New 8-Heterocyclic Xanthine Derivatives as Antiproliferative Agents: Synthesis and Biological Evaluation

Yıl 2024, Cilt: 11 Sayı: 2, 533 - 540

Bilgesu Onur Sucu

https://doi.org/10.18596/jotcsa.1340105

Öz

This research focuses on the synthesis, characterization, and evaluation of the anti-cancer activity of novel 8-aryl substituted 1,3-diethylxanthine derivatives. The anti-proliferative activities of all the compounds were assessed using an MTT assay on four human cancer cell lines: breast cancer MCF7, human lung cancer A549, human brain cancers LN229, and U87. One of the derivatives of 1,3-diethylxanthine with a thiazole structure displayed strong anti-proliferative activity. 1,3-Diethyl-8-(thiazol-4-yl)-3,7-dihydro-1H-purine-2,6-dione (5) exhibited the strongest activity against A549, MCF7, LN229, and U87 cell lines, with IC50 values of 16.70, 78.06, 22.07, and 25.07 μM, respectively. Furthermore, the scratch assay was conducted to evaluate the effect of compound 5 on the inhibition of cell migration in A549 cells. The consistent results demonstrate that compound 5 exhibits potent anti-cancer activity, which could be further investigated to enhance its biological potential.

Anahtar Kelimeler

Xanthine, Heterocyclic compounds, Antiproliferative activity, Anti-cancer, MTT

Kaynakça

• 1. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics. CA: A Cancer Journal for Clinicians. 2023 Jan;73(1):17–48. Available from:<URL>
• 2. Ioele G, Chieffallo M, Occhiuzzi MA, De Luca M, Garofalo A, Ragno G, et al. Anticancer Drugs: Recent Strategies to Improve Stability Profile, Pharmacokinetic and Pharmacodynamic Properties. Molecules. 2022 Aug;27(17):5436. Available from:<URL>
• 3. Pal R, Teli G, Matada GSP, Dhiwar PS. Designing strategies, structural activity relationship and biological activity of recently developed nitrogen containing heterocyclic compounds as epidermal growth factor receptor tyrosinase inhibitors. Journal of Molecular Structure. 2023 Nov;1291:136021. Available from:<URL>
• 4. Taruneshwar Jha K, Shome A, Chahat, Chawla PA. Recent advances in nitrogen-containing heterocyclic compounds as receptor tyrosine kinase inhibitors for the treatment of cancer: Biological activity and structural activity relationship. Bioorganic Chemistry. 2023 Sep;138:106680. Available from:<URL> 5. Sharma PC, Bansal KK, Sharma A, Sharma D, Deep A. Thiazole-containing compounds as therapeutic targets for cancer therapy. European Journal of Medicinal Chemistry. 2020 Feb;188:112016. Available from:<URL> 6. Roy A, Kumar Bahe A, Chanderiya A, Dangi H, Mishra P, Mishra AK, et al. Synthesis of Nitrogen-and Oxygen-Containing Heterocyclic Compounds Using Nanocatalyst: A Review. Journal of the Turkish Chemical Society Section A: Chemistry. 2021 Aug;8(3):851-862. Available from:<URL>
• 7. Persson C. Development of safer xanthine drugs for treatment of obstructive airways disease. Journal of Allergy and Clinical Immunology. 1986 Oct;78(4):817–24. Available from:<URL>
• 8. Persson CGA, Kjellin G. Enprofylline, a Principally New Antiasthmatic Xanthine. Acta Pharmacol Toxicol (Copenh). 1981 Oct;49:313-316. Available from:<URL> 9. Müller CE, Jacobson KA. Xanthines as Adenosine Receptor Antagonists. Handbook of Experimental Pharmacology. 2011 200:151-99. Available from:<URL>
• 10. Hayallah AM, Elgaher WA, Salem OI, Abdel Alim AAM. Design and synthesis of some new theophylline derivatives with bronchodilator and antibacterial activities. Archives of Pharmacal Research. 2011 Jan;34(1):3–21. Available from:<URL> 11. Singh N, Kumar Shreshtha A, Thakur MS, Patra S. Xanthine scaffold: scope and potential in drug development. Heliyon. 2018 Sep;4:829. Available from:<URL>
• 12. Bhat VB, Madyastha KM. Antioxidant and radical scavenging properties of 8-oxo derivatives of xanthine drugs pentoxifylline and lisofylline. Biochemical and Biophysical Research Communications. 2001 Nov;288(5):1212–7. Available from:<URL>
• 13. Sierakowska A, Jasiewicz B, Piosik Ł, Mrówczyńska L. New C8-substituted caffeine derivatives as promising antioxidants and cytoprotective agents in human erythrocytes. Scientific Reports. 2023 Dec 1;13(1): 1785. Available from:<URL>
• 14. Hisham M, Youssif BGM, Osman EEA, Hayallah AM, Abdel-Aziz M. Synthesis and biological evaluation of novel xanthine derivatives as potential apoptotic antitumor agents. European Journal of Medicinal Chemistry. 2019 Aug;176:117–28. Available from:<URL>
• 15. Kalla R V., Zablocki J. Progress in the discovery of selective, high affinity A2B adenosine receptor antagonists as clinical candidates. Purinergic Signalling. 2009 Mar;5:21–9. Available from:<URL>
• 16. Sun CX, Zhong H, Mohsenin A, Morschl E, Chunn JL, Molina JG, et al. Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury. Journal of Clinical Investigation. 2006 Aug;116(8):2173–82. Available from:<URL>
• 17. Hayallah AM, Elgaher WA, Salem OI, Abdel Alim AAM. Design and synthesis of some new theophylline derivatives with bronchodilator and antibacterial activities. Archives of Pharmacal Research. 2011 Jan;34(1):3–21. Available from:<URL>
• 18. Yasui K, Komiyama A. New clinical applications of xanthine derivatives: Modulatory actions on leukocyte survival and function. International Journal of Hematology. 2001 Jan;73(1):87–92. Available from:<URL>
• 19. Onan D, Güven Um, Demirtürk E, Çevikelli T. Preparation, characterization and in-vitro evaluation of theophylline loaded microemulsion formulations. Journal of Pharmaceutical Technolgy. 2020 Apr;1(1):7–12. Available from:<URL>
• 20. Mentz F, Mossalayi M, Ouaaz F, Baudet S, Issaly F, Ktorza S, et al. Theophylline synergizes with chlorambucil in inducing apoptosis of B- chronic lymphocytic leukemia cells. Blood. 1996 Sep;88(6):2172–82. Available from:<URL>
• 21. Xu H, Wang L, Shi B, Hu L, Gan C, Wang Y, et al. Caffeine inhibits the anticancer activity of paclitaxel via down-regulation of α-tubulin acetylation. Biomedicine and Pharmacotherapy. 2020 Sep;129:110441. Available from:<URL>
• 22. Tilaoui M, Ait Mouse H, Zyad A. Update and New Insights on Future Cancer Drug Candidates From Plant-Based Alkaloids. Frontiers in Pharmacology. 2021 Dec;12. Available from:<URL>
• 23. Sinn B, Tallen G, Schroeder G, Grassl B, Schulze J, Budach V, et al. Caffeine confers radiosensitization of PTEN-deficient malignant glioma cells by enhancing ionizing radiation-induced G1 arrest and negatively regulating akt phosphorylation. Molecular Cancer Therapeutics. 2010 Feb;9(2):480–8. Available from:<URL>
• 24. Tokusoglu O. Food and Beverage Methylxanthines, Glycoalkaloids, Pyrolizidines and Phenolic Alkaloids: Processing Effects. Journal of Food Health and Technology Innovations. 2019 Sep;2(5):130-133.
• 25. Hisham M, Youssif BGM, Osman EEA, Hayallah AM, Abdel-Aziz M. Synthesis and biological evaluation of novel xanthine derivatives as potential apoptotic antitumor agents. European Journal of Medicinal Chemistry. 2019 Aug;176:117–28. Available from:<URL>
• 26. Yadav K, Yadav D, Bhandari DD, Yadav R. Identification of 1,3-(Dimethyl / Propyl)-8-Susbtituted (Cinnamic acid/Furan) Xanthine Derivatives with Anti-bronchospasmodic Activity Using in silico and in vivo Techniques. ChemistrySelect. 2022 May;7(17). Available from:<URL>
• 27. Kadi AA, El-Tahir KEH, Jahng Y, Rahman AFMM. Synthesis, biological evaluation and Structure Activity Relationships (SARs) study of 8-(substituted)aryloxycaffeine. Arabian Journal of Chemistry. 2019 Dec;12(8):2356–64. Available from:<URL>
• 28. Van Der Walt MM, Terre’Blanche G. 1,3,7-Triethyl-substituted xanthines - Possess nanomolar affinity for the adenosine A1 receptor. Bioorganic & Medicinal Chemistry. 2015 Oct;23(20):6641–9. Available from:<URL>
• 29. Baraldi PG, Fruttarolo F, Tabrizi MA, Romagnoli R, Preti D. Novel 8-heterocyclyl xanthine derivatives in drug development - an update. Expert Opinion on Drug Discovery. 2007 Sep;2(9):1161-83. Available from:<URL>
• 30. Van Der Walt MM, Terre’Blanche G, Petzer A, Lourens ACU, Petzer JP. The adenosine A2A antagonistic properties of selected C8-substituted xanthines. Bioorganic Chemistry. 2013 July;49:49–58. Available from:<URL>
• 31. Demiral A, Verimli N, Goralı Sİ, Yılmaz H, Çulha M, Erdem SS. A Rational design of multi-functional nanoplatform: Fluorescent-based “off-on” theranostic gold nanoparticles modified with D-α-Tocopherol succinate. Journal of Photochemistry and Photobiology B: Biology. 2021 Sep;222:112261.
• 32. Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports. 2017 Mar;7:42717. Available from:<URL>
• 33. Walters WP. Going further than Lipinski’s rule in drug design. Expert Opinion on Drug Discovery. 2012 Jan;7:99–107. Available from:<URL>