Synthesis and Characterization of New Shiff Bases Containing N-Benzylethylenediamine Unit and Determination of Their Cytotoxic Effects on Human Colon Cancer Cells

Abstract

In this study, three new Schiff bases were synthesized as a result of the condensation reaction of N-benzyl ethylene diamine and 2-Hydroxy-5-methylbenzaldehyde, 2-Hydroxy-5-methylacetophenone, 2-Hydroxy-5-chloroacetophenone compounds (L1, L2 and L3). The structures of the newly synthesized compounds were characterized by 1H NMR, 13C NMR, FT-IR and elemental analysis methods. Next, the cytotoxic activities of the obtained compounds were investigated using human colon cancer cell lines (Caco-2, colon and HT-29 colon carcinoma cell lines). The results obtained were compared with the standard chemotherapy drug 5-Fluorouracil (5-FU). According to cytotoxicity results, L2 compound was found to have the highest anticancer activity in Caco-2 (column) and HT-29 (column) cell lines.

Keywords

• Schiff base
• N-benzylethylenediamine
• Anticancer activity

N-Benziletilendiamin Birimi İçeren Yeni Shiff Bazlarının Sentezi, Karakterizasyonu ve İnsan Kolon Kanseri Hücreleri Üzerine Sitotoksik Etkilerinin Belirlenmesi

Öz

Bu çalışmada N-benziletilendiamin ile 2-Hidroksi-5-metilbenzaldehit, 2-Hidroksi-5-metilasetofenon, 2-Hidroksi-5-kloroasetofenon bileşiklerinin kondenzasyon reaksiyonu sonucu üç yeni Schiff bazı sentezlendi (L1, L2 ve L3). Sentezlenen yeni bileşiklerin yapıları, 1H NMR, 13C NMR, FT-IR ve elemental analiz yöntemleri ile karakterize edildi. Daha sonra, elde edilen bileşiklerin sitotoksik aktiviteleri, insan kolon kanser hücre dizisi (Caco-2, kolon ve HT-29 kolon karsinoma hücre dizisi) kullanılarak araştırıldı. Elde edilen sonuçlar standart kemoterapi ilacı 5-Fluorourasil (5-FU) ile karşılaştırıldı. Sitotoksisite sonuçlarına göre L2 bileşiğinin Caco-2 (kolon) ve HT-29 (kolon) hücre hatlarında en yüksek antikanser aktiviteye sahip olduğu bulundu.

Anahtar Kelimeler

• Schiff bazı
• N-benziletilendiamin
• Antikanser aktivite

Kaynakça

1. [1] Patai S., Chemistry of the carbon-nitrogen double bond, John Wiley & Sons, NY, USA, 1970.
2. [2] Abu-Dief A.M., Mohamed I.M.A., A review on versatile applications of transition metal complexes incorporating Schiff bases, Beni Suef Univ J Basic Appl Sci. 2015;4:(2)119-133.
3. [3] Vigato P.A., Tamburini S., The challenge of cyclic and acyclic schiff bases and related derivatives, Coordination Chemistry Reviews. 2004;248:(17) 1717-2128.
4. [4] More M.S., Joshi P.G., Mishra Y.K., Khanna P.K., Metal complexes driven from Schiff bases and semicarbazones for biomedical and allied applications: a review, Mater Today Chem. 2019; 14:100195.
5. [5] Sharaby C.M., Amine M.F., Hamed A.A., Synthesis, structure characterization and biological activity of selected metal complexes of sulfonamide Schiff base as a primary ligand and some mixed ligand complexes with glycine as a secondary ligand, Journal of Molecular Structure. 2017; 1134: 208-216.
6. [6] Roberts D.W., Schultz T.W., Api A.M., Skin Sensitization QMM for HRIPT NOEL Data: Aldehyde Schiff-Base Domain, Chemical research in toxicology. 2017; 30:(6) 1309-1316.
7. [7] Redshaw C., Use of Metal Catalysts Bearing Schiff Base Macrocycles for the Ring Opening Polymerization (ROP) of Cyclic Esters, Catalysts. 2017;7:(5) 165.
8. [8] R.J. DiRisio, Armstrong J.E., Frank M.A., Lake W.R., McNamara W.R., Cobalt Schiff-base complexes for electrocatalytic hydrogen generation, Dalton Transactions. 2017; 46:(31) 10418-10425.

9. [9] Berhanu A.L., Gaurav, I. Mohiuddin, A.K. Malik, J.S. Aulakh, V. Kumar, K.H. Kim, A review of the applications of Schiff bases as optical chemical sensors, TrAC Trends in Analytical Chemistry. 2019;116: 74-91.
10. [10] da Silva C.M., da Silva D.L., Modolo L.V., Alves R.B., de Resende M.A., Martins C.V.B., de Fátima Â., Schiff bases: A short review of their antimicrobial activities, Journal of Advanced Research. 2011;2:(1) 1-8.
11. [11] Müller I.M., Spillmann S., Franck H., Pietschnig R., Rational Design of the First Closed Coordination Capsule with Octahedral Outer Shape, Chemistry – A European Journal. 2004;10:(9): 2207-2213.
12. [12] Abdel Aziz A.A., Seda S.H., Synthesis, structural features and biochemical activity assessment of N,N‐bis‐(2‐mercaptophenylimine)‐2,5‐thiophene dicarboxaldehyde Schiff base and its Co(II), Ni(II), Cu(II) and Zn(II) complexes, Applied Organometallic Chemistry. 2017;31: 3879.
13. [13] Deswal Y., Asija S., Tufail A., Dubey A., Deswal, L. Kumar N., Gupta N.M., Instigating the in vitro antidiabetic activity of new tridentate Schiff base ligand appended M(II) complexes: From synthesis, structural characterization, quantum computational calculations to molecular docking, and molecular dynamics simulation studies Applied Organometallic Chemistry. 2023;37: (4) 7050.
14. [14] Deswal Y., Asija S., Dubey A., Deswal L., Kumar D., Jindal D.K., Devi J., Cobalt(II), nickel(II), copper(II) and zinc(II) complexes of thiadiazole based Schiff base ligands: Synthesis, structural characterization, DFT, antidiabetic and molecular docking studies, Journal of Molecular Structure. 2022;1253: 132266.
15. [15] Deswal Y., Asija S., Kumar D., Jindal D.K., Chandan G., Panwar V., Kumar N., Transition metal complexes of triazole-based bioactive ligands: synthesis, spectral characterization, antimicrobial, anticancer and molecular docking studies, Research on Chemical Intermediates. 2022; 48: 703-729.
16. [16] Agarwal P., Asija S., Deswal Y., Kumar N., Recent advancements in the anticancer potentials of first row transition metal complexes Journal of the Indian Chemical Society. 2022;99: 100556.
17. [17] Hajra S., Ghosh R., Chakrabarti S., Ghosh A., Dutta S., Dey T.K., Basu S., Rhodium‐Catalyzed Enantioselective Conjugate Addition of Arylboronic Acids to Dihydronitronaphthalenes, Advanced Synthesis & Catalysis. 2012; 354: 2433-2437.
18. [18] Prakash A., Adhikari D., Application of Schiff bases and their metal complexes-A Review, International Journal of ChemTech Research. 2011; 3:(4) 1891-1896.
19. [19] Krishnamoorthy P., Sathyadevi P., Muthiah P.T., Dharmaraj N., Nickel and cobalt complexes of benzoic acid (2-hydroxy-benzylidene)-hydrazide ligand: synthesis, structure and comparative in vitro evaluations of biological perspectives, RSC Advances. 2012; 2:(32) 12190-12203.
20. [20] Alagesan M., Sathyadevi P., Krishnamoorthy P., Bhuvanesh N., Dharmaraj N., DMSO containing ruthenium (II) hydrazone complexes: in vitro evaluation of biomolecular interaction and anticancer activity, Dalton Transactions, 43(42) (2014) 15829-15840.
21. [21] Aslam M.A.S., Mahmood S., Shahid M., Saeed A., Iqbal J., Synthesis, biological assay in vitro and molecular docking studies of new Schiff base derivatives as potential urease inhibitors, European Journal of Medicinal Chemistry. 2011; 46:(11): 5473-5479.
22. [22] Liu Y.T., Sheng J., Yin D.W., Xin H., Yang X.M., Qiao Q.Y., Yang Z.J., Ferrocenyl chalcone-based Schiff bases and their metal complexes: Highly efficient, solvent-free synthesis, characterization, biological research, Journal of Organometallic Chemistry. 2018;856: 27-33.
23. [23] Koeffler H.P., McCormick F., Denny C., Molecular mechanisms of cancer, The Western Journal of Medicine. 1991; 155:(5): 505-14.
24. [24] Pereira C., Leão M., Soares J., Bessa C., Saraiva L., New Therapeutic Strategies for Cancer and Neurodegeneration Emerging from Yeast Cell-based Systems, Current Pharmaceutical Design. 2012; 18:(27):4223-4235.
25. [25] Ferlay J., Colombet M., Soerjomataram I., Parkin D. M., Piñeros, M., Znaor A., Bray F., Cancer statistics for the year 2020: An overview, International Journal of Cancer, 2021;149: 778-789.
26. [26] Feng S.S., Chien S., Chemotherapeutic engineering: application and further development of chemical engineering principles for chemotherapy of cancer and other diseases, Chemical Engineering Science. 2003;58: 4087-4114.
27. [27] Sibel K. 2013. (New-Generation Metallocene Catalysts for Olefin Polymerization, Doktora Tezi, İstanbul Teknik Üniversitesi Fen Bilimleri Enstitüsü, İstanbul.
28. [28] Mosmann T., Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays, Journal of Immunological Methods. 1983; 65:55-63.
29. [29] Tadele K.T., Tsega T.W., Anti-Cancer Agents in Medicinal Chemistry. 2019; 19:(15):1786-1795.
30. [30] Savcı A., Buldurun K., Alkış M.E., Alan Y., Turan N., Synthesis, characterization, antioxidant and anticancer activities of a new Schiff base and its M(II) complexes derived from 5-fluorouracil, Medical Oncology. 2022; 39: 172.
31. [31] Shi S., Yu S., Quan L., Mansoor M., Chen Z., Hu H., Liu D., Liang Y., Liang F., Synthesis and antitumor activities of transition metal complexes of a bis-Schiff base of 2-hydroxy-1-naphthalenecarboxaldehyde, Journal of Inorganic Biochemistry. 2020;210 111173