Synthesis, Characterization, and Cytotoxic Activities of a Schiff Base Ligand and Its Binuclear Copper(II) and Manganese(III) Complexes

Abstract

A novel symmetrical N2O2 type Schiff base (1) and its copper (II) (2) and manganese (III) (3) complexes were synthesized and characterized by spectroscopic, analytical, and magnetic susceptibility studies. Spectroscopic and magnetic susceptibility studies suggested that copper and manganese ions are in 2+ and 3+ states and their complexes have a binuclear double stranded helical structure in the form of 2:2 (metal to ligand) stoichiometry. Cytotoxic effects of the ligand and its metal complexes against MCF-7 (human breast cancer cell line), DLD-1 (human colorectal cancer cell line), ECC-1 (human endometrium cancer cell line), DU-145 (human prostate cancer line), MDA-MB231 (human breast cancer cell line), PC-3 (human prostate cancer line) and HEK293 (normal cells) were evaluated by determining their cellular viability using the colorimetric 3-(4,5- dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) assay. It has been found that cytotoxicity of the ligand was significantly enhanced towards cancer cells and declined towards normal HEK293 cells by metal chelation. Copper complex yielded better results in comparison with manganese complex. Particularly, copper complex showed a selective cytotoxicity, harming the cancerous cell lines while not impairing the normal cells, which is considered as the key to the future of cytotoxic therapy.

Keywords

• N2O2 Schiff base
• transition metal complexes
• binuclear complexes
• selective cytotoxicity
• metal chelation

References

1. 1. Schiff H. Mittheilungen aus dem Universitätslaboratorium in Pisa: eine neue Reihe organischer Basen. Justus Liebigs Annalen der Chemie. 1864 Jan 1;131(1):118-9.
2. 2. Luo XF, Hu X, Zhao XY, Goh SH, Li XD. Miscibility and interactions in blends and complexes of poly (4-methyl-5-vinylthiazole) with proton-donating polymers. Polymer. 2003 Aug 31;44(18):5285-91.
3. 3. Stryer L. Biochemistry, 4th Ed. New York: W H Freeman & Co; 1995.
4. 4. Baumgrass R, Weiwad M, Erdmann F, Liu JO, Wunderlich D, Grabley S, Fischer G. Reversible inhibition of calcineurin by the polyphenolic aldehyde gossypol. Journal of Biological Chemistry. 2001 Dec 21;276(51):47914-21.
5. 5. Pfeiffer P, Breith E, Lűbbe E, Tsumaki T. Tricyclic ortho-condensed partial valence rings. Justus Liebigs Ann Chem. 1933;503:84-130.
6. 6. Hernández-Molina R, Mederos A. 1.19 - Acyclic and Macrocyclic Schiff Base Ligands. In: Meyer TJ, McCleverty JA, editors. Comprehensive Coordination Chemistry II. Oxford: Pergamon; 2003. p. 411-46.
7. 7. Andruh M, Tuna F. Organic Chemistry for Inorganic Chemists. Unsymmetrical Schiff-Bases Derived from 3-Formyl-Salycilic Acid as Versatile Ligands in Coordination Chemistry. In: Cato MA, editor. Focus on Organometallic Chemistry Research. Hauppauge, New York: Nova Science Publishers; 2005. p. 144-66.
8. 8. Rosu T, Pahontu E, Ilies DC, Georgescu R, Mocanu M, Leabu M, Shova S, Gulea A. Synthesis and characterization of some new complexes of Cu (II), Ni (II) and V (IV) with Schiff base derived from indole-3-carboxaldehyde. Biological activity on prokaryotes and eukaryotes. European journal of medicinal chemistry. 2012 Jul 31;53:380-9.

9. 9. Sinha D, Tiwari AK, Singh S, Shukla G, Mishra P, Chandra H, Mishra AK. Synthesis, characterization and biological activity of Schiff base analogues of indole-3-carboxaldehyde. European journal of medicinal chemistry. 2008 Jan 31;43(1):160-5.
10. 10. Shukla G, Tiwari AK, Sinha D, Srivastava R, Cahndra H, Mishra AK. Synthesis and assessment of 99mTc chelate-conjugated alendronate for development of specific radiopharmaceuticals. Cancer Biotherapy and Radiopharmaceuticals. 2009 Apr 1;24(2):209-14.
11. 11. Vicini P, Geronikaki A, Incerti M, Busonera B, Poni G, Cabras CA, et al. Synthesis and biological evaluation of benzo [d] isothiazole, benzothiazole and thiazole Schiff bases. Biorg Med Chem. 2003;11(22):4785-9.
12. 12. Eckhardt S. Recent progress in the development of anticancer agents. Curr Med Chem Anticancer Agents. 2002;2(3):419-39.
13. 13. Sierra JR, Cepero V, Giordano S. Molecular mechanisms of acquired resistance to tyrosine kinase targeted therapy. Molecular cancer. 2010 Apr 12;9(1):75.
14. 14. Qin DD, Yang ZY, Zhang FH, Du B, Wang P, Li TR. Evaluation of the antioxidant, DNA interaction and tumor cell cytotoxicity activities of Copper (II) complexes with Paeonol Schiff-base. Inorganic Chemistry Communications. 2010 Jun 30;13(6):727-9.
15. 15. Sampath K, Sathiyaraj S, Jayabalakrishnan C. DNA binding, DNA cleavage, antioxidant and cytotoxicity studies on ruthenium (II) complexes of benzaldehyde 4-methyl-3-thiosemicarbazones. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 2013 Mar 15;105:582-92.
16. 16. Sampath K, Sathiyaraj S, Jayabalakrishnan C. Evaluation of DNA-binding, DNA cleavage, antioxidant and cytotoxic activity of mononuclear ruthenium (II) carbonyl complexes of benzaldehyde 4-phenyl-3-thiosemicarbazones. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 2013 Nov 30;115:287-96.
17. 17. Aly MR, Fodah HH, Saleh SY. Antiobesity, antioxidant and cytotoxicity activities of newly synthesized chalcone derivatives and their metal complexes. European journal of medicinal chemistry. 2014 Apr 9;76:517-30.
18. 18. Lee SM, Ali HM, Sim KS, Malek SN, Lo KM. Synthesis, characterization and biological activity of diorganotin complexes with ONO terdentate Schiff base. Inorganica Chimica Acta. 2013 Sep 1;406:272-8.
19. 19. Naseri Z, Kharat AN, Banavand A, Bakhoda A, Foroutannejad S. First row transition metal complexes of thienyl substituted terpyridine: Structural, photophysical and biological studies. Polyhedron. 2012 Feb 9;33(1):396-403.
20. 20. Zhao X, Loo SC, Lee PP, Tan TT, Chu CK. Synthesis and cytotoxic activities of chloropyridylimineplatinum (II) and chloropyridyliminecopper (II) surface-functionalized poly (amidoamine) dendrimers. Journal of inorganic biochemistry. 2010 Feb 28;104(2):105-10.
21. 21. Sathiyaraj S, Sampath K, Raja G, Butcher RJ, Gupta SK, Jayabalakrishnan C. DNA binding/cleavage, antioxidant and cytotoxic activities of water soluble cobalt (II) and copper (II) antipyrine complexes. Inorganica Chimica Acta. 2013 Sep 1;406:44-52.
22. 22. Khoo TJ, bin Break MK, Crouse KA, Tahir MI, Ali AM, Cowley AR, Watkin DJ, Tarafder MT. Synthesis, characterization and biological activity of two Schiff base ligands and their nickel (II), copper (II), zinc (II) and cadmium (II) complexes derived from S-4-picolyldithiocarbazate and X-ray crystal structure of cadmium (II) complex derived from pyridine-2-carboxaldehyde. Inorganica Chimica Acta. 2014 Mar 24;413:68-76.
23. 23. Chaves JD, Neumann F, Francisco TM, Corrêa CC, Lopes MT, Silva H, Fontes AP, de Almeida MV. Synthesis and cytotoxic activity of gold (I) complexes containing phosphines and 3-benzyl-1, 3-thiazolidine-2-thione or 5-phenyl-1, 3, 4-oxadiazole-2-thione as ligands. Inorganica Chimica Acta. 2014 Apr 1;414:85-90.
24. 24. Kovala-Demertzi D, Staninska M, Garcia-Santos I, Castineiras A, Demertzis MA. Synthesis, crystal structures and spectroscopy of meclofenamic acid and its metal complexes with manganese (II), copper (II), zinc (II) and cadmium (II). Antiproliferative and superoxide dismutase activity. Journal of inorganic biochemistry. 2011 Sep 30;105(9):1187-95.
25. 25. Cucos P, Tuna F, Sorace L, Matei I, Maxim C, Shova S, Gheorghe R, Caneschi A, Hillebrand M, Andruh M. Magnetic and luminescent binuclear double-stranded helicates. Inorganic chemistry. 2014 Jul 7;53(14):7738-47.
26. 26. Hasi QM, Fan Y, Yao XQ, Hu DC, Liu JC. Synthesis, characterization, antioxidant and antimicrobial activities of a bidentate Schiff base ligand and its metal complexes. Polyhedron. 2016 Apr 18;109:75-80.
27. 27. Mondal AK, Parmar VS, Biswas S, Konar S. Tetrahedral M II based binuclear double-stranded helicates: single-ion-magnet and fluorescence behaviour. Dalton Transactions. 2016;45(11):4548-57.
28. 28. A. Earnshaw, Introduction to Magnetochemistry, Academic Press, London, 1968, p. 4.
29. 29. Arslan F, Odabaşoğlu M, Ölmez H, Büyükgüngör O. Synthesis, crystal structure, spectral and thermal characterization of bis (o-vanillinato)-triethylenglycoldiiminecopper (II) and bis [(R)-(−)-hydroxymethylpropylimine o-vanillinato] copper (II). Polyhedron. 2009 Sep 23;28(14):2943-8.
30. 30. Liu SB, Bi CF, Fan YH, Zhao Y, Zhang PF, Luo QD, Zhang DM. Synthesis, characterization and crystal structure of a new fluorescent probe based on Schiff Base for the detection of Zinc (II). Inorganic Chemistry Communications. 2011 Aug 31;14(8):1297-301.
31. 31. Ejidike IP, Ajibade PA. Synthesis, characterization and biological studies of metal (II) complexes of (3E)-3-[(2-{(E)-[1-(2, 4-dihydroxyphenyl) ethylidene] amino} ethyl) imino]-1-phenylbutan-1-one Schiff base. Molecules. 2015 May 27;20(6):9788-802.
32. 32. Yaftian MR, Rayati S, Safarbali R, Torabi N, Khavasi HR. A new tetradentate N2O2-type Schiff base ligand. Synthesis, extractive properties towards transition metal ions and X-ray crystal structure of its nickel complex. Transition Metal Chemistry. 2007 Mar 27;32(3):374-8.
33. 33. Shelke VA, Jadhav SM, Patharkar VR, Shankarwar SG, Munde AS, Chondhekar TK. Synthesis, spectroscopic characterization and thermal studies of some rare earth metal complexes of unsymmetrical tetradentate Schiff base ligand. Arabian Journal of Chemistry. 2012 Oct 31;5(4):501-7.
34. 34. Xinde Z, Chenggang W, Zhiping L, Zhifeng L, Zishen W. Synthesis and Biological Activity of the Schiff Base N, N′-bis (Salicylidene) thiourea and Its Complexes of Copper (II), Nickel (II) and Zinc (II). Synthesis and Reactivity in Inorganic and Metal-Organic Chemistry. 1996 Jul 1;26(6):955-66.
35. 35. Abd‐Elzaher MM. Spectroscopic characterization of some tetradentate Schiff bases and their complexes with nickel, copper and zinc. Journal of the Chinese Chemical Society. 2001 Apr 1;48(2):153-8.
36. 36. Guguloth H. Synthesis, Characterization and Biological Studies: N2O2 Donor Novel Schiff Base Ligands and Their Co(II), Ni(II), Cu(II), Rh(III), Pd(II) Metal Complexes. International Journal of Pharmacy and Biological Sciences. 2015 Jul 1; 5(3):102-118.
37. 37. Jeslin Kanaga Inba P, Annaraj B, Thalamuthu S, Neelakantan MA. Cu (II), Ni (II), and Zn (II) complexes of salan-type ligand containing ester groups: synthesis, characterization, electrochemical properties, and in vitro biological activities. Bioinorganic chemistry and applications. 2013 Jul 25;2013.
38. 38. Talukder P, Datta A, Mitra S, Rosair G. Square planar complexes of Cu (II) with an N2O donor set of a new Schiff base ligand: synthesis and structural aspects. Zeitschrift für Naturforschung B. 2004 Jun 1;59(6):655-60.
39. 39. Lever A B P. Inorganic Electronic Spectroscopy (2nd edition). Amsterdam- New York: Elsevier (1984).
40. 40. Anjaneyulu Y, Rao RP. Preparation, characterization and antimicrobial activity studies on some ternary complexes of Cu (II) with acetylacetone and various salicylic acids. Synthesis and Reactivity in Inorganic and Metal-Organic Chemistry. 1986 Jan 1;16(2):257-72.
41. 41. Tweedy B. Plant extracts with metal ions as potential antimicrobial agents. Phytopathology. 1964;55:910-4.
42. 42. Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. The Journal of general physiology. 1927 Mar 7;8(6):519.