Abstract
Aim: To determine the anticancer and antioxidant activity levels of the synthesized heterocyclic molecule named 1-benzyl-1-(2- methyl-3-oxo-3-(p-tolyl)propyl) piperidin-1-ium chloride.
Methods: The molecule 1-benzyl-1-(2-methyl-3-oxo-3-(p-tolyl) propyl)piperidin-1-ium chloride was synthesized solvent-free via microwave synthesis. Piperidine purification involved dichloromethane extraction with 2 M HCl, followed by 5% NaHCO3 and precipitation with n-hexane. Anticancer activity on A549 lung cancer cells was assessed using the MTT assay. Antioxidant activity was evaluated by DPPH and CUPRAC methods at five concentrations (250-15.6 µM), with ascorbic acid as a control.
Results: The heterocyclic molecule dissolved in PBS was tested for anticancer activity on A549 cells at concentrations ranging from 6.25 to 100 µM. Cytotoxicity was highest at 66.90% for 100 µM and decreased to 5.57% at 6.25 µM, with an IC50 of 32.43 µM. In DPPH assays, the absorbance for AscA varied from 1.263±0.057 to 0.675±0.093, while the piperidine molecule ranged from 1.339±0.044 to 1.072±0.120. In CUPRAC assays, AscA absorbance was 0.227±0.052 and 1.768±0.176, and for the piperidine molecule, it was 0.132±0.042 and 0.142±0.031.
Conclusion: Piperidine is considered a saturated heterocyclic ring and possesses a wide range of biological activities. In this study, it was observed that the synthesized piperidine molecule showed limited DPPH radical scavenging activity. It also showed a high level of cytotoxic effect on A549 cancer cells and could be an important molecule for anticancer studies.
Keywords: antioxidant activity, cancer, cytotoxicity, drug synthesis
Copyright and license
Copyright © 2025 The Author(s). This is an open-access article published by Bolu İzzet Baysal Training and Research Hospital under the terms of the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is properly cited.
How to cite
References
- Karakan M, Nazlıkul H. Oxidative stress and free radicals effect on the body. Bilimsel Tamamlayıcı Tıp Regülasyon ve Nöral Terapi Dergisi. 2017; 11(2): 7-11.
- Karabulut H, Gülay MŞ. Free radicals. Mehmet Akif Ersoy University Journal of Health Sciences Institute. 2016; 4(1): 50-9.
- Snezhkina AV, Kudryavtseva AV, Kardymon OL, et al. ROS Generation and Antioxidant Defense Systems in Normal and Malignant Cells. Oxid Med Cell Longev. 2019; 2019: 6175804. https://doi.org/10.1155/2019/6175804
- Gupta D. Methods for determination of antioxidant capacity: A review. Int J Pharm Sci Res. 2015; 6(2): 546-66.
- Pistritto G, Trisciuoglio D, Ceci C, Garufi A, D'Orazi G. Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies. Aging (Albany NY). 2016; 8(4): 603-19. https://doi.org/10.18632/aging.100934
- Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011; 147(2): 275-92. https://doi.org/10.1016/j.cell.2011.09.024
- Bayat Mokhtari R, Homayouni TS, Baluch N, et al. Combination therapy in combating cancer. Oncotarget. 2017; 8(23): 38022-43. https://doi.org/10.18632/oncotarget.16723
- Walter FM, Rubin G, Bankhead C, et al. Symptoms and other factors associated with time to diagnosis and stage of lung cancer: a prospective cohort study. Br J Cancer. 2015; 112(Suppl 1): S6-13. https://doi.org/10.1038/bjc.2015.30
- Guan X. Cancer metastases: challenges and opportunities. Acta Pharm Sin B. 2015; 5(5): 402-18. https://doi.org/10.1016/j.apsb.2015.07.005
- Ganesh K, Massagué J. Targeting metastatic cancer. Nat Med. 2021; 27(1): 34-44. https://doi.org/10.1038/s41591-020-01195-4
- Ashrafi A, Akter Z, Modareszadeh P, et al. Current Landscape of Therapeutic Resistance in Lung Cancer and Promising Strategies to Overcome Resistance. Cancers (Basel). 2022; 14(19): 4562. https://doi.org/10.3390/cancers14194562
- Mitra S, Anand U, Jha NK, et al. Anticancer Applications and Pharmacological Properties of Piperidine and Piperine: A Comprehensive Review on Molecular Mechanisms and Therapeutic Perspectives. Front Pharmacol. 2022; 12: 772418. https://doi.org/10.3389/fphar.2021.772418
- Manjusha RK, Begum S, Begum A, Bharathi K. Antioxidant potential of piperidine containing compounds - a short review. Asian Journal of Pharmaceutical and Clinical Research. 2018; 11(8): 66-73. https://doi.org/10.22159/ajpcr.2018.v11i8.26536
- Haq IU, Imran M, Nadeem M, Tufail T, Gondal TA, Mubarak MS. Piperine: A review of its biological effects. Phytother Res. 2021; 35(2): 680-700. https://doi.org/10.1002/ptr.6855
- Frolov NA, Vereshchagin AN. Piperidine Derivatives: Recent Advances in Synthesis and Pharmacological Applications. Int J Mol Sci. 2023; 24(3): 2937. https://doi.org/10.3390/ijms24032937
- Trnka J, Blaikie FH, Logan A, Smith RAJ, Murphy MP. Antioxidant properties of MitoTEMPOL and its hydroxylamine. Free Radic Res. 2009; 43(1): 4-12. https://doi.org/10.1080/10715760802582183
- Goel P, Alam O, Naim MJ, Nawaz F, Iqbal M, Alam MI. Recent advancement of piperidine moiety in treatment of cancer- A review. Eur J Med Chem. 2018; 157: 480-502. https://doi.org/10.1016/j.ejmech.2018.08.017
- Horáková K, Sovcíková A, Seemannová Z, et al. Detection of drug-induced, superoxide-mediated cell damage and its prevention by antioxidants. Free Radic Biol Med. 2001; 30(6): 650-64. https://doi.org/10.1016/s0891-5849(00)00508-6
- Denizot F, Lang R. Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J Immunol Methods. 1986; 89(2): 271-7. https://doi.org/10.1016/0022-1759(86)90368-6
- Şahna KÖ. Investigation of the effects of protein hydrolysates obtained from goat milk on MCF-7 breast cancer cells [master's thesis]. Marmara University; 2019.
- Blois MS. Antioxidant determinations by the use of a stable free radical. Nature. 1958; 181: 1199-200. https://doi.org/10.1038/1811199a0
- Benaka Prasad SB, Vinaya K, Ananda Kumar CS, Swarup S, Rangappa KS. Synthesis and in vitro antiproliferative activity of diphenyl(sulphonylpiperidin-4-yl)methanol derivatives. Med Chem Res. 2010; 19(3): 220-35. https://doi.org/10.1007/s00044-009-9186-8
- Bezerra DP, Pessoa C, de Moraes MO, et al. Antiproliferative effects of two amides, piperine and piplartine, from Piper species. Z Naturforsch C J Biosci. 2005; 60(7-8): 539-43. https://doi.org/10.1515/znc-2005-7-805
- Vinaya K, Kavitha CV, Chandrappa S, Prasanna DS, Raghavan SC, Rangappa KS. Synthesis and antileukemic activity of novel 4-(3-(piperidin-4-yl) propyl)piperidine derivatives. Chem Biol Drug Des. 2011; 78(4): 622-30. https://doi.org/10.1111/j.1747-0285.2011.01184.x
- Lahmidi S, Anouar EH, El Hafi M, et al. Synthesis, structural elucidation, and antioxidant activity of new phenolic derivatives containing piperidine moiety: Experimental and theoretical investigations. J Heterocycl Chem. 2021; 58(6): 1268-77. https://doi.org/10.1002/jhet.4253
- Prashanth MK, Revanasiddappa HD, Lokanatha Rai KM, Veeresh B. Synthesis, characterization, antidepressant and antioxidant activity of novel piperamides bearing piperidine and piperazine analogues. Bioorg Med Chem Lett. 2012; 22(23): 7065-70. https://doi.org/10.1016/j.bmcl.2012.09.089
- Karaman N, Sıcak Y, Taşkın-Tok T, et al. New piperidine-hydrazone derivatives: Synthesis, biological evaluations and molecular docking studies as AChE and BChE inhibitors. Eur J Med Chem. 2016; 124: 270-83. https://doi.org/10.1016/j.ejmech.2016.08.037