Несмотря на то, что энантиомеры лекарственных препаратов обладают идентичными физико-химическими свойствами в изотропной среде, они могут проявлять совершенно разную биологическую активность. Особенности взаимодействия изомеров с асимметричными соединениями организма важно учитывать при создании лекарственных препаратов, так как может оказаться, что одна форма лекарственного средства обладает терапевтическим эффектом, а другая не усваивается, является менее активной или даже вызывает серьезные осложнения, являясь для организма токсичной. Биоактивность энантиомеров, их фармакодинамика и фармакокинетика, процесс хиральной инверсии оптических изомеров в живых системах интенсивно исследуются в настоящее время. Различия в фармакодинамических и фармакокинетических свойствах энантиомеров определяются их специфическими взаимодействиями с хиральными биомакромолекулами. Выяснение природы хирально-иерархической структуры биомакромолекул-мишеней и симметрийной структуры лекарственных препаратов направлено на установление системности и хиральных соответствий лекарств и мишеней.
хиральность, энантиомеры, хиральные лекарства, стереоспецифичность, структурные иерархии
1. Реутов О.А., Курц А.Л., Бутин К.П. Органическая химия: учебник. М.: Бином, 2005, 455 с. @@Reutov O.A., Kurtz A.L., Butin K.P. Organic сhemistry: textbook. Moskva: Binom 2005, 455 p. (In Russ.)
2. Nguyen L.A., He H., Pham-Huy C. Chiral drugs: an overview.International journal of biomedical science: IJBS, 2006, vol. 2, no. 2, pp. 85-100.
3. Budаu M., Hancu G., Rusu A., Cаrcu-Dobrin M., Muntean D.L. Chirality of Modern Antidepressants: An Overview. Advanced pharmaceutical bulletin, 2017, vol. 7, no. 4, pp. 495-500. DOI:https://doi.org/10.15171/apb.2017.061
4. Cizmarikova R., Habala L., Valentova J., Markuliak M. Survey of Pharmacological Activity and Pharmacokinetics of Selected β-Adrenergic Blockers in Regard to Their Stereochemistry. Applied Sciences, 2019, vol. 9, p. 625. DOI:https://doi.org/10.3390/app9040625
5. Raikar P., Gurupadayya B., Koganti V.S. Recent Advances in Chiral Separation of Antihistamine Drugs: Analytical and Bioanalytical Methods. Current drug delivery, 2018, vol. 15, no. 10, pp. 1393-1410. DOI:https://doi.org/10.2174/1567201815666180830100015
6. Qin F., Wang X., Jing L., Pan L., Cheng M., Sun G., Li F. Bidirectional chiral inversion of trantinterol enantiomers after separate doses to rats. Chirality, 2013, vol. 25, no. 12, pp. 934-938. DOI:https://doi.org/10.1002/chir.22236
7. Tverdislov V.A. Chirality as a Primary Switch of Hierarchical Levels in Molecular Biological Systems. Biophysics, 2013, vol. 58, no. 1, pp. 128-132. DOI:https://doi.org/10.1134/S0006350913010156
8. Tverdislov V.A., Malyshko E.V. On regularities in the spontaneous formation of structural hierarchies in chiral systems of nonliving and living matter. Physics Uspekhi, 2019, vol. 62, no. 4, pp. 354-363. DOI:https://doi.org/10.3367/UFNe.2018.08.038401
9. Tverdislov V.A., Malyshko E.V. Chiral Dualism as an Instrument of Hierarchical Structure Formation in Molecular Biology. Symmetry, 2020, vol. 12, p. 587. DOI:https://doi.org/10.3390/sym12040587
10. Souza M., Marques M.P., Duarte G., Lanchote V.L. Analysis of bupivacaine enantiomers in plasma as total and unbound concentrations using LC-MS/MS: Application in a pharmacokinetic study of a parturient with placental transfer. Journal of pharmaceutical and biomedical analysis, 2019, vol. 164, pp. 268-275. DOI: 0.1016/j.jpba.2018.10.040
11. Wang Y., Zhou J., Han Q., Chen Q., Guo L., Fu Y. Chiral Recognition of Penicillamine Enantiomers Based on DNA-MWNT Complex Modified Electrode. Electroanalysis, 2012, vol. 24, no. 7, pp. 1561-1566. DOI:https://doi.org/10.1002/elan.201200010
12. Van Wart S.A., Mager D.E. Clinical pharmacokinetics and pharmacodynamics of stereoisomeric drugs. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: CRC Press, 2012, 322 p.
13. Hancu G., Budau M., Kantor L.K., Carje A. Cyclodextrine screening for the chiral separation of amlodipine enantiomers by capillary electrophoresis. Advanced pharmaceutical bulletin, 2015, vol. 5, no. 1, p. 35-40. DOI:https://doi.org/10.5681/apb.2015.005
14. Dalal J., Mohan J.C., Iyengar S.S., Hiremath J., Sathyamurthy I., Bansal S., Kahali D., Dasbiswas A. S-Amlodipine: An Isomer with Difference-Time to Shift from Racemic Amlodipine.International journal of hypertension, 2018, article ID 8681792. DOI:https://doi.org/10.1155/2018/8681792
15. Gonzalez J.P., Clissold S.P. Ocular levobunolol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs, 1987, vol. 34, no. 6, pp. 648-661. DOI:https://doi.org/10.2165/00003495-198734060-00002
16. Shrivastav P.S., Buha S.M., Sanyal M. Detection and quantitation of β-blockers in plasma and urine. Bioanalysis, 2010, vol. 2, no. 2, pp. 263-276. DOI:https://doi.org/10.4155/bio.09.184
17. Fernandez C., Martin C., Gimenez F., Farinotti R. Clinical Pharmacokinetics of Zopiclone. Clinical Pharmacokinetics, 1995, vol. 29, pp. 431-441. DOI:https://doi.org/10.2165/00003088-199529060-00004
18. Zaazaa H.E., Salama N.N., Abd El Halim L.M., Salem M.Y., Abd El Fattah L.E. Thin-Layer Chromatographic Enantioseparation of Ofloxacin and Zopiclone using Hydroxy-Propyl-Beta-Cyclodextrin as Chiral Selector and Thermodynamic Studies of Complexation. JPC-J Planar Chromat, 2014, vol. 27, pp. 166-173. DOI:https://doi.org/10.1002/chir.22536
19. Franks M.E., Macpherson G.R., Figg W.D. Thalidomide. Lancet, 2004, vol. 363, no. 9423, pp. 1802-1811. DOI:https://doi.org/10.1016/S0140-6736(04)16308-3
20. Knobloch J., Jungck D., Koch A. The Molecular Mechanisms of Thalidomide Teratogenicity and Implications for Modern Medicine. Current molecular medicine, 2017, vol. 17, no. 2, pp. 108-117. DOI:https://doi.org/10.2174/1566524017666170331162315
21. Tokunaga E., Yamamoto T., Ito E., Shibata N. Understanding the Thalidomide Chirality in Biological Processes by the Self-disproportionation of Enantiomers. Scientific reports, 2018, vol. 8, no. 1, p. 17131. DOI:https://doi.org/10.1038/s41598-018-35457-6
22. 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. Scientific reports, 2018, vol. 8, no. 1, p. 1294. DOI:https://doi.org/10.1038/s41598-018-19202-7
23. Beng H., Zhang H., Jayachandra R., Li J., Wu J., Tan W. Enantioselective resolution of Rac-terbutaline and evaluation of optically pure R-terbutaline hydrochloride as an efficient anti-asthmatic drug. Chirality, 2018, vol. 30, no. 6, pp. 759-768. DOI:https://doi.org/10.1002/chir.22846
24. Jacobson G.A., Raidal S., Robson K., Narkowicz C.K., Nichols D.S., Haydn Walters E. Bronchopulmonary pharmacokinetics of (R)-salbutamol and (S)-salbutamol enantiomers in pulmonary epithelial lining fluid and lung tissue of horses. British journal of clinical pharmacology, 2017, vol. 83, no. 7, pp. 1436-1445. DOI:https://doi.org/10.1111/bcp.13228
25. Funck-Brentano C. Pharmacokinetic and pharmacodynamic profiles of d-sotalol and d,l-sotalol. European heart journal, 1993, vol. 14 (Supplement H), pp. 30-35. DOI:https://doi.org/10.1093/eurheartj/14.suppl_h.30
26. Waldo A.L., Camm A.J., deRuyter H., Friedman P.L., MacNeil D.J., Pauls J.F., Pitt B., Pratt C.M., Schwartz P.J., Veltri E.P. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival with Oral d-Sotalol. Lancet, 1996, vol. 348, no. 9019, pp. 7-12. DOI:https://doi.org/10.1016/s0140-6736(96)02149-6
27. Godbillon J., Richard J., Gerardin A., Meinertz T., Kasper W., Jähnchen E. Pharmacokinetics of the enantiomers of acenocoumarol in man. British journal of clinical pharmacology, 1981, vol. 12, no. 5, pp. 621-629. DOI:https://doi.org/10.1111/j.1365-2125.1981.tb01280.x
28. Meinertz T., Kasper W., Kahl C., Jähnchen E. Anticoagulant activity of the enantiomers of acenocoumarol. British journal of clinical pharmacology, 1978, vol. 5, no. 2, pp. 187-188. DOI:https://doi.org/10.1111/j.1365-2125.1978.tb01622.x
29. Kim H., Radwanski E., Lovey R., Lin C.C., Nomeir A.A. Pharmacokinetics of the active antifungal enantiomer, SCH 42427 (RR), and evaluation of its chiral inversion in animals following its oral administration and the oral administration of its racemate genaconazole (RR/SS). Chirality, 2002, vol. 14, no. 5, pp. 436-441. DOI:https://doi.org/10.1002/chir.10114
30. Cai X.J., Xu X.Z., Pan C.X. Study of Optical Isomer Separation of Chiral Antifungal Drugs Tetramisole, Miconazole, and Paclobutrazol on Two Chiral Stationary Phases. Analytical Letters, 2005, vol. 38, no. 7, pp. 1149-1157. DOI:https://doi.org/10.1081/AL-200057224
31. Mangas-Sanchez J., Busto E., Gotor-Fernandez V., Malpartida F., Gotor V. Asymmetric chemoenzymatic synthesis of miconazole and econazole enantiomers. The importance of chirality in their biological evaluation. The Journal of organic chemistry, 2011, vol. 76, no. 7, pp. 2115-2122. DOI:https://doi.org/10.1021/jo102459w
32. Tedesco D., Di Pietra A.M., Rossi F., Garagnani M., Del Borrello E., Bertucci C., Andrisano V. Determination of dextromethorphan and levomethorphan in seized heroin samples by enantioselective HPLC and electronic CD. Journal of pharmaceutical and biomedical analysis, 2013, vol. 81-82, pp. 76-79. DOI:https://doi.org/10.1016/j.jpba.2013.03.024
33. Inoue N., Nogawa M., Ito S., Tajima K., Kume S., Kyoi T. The enantiomers of etodolac, a racemic anti-inflammatory agent, play different roles in efficacy and gastrointestinal safety. Biological & pharmaceutical bulletin, 2011, vol. 34, no. 5, pp. 655-659. DOI:https://doi.org/10.1248/bpb.34.655
34. Wishart D.S., Feunang Y.D., Guo A.C., Lo E.J., Marcu A., Grant J.R., Sajed T., Johnson D., Li C., Sayeeda Z., Assempour N., Iynkkaran I., Liu Y., Maciejewski A., Gale N., Wilson A., Chin L., Cummings R., Le D., Pon A., Knox C., Wilson M. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res, 2017, vol. 46, pp. D1074-D1082. DOI:https://doi.org/10.1093/nar/gkx1037
35. Tang J., Tanoli Z.U., Ravikumar B., Alam Z., Rebane A., Vaha-Koskela M., Peddinti G., van Adrichem A.J., Wakkinen J., Jaiswal A., Karjalainen E., Gautam P., He L., Parri E., Khan S., Gupta A., Ali M., Yetukuri L., Gustavsson A.L., Seashore-Ludlow B., Hersey A., Leach A.R., Overington J.P., Repasky G., Wennerberg K., Aittokallio T. Drug Target Commons: A Community Effort to Build a Consensus Knowledge Base for Drug-Target Interactions. Cell chemical biology, 2018, vol. 25, no. 2, pp. 224-229. e2, DOI:https://doi.org/10.1016/j.chembiol.2017.11.009
36. Wang Y., Zhang S., Li F., Zhou Y., Zhang Y., Wang Z., Zhang R., Zhu J., Ren Y., Tan Y., Qin C., Li Y., Li X., Chen Y., Zhu F. Therapeutic target database 2020: enriched resource for facilitating research and early development of targeted therapeutics. Nucleic acids research, 2020, vol. 48, no. D1, pp. D1031-D1041. DOI:https://doi.org/10.1093/nar/gkz981
37. Vlasses P.H., Rotmensch H.H., Swanson B.N., Irvin J.D., Johnson C.L., Ferguson R.K. Indacrinone: natriuretic and uricosuric effects of various ratios of its enantiomers in healthy men. Pharmacotherapy, 1984, vol. 4, no. 5, pp. 272-277. DOI:https://doi.org/10.1002/j.1875-9114.1984.tb03374.x
38. Davies N.M., Teng X.W. Importance of chirality in drug therapy and pharmacy practice: Implications for psychiatry. Advances in Pharmacy, 2003, vol. 1, no. 3, pp. 242-252.
