Experimental study of somatostatin analogue cyphetrylin lipophilicity

Background. Lipophilicity is a fundamental physicochemical property that determines the solubility and transport of a drug through biological membranes, as well as its behavior in the body. Lipophilicity also affects the ability of a drug to bind to plasma proteins and reach the corresponding receptors. The standard for drug lipophilicity experimental study is measuring the distribution between two immiscible phases – aqueous (water and buffer solutions) and hydrophobic (most often octanol).

Aim. The experimental study of somatostatin analogue cyphetrylin lipophilicity in octanol/water system distribution test.

Materials and methods. The lipophilicity of cyphetrylin, synthesized in the Laboratory of Chemical Synthesis of the N.N. Blokhin National Medical Research Center for Oncology of the Russian Ministry of Health, was studied in the octanol/water system; ethanol was used to study cyphetrylin spectral characteristics and its quantitative determination; shake flask method, UV-spectrometry.

Results. The experimental assessment of cyphetrylin lipophilicity was carried out by shake flask method in a system of mutually saturated water and octanol 1:1. Since cyphetrylin is practically insoluble in water, the concentration of the drug in the octanol phase was determined by UV-spectrometry and the concentration in water was calculated by mass balance. Lipophilicity was expressed as the decimal logarithm of the concentration of cyphetrylin in the octanol phase to its concentration in the aqueous phase (logPo/w) ratio. The experimentally determined value of logPo/w was 1.14.

Conclusion. The lipophilicity of cyphetrylin was studied experimentally by shake flask method as a parameter that determines the molecule probability to reach the biological target. The logPo/w value 1.14 in decimal logarithmic form indicates moderate lipophilicity of cyphetrylin, which exhibits antitumor activity when interacting with somatostatin receptors.

1. Wardecki D., Dołowy M., Bober-Majnusz K. Evaluation of the usefulness of topological indices for predicting selected physicochemical properties of bioactive substances with antiandrogenic and hypouricemic activity. Molecules 2023;28(15):5822. DOI: 10.3390/molecules28155822

2. Kempińska D., Chmiel T., Kot-Wasik A. et al. State of the art and prospects of methods for determination of lipophilicity of chemical compounds. Trends Anal Chem 2019;113:54–73. DOI: 10.1016/j.trac.2019.01.011

3. Arnott J.A., Planey S.L. The influence of lipophilicity in drug discovery and design. Expert Opin Drug Discov 2012;7(10): 863–75. DOI: 10.1517/17460441.2012.714363

4. Broccatelli F., Aliagas I., Zheng H. Why decreasing lipophilicity alone is often not a reliable strategy for extending IV half-life. ACS Med Chem Lett 2018;9(6):522–7. DOI: 10.1021/acsmedchemlett.8b00047

5. Amezqueta S., Subirats X., Fuguet E. et al. Chapter 6 – Octanol– Water Partition Constant. Editor C.F. Poole. In: Handbooks in Separation Science Liquid-Phase Extraction. Elsevier, 2020. P. 183–208. DOI: 10.1016/B978-0-12-816911-7.00006-2

6. Sharapova A., Ol’khovich M., Blokhina S., Perlovich G.L. Experimental Examination of Solubility and Lipophilicity as Pharmaceutically Relevant Points of Novel Bioactive Hybrid Compounds. Molecules 2022;27(19):6504. DOI: 10.3390/molecules27196504

7. Bahmani A., Saaidpour S., Rostami A. A simple, robust and efficient computational method for n-octanol/water partition coefficients of substituted aromatic drugs. Sci Rep 2017;7:5760. DOI:10.1038/s41598-017-05964-z

8. Roy D., Patel C. Revisiting the use of quantum chemical calculations in LogPoctanol-water prediction. Molecules 2023;28(2):801. DOI: 10.3390/molecules28020801

9. Ramli N.A.S., Rania H., Roslan N.A. et al. Evaluation of distribution and partition coefficients of levulinic acid in octanol-water system at 298.15 K. J Solution Chem 2024;53: 471–85. DOI: 10.1007/s10953-023-01345-5

10. Santos A., Soares J.X., Cravo S. et al. Lipophilicity assessement in drug discovery: experimental and theoretical methods applied to xanthone derivatives. J Chromatogr B Analyt Technol Biomed Life Sci 2018;1072:182–92. DOI: 10.1016/j.jchromb.2017.10.018

11. Katz D., Fike K., Longenberger J. et al. AlphaLogD determination: an optimized reversed-phase liquid chromatography method to measure lipophilicity on neutral and basic small and beyond-rule-of-five compounds. J Chromatogr A 2022;1674:463146. DOI: 10.1016/j.chroma.2022.463146

12. Smirnova L.I., Ustinkina S.V., Orlova O.L. et al. Drug with antitumor effect. RU2254139С1. (In Russ.).

13. Shprakh Z.S., Yartseva I.V., Smirnova L.I. et al. Synthesis and chemico-pharmaceutical characteristics of a somatostatin analog with antitumor activity. Khimikofarmatsevticheskii zhurnal = Chemical and Pharmaceutical Journal 2012;48(3):19–22. (In Russ.) DOI: 10.30906/0023-1134-2014-48-3-19-22

14. Shprakh Z.S., Borisova L.M., Kiseleva M.P., Smirnova Z.S. Preclinical study of cyphetrylin antitumor efficiency on experimental animal tumors. Eksperimental’naya i klinicheskaya farmakologiya = Experimental and clinical pharmacology 2019;48(3):19–22. (In Russ.). DOI: 10.30906/0869-2092-2019-82-8-27-31

15. Shprakh Z.S. Analogue of the hypothalamic hormone cyphetrylin: preclinical study and the first experience of clinical use. Materials of the IVth St. Petersburg International Oncological Forum “White Nights”: report abstract. Saint Petersburg, 2018. P. 169. (In Russ.).

16. Borisova L.M., Kiseleva M.P., Osipov V.N. Cyphetrylin cytotoxic analogues (report II). Rossijskij bioterapevticeskij zurnal = Russian Journal of Biotherapy. 2017;16(2):23–9. (In Russ.). DOI: 10.17650/1726-9784-2017-16-2-23-29

17. OECD, Test No. 107: Partition coefficient (n-octanol/water): Shake flask method. OECD Guidelines for the Testing of Chemicals, Sect. 1. URL: https://www.oecd-ilibrary.org. DOI: 10.1787/9789264069626-en

18. Teerasong S., Wattanasin P., Wilairat P., Nacapricha D. A simple method based on one phase measurement for determination of the octanol-water partition coefficient of drugs. Chiang Mai J Sci 2015;42(3):691–8.

19. Mohsen-Nia M., Ebrahimabadi A.H., Niknahad B. Partition coefficient n-octanol/water of propranolol and atenolol at different temperatures: Experimental and theoretical studies. J Chem Thermodyn 2012;54:393–7. DOI: 10.1016/j.jct.2012.05.021

20. Port A., Bordas M., Enrech R. et al. Critical comparison of shake-flask, potentiometric and chromatographic methods for lipophilicity evaluation (logP) of neutral, acidic, basic, amphoteric, and zwitterionic drugs. Eur J Pharm Sci 2018;122:331–40. DOI:10.1016/j.ejps.2018.07.010

21. Shprakh Z. Formulation of somatostatin analog tablets using quality by design approach. J Appl Pharm Sci 2021;11(4):96–105. DOI: 10.7324/JAPS.2021.110412

22. Virtual Computational Chemistry Laboratory. URL: https://vcclab.org

23. Wolk O., Agbaria R., Dahan A. Provisional in-silico biopharmaceutics classification (BCS) to guide oral drug product development. Drug Des Devel Ther 2014;24(8):1563–75. DOI: 10.2147/DDDT.S68909

24. Morak-Młodawska B., Jeleń M., Martula E., Korlacki R. Study of lipophilicity and adme properties of 1,9-diazaphenothiazines with anticancer action. Int J Mol Sci 2023;24(8):6970. DOI: 10.3390/ijms24086970

25. Alqahtani M.S., Kazi M., Alsenaidy M.A., Ahmad M.Z. Advances in oral drug delivery. Front Pharm 2021;12:618411. DOI: 10.3389/fphar.2021.618411