabó W. Deuterium Depleted Water Effects on Survival of Lung Cancer Patients and Expression of Kras, Bcl2, and Myc Genes in Mouse Lung, Nutr Cancer. 2013;65(2):240-6.
45. Tracey Pirali, Marta Serafini, Sarah Cargnin, and Armando A. Genazzani Applications of Deuterium in Medicinal Chemistry. Journal of Medicinal Chemistry. 2019; 62(11): 5276-5297. DOI: 10.1021/acs.jmedchem.8b01808.
46. Kovács A, Guller I, Krempels K, Somlyai I, Jánosi I, Gyöngyi Z. Deuterium depletion may delay the progression of prostate cancer. J. Cancer Therapy. 2011; 2: 548-56.
47. Thulasiram HV, Phan RM, Rivera SB, Poulter CD. Synthesis of deuterium-labeled derivatives of dimethylallyl diphosphate. J. Org. Chem. 2006; 71: 1739-1741.
48. Sattler A. Hydrogen/Deuterium (H/D) exchange catalysis in alkanes. ACS Catal. 2018; 8: 2296-2312.
49. Belleau B, Burba J, Pindell M, Reiffenstein J. Effect of deuterium substitution in sympathomimetic amines on adrenergic responses. Science. 1961; 133: 102-104.
50. Elison C, Rapoport H, Laursen R, Elliott HW. Effect of deuteration of N–CH3 group on potency and enzymatic N-demethylation of morphine. Science. 1961; 134: 1078-1079.
51. Sipes IG, Gandolfi AJ, Pohl LR, Krishna G, Brown BR. Comparison of the biotransformation and hepatotoxicity of halothane and deuterated halothane. J. Pharmacol. Exp. Ther. 1980; 214: 716-720.
52. Claassen DO, Carroll B, De Boer LM, Wu E, Ayyagari R, Gandhi S, Stamler D. Indirect tolerability comparison of deutetrabenazine and tetrabenazine for Huntington disease. J. Clin.Mov. Disord. 2017; 4: 3-13.
53. Garay RP, Grossberg GT. AVP-786 for the treatment of agitation in dementia of the Alzheimer’s type. Expert Opin. Invest. Drugs. 2017; 26: 121-132.
54. Xie JH, Gillooly K, Zhang Y, Yang X, Zupa-Fernandez A, Cheng L, Strnad J, Heimrich E, Zhou X, Chen J, Chaudhry C, Li S, Moslin R, Wrobleski S, Weinstein D, Burke J. 349 - BMS-986165 is a highly potent and selective allosteric inhibitor of TYK2, blocks IL-12, IL-23 and type I interferon signaling and provides for robust efficacy in preclinical models of systemic lupus erythematosus and inflammatory bowel disease. Gastroenterology. 2018; 154: S-1357.
55. Khan AJ, Misenko SM, Thandoni A, Schiff D, Jhawar SR, Bunting SF, Haffty BG. VX-984 is a selective inhibitor of non-homologous end joining, with possible preferential activity in transformed cells. Oncotarget. 2018; 9: 25833-25841.
56. First-in-Human Study of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of VX-984 in Combination with Chemotherapy. ClinicalTrials.gov identifier: NCT02644278. Last update: June 5, 2018. Accessed on November 15, 2018.
57. Hearn BR, Fontaine SD, Pfaff SJ, Schneider EL, Henise J, Ashley GW, Santi DV. Primary deuterium kinetic isotope effects prolong drug release and polymer biodegradation in a drug delivery system. J. Controlled Release. 2018; 278: 74-79.
58. Malmlöf T, Rylander D, Alken RG, Schneider F, Svensson TH, Cenci MA, Schilstro?m B. Deuterium substitutions in the L-DOPA molecule improve its anti-akinetic potency without increasing dyskinesias. Exp. Neurol. 2010; 225: 408-415.
59. Calinski DM, Zhang H, Ludeman S, Dolan ME, Hollenberg PF. Hydroxylation and N-dechloroethylation of ifosfamide and deuterated ifosfamide by the human cytochrome p450s and their commonly occurring polymorphisms. Drug Metab.Dispos. 2015; 43: 1084-1090.
60. Bhadra PB., Hassanzadeh A, Arsic B, Allison DG, Morris GA, Barber J. Enhancement of the properties of a drug by monodeuteriation: reduction of acid-catalysed formation of a gut-motilide enol ether from 8-deuterio-erythromycin B. Org. Biomol. Chem. 2016; 14: 6289-6296.
61. Shao L, Abolin C, Hewitt MC, Koch P, Varney M. Derivatives of tramadol for increased duration of effect. Bioorg. Med. Chem. Lett. 2006; 16: 691-694.
62. Smith SW. Chiral toxicology: It’s the same thing...only different. Toxicol. Sci. 2009; 110: 4-30.
63. Csuk R. Biocatalysis in the Pharma and Biotech Industries. CRC Press: Boca Raton, FL. 2007; 699-716.
64. Hutt AJ, Valentova J. The chiral switch: The development of single enantiomer drugs from racemates. Acta Fac. Pharm. Univ. Comenianae. 2003; 50: 7-23.
65. Ali I. Homochiral drug design and development by racemization. Comb. Chem. High Throughput Screening. 2007; 10: 326-335.
66. Somogyi A, Bochner F, Foster D. Inside the isomers: The tale of chiral switches. Aust. Prescr. 2004: 27; 47-49.
67. Mori T, Ito T, Liu S, Ando H, Sakamoto S, Yamaguchi Y, Tokunaga E, Shibata N, Handa H, Hakoshima T. Structural basis of thalidomide enantiomer binding to cereblon. Sci. Rep. 2018; 8: 1294-1307.
68. Yamamoto T, Tokunaga E, Nakamura S, Shibata N, Toru T. Synthesis and configurational stability of (S)- and (R)-deuteriothalidomides. Chem. Pharm. Bull. 2010; 58: 110-112.
69. Jacques V, Czarnik AW, Judge TM, Van der Ploeg LH, DeWitt SH. Differentiation of antiinflammatory and antitumorigenic properties of stabilized enantiomers of thalidomide analogs. Proc. Natl. Acad. Sci. U.S.A. 2015; 112: E1471-E1479.
70. Mullard A. Deuterated drugs draw heavier backing. Nat. Rev. Drug Discovery. 2016; 15: 219-221.
71. Graham S Timmins. Deuterated drugs; where are we now? Expert Opin Ther Pat. 24(10): 1067–1075. doi:10.1517/13543776.2014.943184.
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