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Efficient hydrolytic cleavage of DNA and antiproliferative effect on human cancer cells by two dinuclear Cu(II) complexes containing a carbohydrazone ligand and 1,10-phenanthroline as a coligand

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Abstract

We report the synthesis, crystal structures and biological activities of two dinuclear Cu(II) complexes [Cu(o-phen)LCu(OAc)] (1) and [Cu(o-phen)LCu(o-phen)](OAc) (2), where o-phen = 1,10-phenanthroline, H3L = o-HOC6H4C(H)=N–NH–C(OH)=N–N=C(H)–C6H4OH-o, and OAc=CH3COO−. Both compounds display strong and broad X-band EPR spectra at RT in their powder state confirming that these are paramagnetic. The intercalative DNA binding of the compounds as revealed from spectrophotometric studies was found to be consistent with the results of fluorescence spectroscopic studies for ethidium bromide displacement assay as well as enhanced viscosity of DNA in the presence of these compounds. The compounds effectively catalyze hydrolytic cleavage of supercoiled pUC19 DNA and show remarkable cytotoxicity toward human lung cancer A549 cell line (IC50 values are 4.34 and 8.46 µM for 1 and 2, respectively) and breast cancer MCF7 cell line (IC50 values are 6.50 and 8.68 µM for 1 and 2, respectively) and are found to be relatively less toxic toward keratinocyte HaCaT normal cell line (IC50 values are 11.19 and 16.01 µM for 1 and 2, respectively). Annexin-V/PI dual staining results analyzed by flow cytometry strongly suggest the induction of apoptotic pathway for the anticancer activity of these complexes. Flow cytometry experiment for cell cycle analysis showed considerable increase in the G2/M phase in both A549 and MCF7 cell lines by these two compounds. On the other hand, compounds 1 and 2 activate reactive oxygen species (ROS) level in A549 cells, but act as scavengers or inhibitors of ROS in MCF7 cell line as analyzed by DCFDA staining using flow cytometry.

Graphical abstract

Two dinuclear Cu(II) complexes exhibit efficient hydrolytic cleavage of DNA and display remarkable cytotoxicity against human lung cancer A549 and breast cancer MCF7cells. The ROS level in A549 cells is activated, but the ROS level in MCF7 cells is decreased in the presence of these complexes. Cell cycle analysis by flow cytometry shows G2/M phase arrest in both these cell lines.

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References

  1. Santini C, Pellei M, Gandin V, Porchia M, Tisato F, Marzano C (2014) Chem Rev 114:815–862

    Article  CAS  PubMed  Google Scholar 

  2. Barone G, Terenzi A, Lauria A, Almerico AM, Leal JM, Busto N, García B (2013) Coord Chem Rev 257:2848–2862 (and references therein)

    Article  CAS  Google Scholar 

  3. Todd RC, Lippard SJ (2009) Metallomics 1:280–291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhang CX, Lippard SJ (2003) Curr Opin Chem Biol 7:481–489

    Article  CAS  PubMed  Google Scholar 

  5. Nagababu P, Barui AK, Thulasiram B, Shobha Devi C, Satyanarayana S, Patra CR, Sreedhar B (2015) J Med Chem 58:5226–5241

    Article  CAS  PubMed  Google Scholar 

  6. Adak P, Ghosh B, Bauza A, Frontera A, Blake AJ, Corbella CM, Das-Mukhopadhyay C, Chattopadhyay SK (2016) RSC Adv 6:86851–86861

    Article  CAS  Google Scholar 

  7. Chauhan M, Banerjee K, Arjmand F (2007) Inorg Chem 46:3072–3082

    Article  CAS  PubMed  Google Scholar 

  8. Vijayalakshmi R, Kanthimathi M, Parthasarathi R, Nair BU (2006) Bioorg Med Chem 14:3300–3306

    Article  CAS  PubMed  Google Scholar 

  9. Walker MG, Gonzalez V, Chekmeneva E, Thomas JA (2012) Angew Chem Int Ed 51:12107–12110

    Article  CAS  Google Scholar 

  10. Fabbro C, Ali-Boucetta H, Ros TD, Kostarelos K, Bianco A, Prato M (2012) Chem Commun 48:3911–3926

    Article  CAS  Google Scholar 

  11. Farrer NJ, Salassa L, Sadler PJ (2009) Dalton Trans 10690–10701

  12. Rajalakshmi S, Kiran MS, Nair BU (2014) Eur J Med Chem 80:393–406

    Article  CAS  PubMed  Google Scholar 

  13. Rajalakshmi S, Weyhermuller T, Dinesh M, Nair BU (2012) J Inorg Biochem 117:48–59

    Article  CAS  PubMed  Google Scholar 

  14. Basu U, Khan I, Hussain A, Kondaiah P, Chakravarty AR (2012) Angew Chem Int Ed 51:2658–2661

    Article  CAS  Google Scholar 

  15. Basu U, Khan I, Koley D, Saha S, Kondaiah P, Chakravarty AR (2012) J Inorg Biochem 116:77–87

    Article  CAS  PubMed  Google Scholar 

  16. Goswami TK, Gadadhar S, Roy M, Nethaji M, Karande AA, Chakravarty AR (2012) Organometallics 31:3010–3021

    Article  CAS  Google Scholar 

  17. Goswami TK, Chakravarthi BVSK, Roy M, Karande AA, Chakravarty AR (2011) Inorg Chem 50:8452–8464

    Article  CAS  PubMed  Google Scholar 

  18. Devereux M, Shea DO, Kellett A, McCann M, Walsh M, Egan D, Deegan C, Kedziora K, Rosair G, Muller-Bunz H (2007) J Inorg Biochem 101:881–892

    Article  CAS  PubMed  Google Scholar 

  19. O’Connor M, Kellett A, McCann M, Rosair G, McNamara M, Howe O, Creaven BS, McClean S, Foltyn-Arfa Kia A, O’Shea D, Devereux M (2012) J Med Chem 55:1957–1968

    Article  CAS  PubMed  Google Scholar 

  20. Tardio S, Basanetti I, Bignardi C, Elviri L, Tegoni M, Mucchino C, Bussolati O, Franchi-Gazzola R, Marchio L (2011) J Am Chem Soc 133:6235–6242

    Article  CAS  Google Scholar 

  21. Dey D, Kaur G, Ranjani A, Gayathri L, Chakraborty P, Adhikary J, Pasan J, Dhanasekaran D, Choudhury AR, Akbarsha MA, Kole N, Biswas B (2014) Eur J Inorg Chem 3350–3358

  22. Festa RA, Thiele DJ (2011) Curr Biol 21:877–883

    Article  CAS  Google Scholar 

  23. Parveen S, Tabassum S, Arjmand F (2017) RSC Adv 7:6587–6597

    Article  CAS  Google Scholar 

  24. Liu J, Zhang T, Lu T, Qu L, Zhou H, Zhang Q, Ji L (2002) J Inorg Biochem 91:269–276

    Article  CAS  PubMed  Google Scholar 

  25. Selvakumar B, Rajendiran V, Uma Maheswari P, Stoeckli-Evans H, Palaniandavar M (2006) J Inorg Biochem 100(3):316–330

    Article  CAS  PubMed  Google Scholar 

  26. Mal SK, Mitra M, Kaur G, Manikandamathavan VM, Kiran MS, Roy Choudhury A, Unni Nair B, Ghosh R (2014) RSC Adv 4:61337–61342

    Article  CAS  Google Scholar 

  27. Saswati Chakroborty A, Dash SP, Panda AK, Acharyya R, Biswas A, Mukhopadhyay S, Bhutia SK, Crochet A, Patil YP, Nethaji M, Dinda R (2015) Dalton Trans 44:6140–6157

    Article  CAS  Google Scholar 

  28. Kumaravel G, Utthra PP, Raman N (2018) Bioorg Chem 77:269–279

    Article  CAS  PubMed  Google Scholar 

  29. Burstyn JN, Deal KA (1993) Inorg Chem 32:3585–3586

    Article  CAS  Google Scholar 

  30. Deal KA, Hengge AC, Burstyn JN (1996) J Am Chem Soc 118:1713–1718

    Article  CAS  Google Scholar 

  31. Itoh T, Hisada H, Sumiya T, Hosono M, Usui Y, Fujii Y (1997) Chem Commun 677–678

  32. Sissi C, Mancin F, Gatos M, Palumbo M, Tecilla P, Tonellato U (2005) Inorg Chem 44(7):2310–2317

    Article  CAS  PubMed  Google Scholar 

  33. Wang J, Xia Q, Zheng X, Chen H, Chao H, Mao Z, Ji L (2010) Dalton Trans 39:2128–2136

    Article  CAS  PubMed  Google Scholar 

  34. Lu J, Sun Q, Li JL, Jiang L, Gu W, Liu X, Tian JL, Yan SP (2014) J Inorg Biochem 137:46–56

    Article  CAS  PubMed  Google Scholar 

  35. Li F, Xie J, Feng F (2015) New J Chem 39:5654–5660

    Article  CAS  Google Scholar 

  36. Reddy PAN, Nethaji M, Chakravarty AR (2004) Eur J Inorg Chem 1440–1446

  37. Dhar S, Reddy PAN, Chakravarty AR (2004) Dalton Trans 697–698

  38. Ramakrishnan S, Rajendiran V, Palaniandavar M, Periasamy VS, Srinag BS, Krishnamurthy H, Akbarsha MA (2009) Inorg Chem 48:1309–1322

    Article  CAS  PubMed  Google Scholar 

  39. Reddy PR, Silpa A (2011) Polyhedron 30:565–572

    Article  CAS  Google Scholar 

  40. Reddy PR, Silpa A (2011) Chem Biodivers 8:1245–1265

    Article  CAS  Google Scholar 

  41. Koley MK, Duraipandy N, Kiran MS, Varghese B, Manoharan PT, Koley AP (2017) Inorg Chim Acta 466:538–550

    Article  CAS  Google Scholar 

  42. Bruker I (2016) Apex3 v2017.3-0, SAINT V8.38A, Bruker AXS Inc.: Madison (WI), USA, 2013/2014

  43. Sheldrick GM (2014). SHELXL version 2014. University of Göttingen, Germany

  44. Frrugia LJ (1997) J Appl Cryst 30:565–566

    Article  Google Scholar 

  45. Parsekar SU, Fernandes J, Banerjee A, Chouhan Om P, Biswas S, Singh M, Mishra DP, Kumar M (2018) J Biol Inorg Chem 23:1331–1349

    Article  CAS  PubMed  Google Scholar 

  46. Rastogi N, Duggal S, Singh SK, Porwal K, Srivastava VK, Maurya R, Bhatt ML, Mishra DP (2015) Oncotarget 6:43310–43325

    Article  PubMed  PubMed Central  Google Scholar 

  47. Nicole JY, Marlon JH (2015) Methods Mol Biol 1266:29–53

    Article  CAS  Google Scholar 

  48. Kumar M, Parsekar SU, Duraipandy N, Kiran MS, Koley AP (2019) Inorg Chim Acta 484:219–226

    Article  CAS  Google Scholar 

  49. Kumar M, Parsekar SU, Duraipandy N, Kiran MS, Varghese B, Manoharan PT, Koley AP (2018) Inorg Chim Acta 478:211–221

    Article  CAS  Google Scholar 

  50. Anjomshoa M, Hadadzadeh H, Torkzadeh-Mahani M, Fatemi SJ, Adeli-Sardou M, Rudbari HA, Nardo VM (2015) Eur J Med Chem 96:66–82

    Article  CAS  PubMed  Google Scholar 

  51. Abdi K, Hadadzadeh H, Weil M, Salimi M (2012) Polyhedron 31:638–648

    Article  CAS  Google Scholar 

  52. Meenongwa A, Brissos RF, Soikum C, Chaveerach P, Gamez P, Trongpaniche Y, Chaveerach U (2016) New J Chem 40:5861–5876

    Article  CAS  Google Scholar 

  53. Kellett A, O’Connor M, McCann M, Howe O, Casey A, McCarron P, Kavanagh K, McNamara M, Kennedy S, May DD, Skell PS, O’Shea D, Devereux M (2011) Med Chem Commun 2:579–584

    Article  CAS  Google Scholar 

  54. Glišic BD, Nikodinovic-Runic J, Ilic-Tomic T, Wadepohl H, Veselinovic A, Opsenica IM, Djuran MI (2018) Polyhedron 139:313–322

    Article  CAS  Google Scholar 

  55. Manikandamathavan VM, Nair BU (2013) Eur J Med Chem 68:244–252

    Article  CAS  PubMed  Google Scholar 

  56. Rajalakshmi S, Weyhermller T, Freddy AJ, Vasanthi HR, Nair BU (2011) Eur J Med Chem 46:608–617

    Article  CAS  PubMed  Google Scholar 

  57. Manikandamathavan VM, Rajapandian V, Freddy AJ, Weyhermuller T, Subramanian V, Nair BU (2012) Eur J Med Chem 57:449–458

    Article  CAS  PubMed  Google Scholar 

  58. Feng X, Liu J (2018) J Inorg Biochem 178:1–8

    Article  CAS  PubMed  Google Scholar 

  59. Senderowicz AM, Sausville EA (2000) J Natl Cancer Inst 92:376–387

    Article  CAS  PubMed  Google Scholar 

  60. Jackson JR, Gilmartin A, Imburgia C, Winkler JD, Marshall LA, Roshak A (2000) Can Res 60:566–572

    CAS  Google Scholar 

  61. DiPaola RS (2002) Clin Cancer Res 8:3512–3519

    Google Scholar 

  62. Tyagi AK, Singh RP, Agarwal C, Chan DC, Agarwal R (2002) Clin Cancer Res 8:3512–3519

    CAS  PubMed  Google Scholar 

  63. Wang J, Yi J (2008) Cancer Biol Ther 7:1875–1884

    Article  CAS  PubMed  Google Scholar 

  64. Liou G-Y, Storz P (2010) Free Radic Res 44:479–496

    Article  CAS  Google Scholar 

  65. Irani K, Xia Y, Zweier JL, Sollott SJ, Der CJ, Fearon ER, Sundaresan M, Finkel T, Goldschmidt-Clermont PJ (1997) Science 275:1649–1652

    Article  CAS  PubMed  Google Scholar 

  66. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, Stivala F, Libra M, Basecke J, Evangelisti C, Martelli AM, Franklin RA (2007) Biochim Biophys Acta 1773:1263–1284

    Article  CAS  Google Scholar 

  67. Kumar B, Koul S, Khandrika L, Meacham RB, Koul HK (2008) Cancer Res 68:1777–1785

    Article  CAS  PubMed  Google Scholar 

  68. Chan DW, Liu VW, Tsao GS, Yao KM, Furukawa T, Chan KK, Ngan HY (2008) Carcinogenesis 29:1742–1750

    Article  CAS  PubMed  Google Scholar 

  69. Lee WC, Choi CH, Cha SH, Oh HL, Kim- YK (2005) Neurochem Res 30:263–270

    Article  CAS  PubMed  Google Scholar 

  70. Rygiel TP, Mertens AE, Strumane K, van der Kammen R, Collard JG (2008) J Cell Sci 121:1183–1192

    Article  CAS  PubMed  Google Scholar 

  71. Ostrakhovitch EA, Cherian MG (2005) J Cell Biochem 95:1120–1134

    Article  CAS  PubMed  Google Scholar 

  72. Zhou J, Chen Y, Lang J-Y, Lu J-J, Ding J (2008) Mol Cancer Res 6:194–204

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the SAIF, IIT-Madras, for XRD and SAIF, IIT-Bombay, for EPR facilities. A.P.K. thanks Mr. Atanu Banerjee and Prof. Rupam Dinda, Department of Chemistry, National Institute of Technology, Rourkela, India, for help with the ESI-MS results. MK thanks SERB, DST, Government of India, for the Project EMR/2017/001562.

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Authors and Affiliations

  1. Department of Chemical Engineering, Birla Institute of Technology and Science-Pilani, K.K. Birla Goa Campus, Zuarinagar, Goa, 403726, India

    Sidhali U. Parsekar & Manjuri Kumar

  2. Cell Death Research Laboratory, Endocrinology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India

    Manohar Singh & Durga P. Mishra

  3. Sophisticated Analytical Instrument Facility, Indian Institute of Technology-Madras, Chennai, 600036, India

    P. K. Sudhadevi Antharjanam

  4. Department of Chemistry, Birla Institute of Technology and Science-Pilani, K.K. Birla Goa Campus, Zuarinagar, Goa, 403726, India

    Aditya P. Koley

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  1. Sidhali U. Parsekar
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Fig. S1. ESI–MS of the compounds 1–2. Fig. S2. EPR spectra of compounds 1 and 2. Fig. S3. Electronic spectra of the compounds 1 and 2. Fig. S4. Cell viability of the free Schiff base ligand and free 1,10-phenathroline ligand with human lung cancer A549 cell line after 24 h incubation time. Crystallographic data for the structural analysis have been deposited with the Cambridge Crystallographic Data Center, numbers are CCDC 1887320 for compound 1 and CCDC 1887321 for compound 2, respectively. These data can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: (+044) 1223-336-033; or E-mail: deposit@ccdc.cam.ac.uk (PDF 809 kb)

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Parsekar, S.U., Singh, M., Mishra, D.P. et al. Efficient hydrolytic cleavage of DNA and antiproliferative effect on human cancer cells by two dinuclear Cu(II) complexes containing a carbohydrazone ligand and 1,10-phenanthroline as a coligand. J Biol Inorg Chem 24, 343–363 (2019). https://doi.org/10.1007/s00775-019-01651-8

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