Ukr.Biochem.J. 2024; Volume 96, Issue 3, May-Jun, pp. 75-96

doi: https://doi.org/10.15407/ubj96.03.075

Iodide n,π-chelate complexes of platinum(II) based on N-allyl substituted thioureas and their effect on the activity of hepatobiliary system enzymes in comparison with chloride analogs

12.06.2024   Uncategorized   No comments

V. Orysyk1*, L. Garmanchuk2, S. Orysyk3, Yu. Zborovskii1,
S. Shishkina4, I. Stupak2, P. Novikova3, D. Ostapchenko2,
N. Khranovska5, V. Pekhnyo3, M. Vovk1

1Department of Functional Heterocyclic Systems Chemistry,
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kyiv;
2Department of Biomedicine of Taras Shevchencko National University,
Educational and Scientific Centre “Institute of Biology and Medicine”, Kyiv, Ukraine
3Department of Complex Compounds Chemistry, V.I. Vernadsky Institute of General
and Inorganic Chemistry, National Academy of Sciences of Ukraine, Kyiv;
4Department of X-ray Diffraction Studies and Quantum Chemistry,
SSI “Institute for Single Crystals”, National Academy of Sciences of Ukraine, Kharkiv;
5National Cancer Institute, Kyiv, Ukraine;
*e-mail: vis.viktorys@gmail.com

Received: 21 December 2023; Revised: 30 January 2024;
Accepted: 31 May 2024; Available on-line: 17 June 2024

The search for new effective drugs in the treatment of neoplasm remains relevant even today, since the adaptation of transformed cells to the action of classical drugs contributes to the emergence of drug resistance­. This applies to a number of classic chemotherapy drugs of the platinum series, in particular cisplatin. In this work, we describe the effect of novel analogs of cisplatin on HepG2 cells and on the key enzyme of antioxidant protection system gammaglutamyltranspeptidase, which plays an important role in the acquisition of drug resistance to anticancer drugs by tumor cells. New mononuclear iodide n,π-chelate complexes of Pt(II) with substituted thioureas N-allylmorpholine-4-carbothioamide or 3-allyl-1,1-diethylthiourea were obtained as analogs of cisplatin. All compounds were investigated by UV-Vis, IR, and 1H/13С NMR spectra. Complex I was described by single-crystal X-ray diffraction study. Also, the effect of these analogs on alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, which are marker enzymes of liver cells, release of which into the blood indicates liver pathologies, was investigated. All studies were carried out in comparison with chloride n,π-chelate complexes of platinum obtained earlier (however, the effect of these chloride analogs of platinum on enzymes of the hepatobiliary system was investigated for the first time in this work). The results have shown that the studied compounds are better cytostatics/cytotoxics than cisplatin both according to IC50 and apoptosis level of HepG2 cells. It is established that, for the most part, effect of the studied complexes is reduced to a decrease in the degree of malignancy of cells of hepatocyte lines and the activity of LDH and GHT, as well as a decrease in consumed glucose.

Keywords: , , , , , ,

References:

  1. Deo KM, Pages BJ, Ang DL, Gordon CP, Aldrich-Wright JR. Transition Metal Intercalators as Anticancer Agents-Recent Advances. Int J Mol Sci. 2016;17(11):1818. PubMed, CrossRef
  2. Frezza M, Hindo S, Chen D, Davenport A, Schmitt S, Tomco D, Dou QP. Novel metals and metal complexes as platforms for cancer therapy. Curr Pharm Des. 2010;16(16):1813-1825. PubMed, PubMedCentral, CrossRef
  3. Ndagi U, Mhlongo N, Soliman ME. Metal complexes in cancer therapy – an update from drug design perspective. Drug Des Devel Ther. 2017;11:599-616. PubMed, PubMedCentral, CrossRef
  4. Trudu F, Amato F, Vaňhara P, Pivetta T, Peña-Méndez EM, Havel J, Appl J. Coordination compounds in cancer: Past, present and perspectives. J Appl Biomed. 2015;13:79-103. CrossRef
  5. Lazarevic T, Rilak A, Bugarčić ŽD. Platinum, palladium, gold and ruthenium complexes as anticancer agents: Current clinical uses, cytotoxicity studies and future perspectives. Eur J Med Chem. 2017;142:8-31. PubMed, CrossRef
  6. Pattan SR, Pawar SB, Vetal SS, Gharate UD, Bhawar SB. The scope of metal complexes in drug design – A review. Indian Drugs. 2012;49(11):5-12. CrossRef
  7. Martín J, Alés MR, Asuero AG. An overview on ligands of therapeutically interest. Pharm Pharmacol Int J. 2018;6(3):198-214. CrossRef
  8. Selvaganapathy M, Raman N. Pharmacological Activity of a Few Transition Metal Complexes: A Short Review. J Chem Biol Ther. 2016;1(2):108. CrossRef
  9. Tripathi L, Kumar P, Singhai AK. Role of chelates in treatment of cancer. Indian J Cancer. 2007;44(2):62-71. PubMed, CrossRef
  10.  Zuccolo M, Arrighetti N, Perego P, Colombo D. Recent Progresses in Conjugation with Bioactive Ligands to Improve the Anticancer Activity of Platinum Compounds. Curr Med Chem. 2022;29(15):2566-2601. PubMed, CrossRef
  11. Bajracharya R, Song JG, Patil BR, Lee SH, Noh HM, Kim DH, Kim GL, Seo SH, Park JW, Jeong SH, Lee CH, Han HK. Functional ligands for improving anticancer drug therapy: current status and applications to drug delivery systems. Drug Deliv. 2022;29(1):1959-1970. PubMed, PubMedCentral, CrossRef
  12. Kumar V, Chimni SS. Recent developments on thiourea based anticancer chemotherapeutics. Anticancer Agents Med Chem. 2015;15(2):163-175. PubMed, CrossRef
  13. Mohapatra RK, Das PK, Pradhan MK, El-Ajaily MM, Das D, Salem HF, Mahanta U, Badhei G, Parhi PK, Maihub AA, Kudrat-E-Zahan Md. Recent Advances in Urea- and Thiourea-Based Metal Complexes: Biological, Sensor, Optical, and Corroson Inhibition Studies. Comments Inorg Chem. 2019; 39(3):127-187. CrossRef
  14. Fakhar I, Yamin BM, Hasbullah SA. A comparative study of the metal binding behavior of alanine based bis-thiourea isomers. Chem Cent J. 2017;11(1):76. PubMed, PubMedCentral, CrossRef
  15. Saeed A, Flӧrke U, Erben MF. A review on the chemistry, coordination, structure and biological properties of 1-(acyl/aroyl)-3-(substituted) thioureas. J Sulfur Chem. 2014;35(3):318-355. CrossRef
  16. Repich HH, Orysyk VV, Palchykovska LG, Orysyk SI, Zborovskii YuL, Vasylchenko OV, Storozhuk OV, Biluk AA, Nikulina VV, Garmanchuk LV, Pekhnyo VI, Vovk MV. Synthesis, spectral characterization of novel Pd(II), Pt(II) π-coordination compounds based on N-allylthioureas. Cytotoxic properties and DNA binding ability. J Inorg Biochem. 2017;168:98-106. PubMed, CrossRef
  17. Borovyk PV, Orysyk SI, Repich HH, Likhanov AF, Mishchenko AM, Zborovskii YuL, Orysyk VV, Palchikovska LG, Pekhnyo VI, Vovk MV. Spectral characteristics and cytostatic effect of Pd(II) and Pt(II)carbothioamide π-complexes on Allium cepa L meristem cells. Vopr Khim Khim Tekhnol. 2020;(3):34-45. CrossRef
  18. Orysyk SI, Baranets S, Borovyk PV, Palchykovska LG, Zborovskii YuL, Orysyk VV, Likhanov AF, Platonov MO, Kovalskyy DB, Shyryna TV, Danylenko Y, Hurmach VV, Pekhnyo VI, Vovk MV. Mononuclear π-complexes of Pd(II) and Pt(II) with 1-allyl-3-(2-hydroxyethyl)thiourea: Synthesis, structure, molecular docking, DNA binding ability and genotoxic activity. Polyhedron. 2021;210:115477. CrossRef
  19. Orysyk SI, Zborovskii YuL, Orysyk VV, Garmanchuk LV, Borovyk PV, Shishkina SV, Pavliuk O, Pekhnyo VI, Vovk MV. Synthesis, structural and spectral characteristics of novel n,π-chelate complexes of Pd(II) and Pt(II) with N-allylthioureas and their influence on the growth of spheroids cells MCF-7 and GGT activity. Polyhedron. 2023; 231:116272. CrossRef
  20. Bilyuk AA, Storozhuk OV, Kolotiy OV, Repich HH, Orysyk SI, Garmanchuk LV. Pd(II) and Pt(II) complexes influence on spheroids growth of breast cancer cells. Biotechnol Acta. 2017;10(1):61-67. CrossRef
  21. Otto AM. Warburg effect(s)-a biographical sketch of Otto Warburg and his impacts on tumor metabolism. Cancer Metab. 2016;4:5. PubMed, PubMedCentral, CrossRef
  22. Zhou N, He C-X. An improved method of isomolar series by dual-wavelength spectrophotometry. Mikrochim Acta. 1993;111:183-191. CrossRef
  23. Sheldrick GM. A short history of SHELX. Acta Crystallogr A. 2008;64(Pt 1):112-122. PubMed, CrossRef
  24. Ihrke G, Neufeld EB, Meads T, Shanks MR, Cassio D, Laurent M, Schroer TA, Pagano RE, Hubbard AL. WIF-B cells: an in vitro model for studies of hepatocyte polarity. J Cell Biol. 1993;123(6 Pt 2):1761-1775. PubMed, PubMedCentral, CrossRef
  25. Kamalian L, Chadwick AE, Bayliss M, French NS, Monshouwer M, Snoeys J, Park KB. The utility of HepG2 cells to identify direct mitochondrial dysfunction in the absence of cell death. Toxicol In Vitro. 2015;29(4):732-740. PubMed, CrossRef
  26. Vedenicheva NP, Al-Maali GA, Bisko NA, Kosakivska IV, Ostrovska GV, Khranovska NM, Gorbach OI, Garmanchuk LV, Ostapchenko LI. Effect of Cytokinin-Containing Extracts from Some Medicinal Mushroom Mycelia on HepG2 Cells In Vitro. Int J Med Mushrooms. 2021;23(3):15-28. PubMed, CrossRef
  27. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65(1-2):55-63. PubMed, CrossRef
  28. Alley MC, Scudiero DA, Monks PA, Hursey ML, Czerwinski MJ, Fine DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR. Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res. 1988;48(3):589-601. PubMed
  29. Nikolaienko TV, Nikulina VV, Shelest DV, Garmanchuk LV. The mechanism of VEGF-mediated endothelial cells survival and proliferation in conditions of unfed-culture. Ukr Biochem J. 2016;88(4):12-19. PubMed, CrossRef
  30. Kjeld M. An automated colorimetric method for the estimation of lactate dehydrogenase activity in serum. Scand J Clin Lab Invest. 1972;29(4):421-425. PubMed, CrossRef
  31. Friedman RB, Young DS. Effects of disease on clinical laboratory tests, 3rd Edition, AACC Press, Washington, DC 1997.
  32. Reitman S, Frankel S. A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am J Clin Pathol. 1957;28(1):56-63. PubMed, CrossRef
  33. Bergmeyer HU, Hørder M, Rej R. International Federation of Clinical Chemistry (IFCC) Scientific Committee, Analytical Section: approved recommendation (1985) on IFCC methods for the measurement of catalytic concentration of enzymes. Part 2. IFCC method for aspartate aminotransferase (L-aspartate: 2-oxoglutarate aminotransferase, EC 2.6.1.1). J Clin Chem Clin Biochem. 1986;24(7):497-510. PubMed
  34. Schumann G, Bonora R, Ceriotti F, Férard G, Ferrero CA, Franck PFH, Gella FJ, Hoelzel W, Jørgensen PJ. et al. IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37 degrees C. International Federation of Clinical Chemistry and Laboratory Medicine. Part 5. Reference procedure for the measurement of catalytic concentration of aspartate aminotransferase. Clin Chem Lab Med. 2002;40(7):725-733. PubMed, CrossRef
  35. Nicoletti I, Migliorati G, Pagliacci MC, Grignani F, Riccardi C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J Immunol Methods. 1991;139(2):271-279. PubMed, CrossRef
  36. Livingstone SE. The Chemistry of Ruthenium, Rhodium, Palladium, Osmium, Iridium and Platinum, Pergamon text in Inorganic Chemistry, Volume 25, University of New South Wales, 1975.
  37. Zhan H, Hu Y, Wang P, Chen J. Molecular structures of gas-phase neutral morpholine and its monohydrated complexes: experimental and theoretical approaches. RSC Adv. 2017;7:6179-6186. CrossRef
  38. Lever ABP. Inorganic Electronic Spectroscopy. Toronto, Canada, American Elsevier Publishing Co., New York, 1968, p. 420.
  39. Petrov AI, Lutoshkin MA. TD-DFT assessment of UV-vis spectra palladium and platinum complexes with thiols and disulfides. J Mol Model. 2021;27(6):152. PubMed, CrossRef
  40. Pearson RG. Antisymbiosis and the trans effect. Inorg Chem. 1973;12(3):712-713. CrossRef
  41. Badertscher M, Bühlmann P, Pretsch E. Structure Determination Of Organic Compounds. Tables of Spectral Data. Springer-Verlag Berlin Heidelberg, 2009. 433 p. CrossRef
  42. Socrates G. Infrared and Raman Characteristic Group Frequencies. Tables and Charts, Third ed., by John Wiley & Sons Ltd, 2001. p. 347.
  43. Tucureanu V, Matei A, Avram AM. FTIR Spectroscopy for Carbon Family Study. Crit Rev Anal Chem. 2016;46(6):502-520. PubMed, CrossRef
  44. Burns JS, Manda G. Metabolic Pathways of the Warburg Effect in Health and Disease: Perspectives of Choice, Chain or Chance. Int J Mol Sci. 2017;18(12):2755. PubMed, PubMedCentral, CrossRef
  45. Hanigan MH. Gamma-glutamyl transpeptidase: redox regulation and drug resistance. Adv Cancer Res. 2014:122:103-141. PubMed, PubMedCentral, CrossRef
  46. Hanigan MH, Gallagher BC, Townsend DM, Gabarra V. Gamma-glutamyl transpeptidase accelerates tumor growth and increases the resistance of tumors to cisplatin in vivo. Carcinogenesis. 1999;20(4):553-559. PubMed, PubMedCentral, CrossRef
  47. Wang X, Zhang H, Chen X. Drug resistance and combating drug resistance in cancer. Cancer Drug Resist. 2019;2(2):141-160. PubMed, PubMedCentral, CrossRef
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