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Synthesis, characterisation, nuclease and cytotoxic activity of phosphate-free and phosphate-containing copper \(4^{\prime }\)-(N-methylpyridinium)-\(2{,}2^{\prime }{:}6^{\prime }{,}2^{\prime \prime }\) terpyridine complexes


Mononuclear Cu(II) pyridinium terpyridine based compounds, viz., [Cu(q- pytpy)(I)\((\hbox {CH}_{3}\hbox {COO})](\hbox {I})\cdot (2\hbox {H}_{2}\hbox {O})\) (1) and [Cu(dipp)(dippH)(q-pytpy)]\({\cdot }(2\hbox {H}_{2}\hbox {O}\))(DMF) (2) were isolated by reacting \(\hbox {Cu}(\hbox {OAc})_{2}{\cdot }\hbox {H}_{2}\hbox {O}\) with \(4^{\prime }\)-(N-methylpyridinium)-2,\(2^{\prime }{:}6^{\prime }{,}2^{\prime \prime }\)-terpyridine (q-pytpy) in the presence of 2,6 diisopropylphenyl phosphate (\(\hbox {dippH}_{2}\)). Both the new compounds were isolated as single crystals and characterised by spectroscopic (IR, ESI-MS, EPR, UV–Vis), thermogravimetric and microanalytical techniques. The molecular structures of both the compounds were determined in the solid-state by single crystal X-ray diffraction studies. Complexes 1 and 2 were evaluated for their nuclease and in vitro anti-tumor activities against human breast and colorectal cancer cell lines. The DNA cleavage and cytotoxic assays revealed that both 1 and 2 are effective in cleaving DNA, while the cytotoxic activity of 1 is better than 2 in both human colon and breast cancer cell lines.

Graphical Abstract

SYNOPSIS New phosphate-free and phosphate containing mononuclear pyridinium terpyridine-based Cu (II) compounds, isolated from a single reaction, have been demonstrated as anti-proliferative agents in human colon and breast cancer lines.

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  1. 1.

    Ganeshpandian M, Ramakrishnan S, Palaniandavar M, Suresh E, Riyasdeen A and Akbarsha M A 2014 Mixed ligand copper(II) complexes of 2,9-dimethyl-1,10-phenanthroline: tridentate 3N primary ligands determine DNA binding and cleavage and cytotoxicity J. Inorg. Biochem. 140 202

    CAS  Article  Google Scholar 

  2. 2.

    Manikandamathavan V M, Parameswari R P, Weyhermuller T, Vasanthi H R and Nair B U 2011 Cytotoxic copper (II) mixed ligand complexes: crystal structure and DNA cleavage activity Eur. J. Med. Chem. 46 4537

    CAS  Article  Google Scholar 

  3. 3.

    Manikandamathavan V M, Weyhermuller T, Parameswari R P, Sathishkumar M, Subramanian V and Nair B U 2014 DNA/protein interaction and cytotoxic activity of imidazole terpyridine derived Cu(II)/Zn(II) metal complexes Dalton Trans. 43 13018

    CAS  Article  Google Scholar 

  4. 4.

    Denoyer D, Masaldan S, La Fontaine S and Cater M A 2015 Targeting copper in cancer therapy: ‘Copper That Cancer’ Metallomics 7 1459

    CAS  Article  Google Scholar 

  5. 5.

    Suntharalingam K, Hunt D J, Duarte A A, White A J, Mann D J and Vilar R 2012 A tri-copper(II) complex displaying DNA-cleaving properties and antiproliferative activity against cancer cells Chem. Eur. J. 18 15133

    CAS  Article  Google Scholar 

  6. 6.

    Ghosh S, Mendoza O, Cubo L, Rosu F, Gabelica V, White A J and Vilar R 2014 Assembly of palladium(II) and platinum(II) metallo-rectangles with a guanosine-substituted terpyridine and study of their interactions with quadruplex DNA Chem. Eur. J. 20 4772

    CAS  Article  Google Scholar 

  7. 7.

    Jiang Q, Wu Z, Zhang Y, Hotze A C, Hannon M J and Guo Z 2008 Effect of adenine moiety on DNA binding property of copper(II)-terpyridine complexes Dalton Trans. 3054

  8. 8.

    Thati B, Noble A, Creaven B S, Walsh M, Kavanagh K and Egan D A 2007 Apoptotic cell death: a possible key event in mediating the in vitro anti-proliferative effect of a novel copper(II) complex, [Cu(4-Mecdoa)(phen)(2)] (phen=phenanthroline, 4-Mecdoa=4-methylcoumarin-6,7-dioxactetate), in human malignant cancer cells Eur. J. Pharmacol. 569 16

    CAS  Article  Google Scholar 

  9. 9.

    Gandin V, Porchia M, Tisato F, Zanella A, Severin E, Dolmella A and Marzano C 2013 Novel mixed-ligand copper(I) complexes: role of diimine ligands on cytotoxicity and genotoxicity J. Med. Chem. 56 7416

    CAS  Article  Google Scholar 

  10. 10.

    U Jungwirth C R K, B K Keppler, C G Hartinger, W Berger, P Heffeter 2011 Anticancer Activity of Metal Complexes: Involvement of Redox Processes Antioxid. Redox Signaling 15 1085

  11. 11.

    Sigman D S, Mazumder A and Perrin D M 1993 Chemical Nucleases Chem. Rev. 93 2295

  12. 12.

    Dasari S and Tchounwou P B 2014 Cisplatin in cancer therapy: molecular mechanisms of action Eur. J. Pharmacol. 740 364

    CAS  Article  Google Scholar 

  13. 13.

    Peterson E J, Menon V R, Gatti L, Kipping R, Dewasinghe D, Perego P, Povirk L F and Farrell N P 2015 Nucleolar targeting by platinum: p53-independent apoptosis follows rRNA inhibition, cell-cycle arrest, and DNA compaction Mol. Pharm. 12 287

    CAS  Article  Google Scholar 

  14. 14.

    Chen J and Stubbe J 2005 Bleomycins: Towards better therapeutics Nat. Rev. Cancer 5 102

    CAS  Article  Google Scholar 

  15. 15.

    Galm U, Hager M H, Van Lanen S G, Ju J, Thorson J S and Shen B 2005 Antitumor Antibiotics: Bleomycin, Enediynes, and Mitomycin Chem. Rev. 105 739

  16. 16.

    Rabik C A and Dolan M E Molecular mechanisms of resistance and toxicity associated with platinating agents Cancer Treat. Rev. 33 9

    CAS  Article  Google Scholar 

  17. 17.

    Miller R P, Tadagavadi R K, Ramesh G and Reeves W B 2010 Mechanisms of Cisplatin nephrotoxicity Toxins 2 2490

  18. 18.

    De Jongh F E, van Veen R N, Veltman S J, Wit R de, Burg M E L van der, Bent M J van den, Planting ASTh, Graveland W J, Stoter G and Verweij J 2003 Weekly high-dose cisplatin is a feasible treatment option: analysis on prognostic factors for toxicity in 400 patients Br. J. Cancer 88 1199

  19. 19.

    Barry N P and Sadler P J 2013 Exploration of the medical periodic table: towards new targets Chem. Commun. 49 5106

    CAS  Article  Google Scholar 

  20. 20.

    Van Rijt S H and Sadler P J 2009 Current applications and future potential for bioinorganic chemistry in the development of anticancer drugs Drug Discov. Today 14 1089

    Article  Google Scholar 

  21. 21.

    Sheikhshoaie I, Ebrahimipour S Y, Sheikhshoaie M, Mohamadi M, Abbasnejad M, Rudbari H A and Bruno G 2015 Synthesis, characterization, X-ray crystal structure, electrochemical evaluation and anti-cancer studies of a mixed ligand Cu (II) complex of (E)-\(N^\prime \)-((2-hydroxynaphthalen-1-yl) methylene) acetohydrazide J. Chem. Sci. 127 2193

    CAS  Article  Google Scholar 

  22. 22.

    Kumar S C, Pal A, Mitra M, Manikandamathavan V, Lin C-H, Nair B U and Ghosh R 2015 DNA binding and cleavage activity of a structurally characterized Ni (II) Schiff base complex J. Chem. Sci. 127 1375

  23. 23.

    Das S, Ranjani A, Gayathri L, Saha S, Pasan J, Dhanasekaran D, Akbarsha M A, Maji M and Biswas B 2016 Recognition of self-assembled water-nitrate cluster in a Co (III)-2, \(2^\prime \)-bipyridine host: Synthesis, X-ray structure, DNA cleavage, molecular docking and anticancer activity J. Chem. Sci. 128 1755

    CAS  Article  Google Scholar 

  24. 24.

    Thatituri S, Govindugari B and Chittireddy V R R 2017 Carboxylate-bridged Cu (II) coordination polymeric complex: synthesis, crystal structure, magnetic properties, DNA binding and electrochemical studies J. Chem. Sci. 129 1171

    CAS  Article  Google Scholar 

  25. 25.

    Santini C, Pellei M, Gandin V, Porchia M, Tisato F and Marzano C 2014 Advances in copper complexes as anticancer agents Chem. Rev. 114 815

    CAS  Article  Google Scholar 

  26. 26.

    Iakovidis I, Delimaris I and Piperakis S M 2011 Copper and its complexes in medicine: a biochemical approach Mol. Biol. Int. 2011 594529

    Article  Google Scholar 

  27. 27.

    Manikandamathavan V M, Rajapandian V, Freddy A J, Weyhermuller T, Subramanian V and Nair B U 2012 Effect of coordinated ligands on antiproliferative activity and DNA cleavage property of three mononuclear Cu(II)-terpyridine complexes Eur. J. Med. Chem. 57 449

    CAS  Article  Google Scholar 

  28. 28.

    Hirohama T, Kuranuki Y, Ebina E, Sugizaki T, Arii H, Chikira M, Tamil Selvi P and Palaniandavar M 2005 Copper(II) complexes of 1,10-phenanthroline-derived ligands: studies on DNA binding properties and nuclease activity J. Inorg. Biochem. 99 1205

    CAS  Article  Google Scholar 

  29. 29.

    Ghosh S, Mendoza O, Cubo L, Rosu F, Gabelica V, White A J and Vilar R 2014 Assembly of Palladium (II) and Platinum (II) Metallo-Rectangles with a Guanosine-Substituted Terpyridine and Study of Their Interactions with Quadruplex DNA Chem. Eur. J. 20 4772

    CAS  Article  Google Scholar 

  30. 30.

    Hirohama T, Kuranuki Y, Ebina E, Sugizaki T, Arii H, Chikira M, Selvi P T and Palaniandavar M 2005 Copper (II) complexes of 1, 10-phenanthroline-derived ligands: studies on DNA binding properties and nuclease activity J. Inorg. Biochem. 99 1205

    CAS  Article  Google Scholar 

  31. 31.

    Manikandamathavan V M, Parameswari R P, Weyhermüller T, Vasanthi H R and Nair B U 2011 Cytotoxic copper (II) mixed ligand complexes: Crystal structure and DNA cleavage activity Eur. J. Inorg. Chem. 46 4537

    CAS  Google Scholar 

  32. 32.

    Grau J, Brissos R F, Salinas-Uber J, Caballero A B, Caubet A, Roubeau O, Korrodi-Gregório L, Pérez-Tomás R and Gamez P 2015 The effect of potential supramolecular-bond promoters on the DNA-interacting abilities of copper–terpyridine compounds Dalton Trans. 44 16061

    CAS  Article  Google Scholar 

  33. 33.

    Eryazici I, Moorefield C N and Newkome G R 2008 Square-planar Pd (II), Pt (II), and Au (III) terpyridine complexes: their syntheses, physical properties, supramolecular constructs, and biomedical activities Chem. Rev. 108 1834

    CAS  Article  Google Scholar 

  34. 34.

    Bertrand H, Monchaud D, Cian A De, Guillot R, Mergnyb J-L and Teulade-Fichou M-P 2007 The importance of metal geometry in the recognition of G-quadruplex-DNA by metal-terpyridine complexes Org. Biomol. Chem. 5 2555

  35. 35.

    Bertrand H, Monchaud D, Cian A De, Guillot R, Mergnyb J-L and Teulade-Fichou M-P 2009 Exclusive platination of loop adenines in the human telomeric G-quadruplex Org. Biomol. Chem. 7 2864

  36. 36.

    Constable E C 2007 2, \(2^\prime \): \(6^\prime \), \(2^{\prime \prime }\)-Terpyridines: From chemical obscurity to common supramolecular motifs Chem. Soc. Rev. 36 246

    CAS  Article  Google Scholar 

  37. 37.

    Winter A, Newkome G R and Schubert U S 2011 Catalytic applications of terpyridines and their transition metal complexes ChemCatChem 3 1384

    CAS  Article  Google Scholar 

  38. 38.

    Miller R G and Brooker S 2015 Spin Crossover, Reversible Redox, and Supramolecular Interactions in 3d Complexes of 4-(4-Pyridyl)-2, 5-dipyrazyl-pyridine Inorg. Chem. 54 5398

    CAS  Article  Google Scholar 

  39. 39.

    Hofmeier H and Schubert U S 2004 Recent developments in the supramolecular chemistry of terpyridine–metal complexes Chem. Soc. Rev. 33 373

    CAS  Article  Google Scholar 

  40. 40.

    Wild A, Winter A, Schlütter F and Schubert U S 2011 Advances in the field of \(\pi \)-conjugated 2, \(2^\prime \):\(6^\prime \), \(2^{\prime \prime }\)-terpyridines Chem. Soc. Rev. 40 1459

    CAS  Article  Google Scholar 

  41. 41.

    Sakamoto R, Wu K-H, Matsuoka R, Maeda H and Nishihara H 2015 \(\pi \)-Conjugated bis (terpyridine) metal complex molecular wires Chem. Soc. Rev. 44 7698

    CAS  Article  Google Scholar 

  42. 42.

    Bulut A, Zorlu Y, Wörle M, Paşa S, Kurt H, Zubieta J, Beckmann J and Yücesan G 2016 Rational Design of Two-Dimensional Bimetallic Wave Structures from Zigzag Chains via Site-Specific Coordination around the 2, 6-Naphthalenediphosphonic Acid Motif Eur. J. Inorg. Chem. 2016 3506

    CAS  Article  Google Scholar 

  43. 43.

    Bulut A, Zorlu Y, Kirpi E, Çetinkaya A, Wörle M, Beckmann J and Yücesan G 2015 Synthesis of Cu (II)-organophosphonate framework with predefined void spaces Cryst. Growth Des. 15 5665

    CAS  Article  Google Scholar 

  44. 44.

    Murugavel R, Sathiyendiran M, Pothiraja R, Walawalkar M G, Mallah T and Riviére E 2004 Monomeric, Tetrameric, and Polymeric Copper Di-tert-butyl Phosphate Complexes Containing Pyridine Ancillary Ligands Inorg. Chem. 43 945

    CAS  Article  Google Scholar 

  45. 45.

    Murugavel R, Sathiyendiran M, Pothiraja R and Butcher R J 2003 O–H Bond elongation in co-ordinated water through intramolecular \(\text{P}=\text{ O }\cdots \text{ H }-\text{ O }\) bonding.‘Snap-shots’ in phosphate ester hydrolysis Chem. Commun. 2546

  46. 46.

    Murugavel R, Kuppuswamy S, Maity A N and Singh M P 2009 Di-, Tri-, Tetra-, and Hexanuclear Copper(II) Mono-organophosphates: Structure and Nuclearity Dependence on the Choice of Phosphorus Substituents and Auxiliary N-Donor Ligands Inorg. Chem. 48 183

    CAS  Article  Google Scholar 

  47. 47.

    Bhat G A, Maqbool R, Dar A A, Hussain M U and Murugavel R 2017 Selective formation of discrete versus polymeric copper organophosphates: DNA cleavage and cytotoxic activity Dalton Trans. 46 13409

    CAS  Article  Google Scholar 

  48. 48.

    Gupta S K, Kalita A C, Dar A A, Sen S, Patwari G N and Murugavel R 2017 Elusive Double-Eight-Ring Zeolitic Secondary Building Unit J. Am. Chem. Soc. 139 59

    CAS  Article  Google Scholar 

  49. 49.

    Dar A A, Bhat G A and Murugavel R 2016 Dimensionality Alteration and Intra-versus Inter-SBU Void Encapsulation in Zinc Phosphate Frameworks Inorg. Chem. 55 5180

    CAS  Article  Google Scholar 

  50. 50.

    Dar A A, Sharma S K and Murugavel R 2015 Is single-4-ring the most basic but elusive secondary building unit that transforms to larger structures in zinc phosphate chemistry? Inorg. Chem. 54 4882

    CAS  Article  Google Scholar 

  51. 51.

    Song J W B C, Hu H M, Gou L, Wu Q R, Yang X L, Shangguan Y Q, Dong F X and Xue G L 2011 In situ hydrothermal syntheses, crystal structures and luminescent properties of two novel zinc(II) coordination polymers based on tetrapyridyl ligand Inorg. Chim. Acta 366 134

    CAS  Article  Google Scholar 

  52. 52.

    Kosolapoff G M, Arpke C K, Lamb R W and Reich H 1968 Structural Effects in Reactions of Organophosphorus Compounds,Reactions of Phosphorus Oxychloride with Hindered Phenols J. Chem. Soc. C 815

  53. 53.

    Altomare A, Cascarano G, Giacovazzo C, Guagliardi A, Burla M C, Polidori G and Camalli M 1994 SIRPOW.92 - a program for automatic solution of crystal structures by direct methods optimized for powder data J. Appl. Cryst. 27 435

  54. 54.

    Farrugia Louis J 1999 WinGX suite for small-molecule single-crystal crystallography J. Appl. Crystallogr. 32 837

  55. 55.

    Sheldrick G M 2008 A short history of SHELX Acta Cryst. 64 112

    CAS  Article  Google Scholar 

  56. 56.

    Becher J, Brockway D J, Murray K S, Newman P J and Toftlund H 1982 Electron spin resonance and electrochemical study of thiohydroxamate and 1-phenyl-3-imino-2 (1H)-pyridinethione complexes of copper (II) Inorg. Chem. 21 1791

    CAS  Article  Google Scholar 

  57. 57.

    Casella L 1984 Synthetic approach to the type 1 active site of copper proteins. Copper(I), copper(II), and zinc(II) complexes with N2SS* ligand donor sets Inorg. Chem. 23 2781

  58. 58.

    Vaidyanathan M, Viswanathan R, Palaniandavar M, Balasubramanian T, Prabhaharan P and Muthiah T P 1998 Copper(II) Complexes with Unusual Axial Phenolate Coordination as Structural Models for the Active Site in Galactose Oxidase: X-ray Crystal Structures and Spectral and Redox Properties of [Cu(bpnp)X] Complexes Inorg. Chem. 37 6418

    CAS  Article  Google Scholar 

  59. 59.

    Geoffrey Wilkinson, Robert D Gillard and Jon A McCleverty (Eds.) 1987 Comprehensive Coordination Chemistry Vol. 5 (Oxford: Pergamon Press)

  60. 60.

    Dhanalakshmi T, Suresh E, Stoeckli-Evans H and Palaniandavar M 2006 New copper (II) complexes as efficient catalysts for olefin aziridination: The effect of ligand steric hindrance on reactivity Eur. J. Inorg. Chem. 2006 4687

    Article  Google Scholar 

  61. 61.

    Kivelson D and Neiman R 1961 ESR Studies on the Bonding in Copper Complexes J. Chem. Phys. 35 149

    CAS  Article  Google Scholar 

  62. 62.

    Kobayashi M, Masaoka S and Sakai K 2012 Synthesis, crystal structure, spectroscopic and electrochemical properties, and H 2-evolving activity of a new [PtCl (terpyridine)]+ derivative with viologen-like redox properties Dalton Trans. 41 4903

    CAS  Article  Google Scholar 

  63. 63.

    Ma Z, Wei L, Alegria E C, Martins L M, da Silva M F C G and Pombeiro A J 2014 Synthesis and characterization of copper (ii) \(4^\prime \)-phenyl-terpyridine compounds and catalytic application for aerobic oxidation of benzylic alcohols Dalton Trans. 43 4048

    CAS  Article  Google Scholar 

  64. 64.

    Shi W-J, Hou L, Li D and Yin Y-G 2007 Supramolecular assembly driven by hydrogen-bonding and \(\pi \)\(\pi \) stacking interactions based on copper (II)-terpyridyl complexes Inorg. Chim. Acta 360 588

    CAS  Article  Google Scholar 

  65. 65.

    Hou L, Li D, Shi W-J, Yin Y-G and Ng S W 2005 Ligand-controlled mixed-valence copper rectangular grid-type coordination polymers based on pyridylterpyridine Inorg. Chem. 44 7825

    CAS  Article  Google Scholar 

  66. 66.

    Khatua S G S, Parshamoni S, Jena H S and Konar S 2013 A 2D coordination polymer based on \(\text{ Co }_{3}\)-SBU showing spin-canting ferromagnetic behaviour RSC Adv. 3 25237

    CAS  Article  Google Scholar 

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This work was supported by (1) DST Nanomission (SR/NM/NS-1119/2011), (2) SERB, New Delhi (SB/S1/IC-48/2013) and (3) IIT-Bombay Bridge Funding. R. M. thanks SERB (SB/S2/JCB-85/2014), New Delhi for a J. C. Bose Fellowship, G.A.B thanks UGC New Delhi for a research fellowship. The authors thank Dr. Sandeep Kumar Gupta for help in solving one crystal structure.

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Correspondence to Ramaswamy Murugavel.

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Bhat, G.A., Maqbool, R. & Murugavel, R. Synthesis, characterisation, nuclease and cytotoxic activity of phosphate-free and phosphate-containing copper \(4^{\prime }\)-(N-methylpyridinium)-\(2{,}2^{\prime }{:}6^{\prime }{,}2^{\prime \prime }\) terpyridine complexes. J Chem Sci 130, 21 (2018).

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  • Pyridinium terpyridine
  • X-ray structures
  • DNA cleavage
  • cytotoxic activity