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Dinuclear platinum(II) complexes of imidazophenanthroline-based bridging ligands as potential anticancer agents: synthesis, characterization, and in vitro cytotoxicity studies

  • Carlson Alexander
  • N. U. Prajith
  • P. V. Priyanka
  • A. Nithyakumar
  • N. Arockia SamyEmail author
Original Paper
  • 120 Downloads

Abstract

The synthesis and characterization of the dinucleating ligands 1,2-bis(2-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenoxy)ethane (L1) and 1,2-bis(2-(1H-imidazo[4,5-f][1, 10]phenanthrolin-2-yl)phenoxy)hexane (L2) and their dinuclear complexes [Pt2(L1)Cl4] (1) and [Pt2(L2)Cl4] (2) and the in vitro cytotoxicity of the complexes against HeLa, HepG2, and MCF-7 cell lines are reported. Ligand L1 crystallizes in the orthorhombic system with the space group Pbca. The complexes 1 and 2 undergo aquation following first-order kinetics. The MTT and trypan blue assays indicate higher cytotoxicity of the complexes towards the HepG2 and MCF-7 cell lines compared to cisplatin. The AO/EB assay and flow cytometry by Annexin V alexa fluor®488/PI double staining assay demonstrate distinct morphological changes of apoptosis in a dose dependent manner. The cell cycle analysis shows a marked decrease in the DNA content in the G0/G1 phase with an increase in the G2/M phase on increasing the concentration of the complexes. The potential of the complexes as anticancer agents is demonstrated by their antiproliferative activity on the cell lines. The complexes interact with the major groove of DNA through H-bonding between the imidazole N–H protons and the nucleotide residues DC`21/N4 (cytosine) for complex 1 and DT`7/O2 (thymine) and DT`19/O2 (thymine) for complex 2, with the binding energy of − 1.98 and − 4.45 kcal/mol, respectively.

Graphical Abstract

Dinuclear Pt(II) complexes of imidazophenanthroline-based dinucleating ligands exhibit antiproliferative activity against HeLa, HepG2, and MCF-7 cell lines

Keywords

Anticancer drug Apoptosis DNA damage Docking Dinuclear platinum complexes Imidazophenanthroline 

Notes

Acknowledgements

Partial financial support to Carlson Alexander from Loyola Research Park is gratefully acknowledged. NAS thanks SERB, New Delhi, for financial support. The service rendered by the Sophisticated Analytical Instrumentation Facilities (SAIF) at IIT-Madras and Punjab and Jawaharlal Nehru Universities for recording ESI-TOF and MALDI-TOF mass spectra and NMR spectra is gratefully acknowledged. We thank Dr. P. K. Sudhadevi Antharjanam, SAIF, IIT-Madras, Chennai, for her help in solving the crystal structure. We thank Dr. J. John Kirubaharan and Dr. S. Rajalakshmi, Department of Veterinary Microbiology, Madras Veterinary College, Chennai, for their invaluable help in carrying out the in vitro studies.

Compliance with ethical standards

Conflict of interest

There are no conflicts to declare.

Supplementary material

775_2019_1656_MOESM1_ESM.pdf (682 kb)
Supplementary material 1 (PDF 681 kb)

References

  1. 1.
    Rosenberg B, Vancamp L, Krigas T (1965) Nature 205:698–699CrossRefGoogle Scholar
  2. 2.
    Rosenberg B, Vancamp L, Trosko JE, Mansour VH (1969) Nature 222:385–386CrossRefGoogle Scholar
  3. 3.
    Chu E, DeVita VT Jr (2008) Physician’s cancer chemotherapy drug manual. Jones and Bartlett Publishers, SudburyGoogle Scholar
  4. 4.
    Cvitkovic E (1998) Cancer Treat Rev 24:265–281CrossRefGoogle Scholar
  5. 5.
    Harrap KR (1985) Cancer Treat Rev 12:21–33CrossRefGoogle Scholar
  6. 6.
    Rixe O, Ortuzar W, Alvarez M, Parker R, Reed E, Paull K, Fojo T (1996) Biochem Pharmacol 52:1855–1865CrossRefGoogle Scholar
  7. 7.
    Raymond E, Faivre S, Chaney S, Woynarowski J, Cvitkovic E (2002) Mol Cancer Ther 1:227–235Google Scholar
  8. 8.
    Wheate NJ, Walker S, Craig GE, Oun R (2010) Dalton Trans 39:8113–8127CrossRefGoogle Scholar
  9. 9.
    Shimada M, Itamochi H, Kigawa J (2013) Cancer Manag Res 5:67–76CrossRefGoogle Scholar
  10. 10.
    Welink J, Boven E, Vermorken JB, Gall HE, van der Vijgh WJF (1999) Clin Cancer Res 5:2349–2358Google Scholar
  11. 11.
    Kelland LR, Abel G, McKeage MJ, Jones M, Goddard PM, Valenti M, Murrer BA, Harrap K (1993) Cancer Res 53:2581–2586Google Scholar
  12. 12.
    Sharp SY, Rogers PM, Kelland LR (1995) Clin Cancer Res 1:981–989Google Scholar
  13. 13.
    Sharp SY, O’Neill CF, Rogers PM, Boxall FE, Kelland LR (2002) Eur J Cancer 38:2309–2315CrossRefGoogle Scholar
  14. 14.
    Alderden RA, Hall MD, Hambley TW (2006) J Chem Educ 83:728–734CrossRefGoogle Scholar
  15. 15.
    Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, Castedo M, Kroemer G (2012) Oncogene 31:1869–1883CrossRefGoogle Scholar
  16. 16.
    Wilson JJ, Lippard SJ (2014) Chem Rev 114:4470–4495CrossRefGoogle Scholar
  17. 17.
    Jamieson ER, Lippard SJ (1999) Chem Rev 99:2467–2498CrossRefGoogle Scholar
  18. 18.
    Wang D, Lippard SJ (2005) Nat Rev Drug Discov 4:307–320CrossRefGoogle Scholar
  19. 19.
    Fuertes MA, Alonso C, Pérez JM (2003) Chem Rev 103:645–662CrossRefGoogle Scholar
  20. 20.
    Jung Y, Lippard SJ (2007) Chem Rev 107:1387–1407CrossRefGoogle Scholar
  21. 21.
    Kelland L (2007) Nat Rev Cancer 7:573–584CrossRefGoogle Scholar
  22. 22.
    Apps M, Choi E, Wheate N (2015) Endocr Relat Cancer 22:219–233CrossRefGoogle Scholar
  23. 23.
    Johnstone TC, Suntharalingam K, Lippard SJ (2016) Chem Rev 116:3436–3486CrossRefGoogle Scholar
  24. 24.
    Huang H, Zhu L, Reid BR, Drobny GP, Hopkins PB (1995) Science 270:1842–1845CrossRefGoogle Scholar
  25. 25.
    Takahara PM, Rosenzweig AC, Frederick CA, Lippard SJ (1995) Nature 377:649–652CrossRefGoogle Scholar
  26. 26.
    Teuben JM, Bauer C, Wang AHJ, Reedijk J (1999) Biochemistry 38:12305–12312CrossRefGoogle Scholar
  27. 27.
    Todd RC, Lippard SJ (2009) Metallomics 1:280–291CrossRefGoogle Scholar
  28. 28.
    Lovejoy KS, Lippard SJ (2009) Dalton Trans 48:10651–10659CrossRefGoogle Scholar
  29. 29.
    Farrell N, Kelland LR, Roberts JR, van Beusichem M (1992) Cancer Res 52:5065–5072Google Scholar
  30. 30.
    Kelland LR, Barnard CFJ, Mellish KJ, Jones M, Goddard PM, Valenti M, Bryant A, Murrer BA, Harrap KR (1994) Cancer Res 54:5618–5622Google Scholar
  31. 31.
    Billecke C, Finniss S, Tahash L, Miller C, Mikkelsen T, Farrell NP, Bögler O (2006) Neuro Oncol 8:215–226CrossRefGoogle Scholar
  32. 32.
    Wu PK, Qu Y, Van Houten B, Farrell N (1994) J Inorg Biochem 54:207–220CrossRefGoogle Scholar
  33. 33.
    Zou Y, Van Houten B, Farrell N (1994) Biochemistry 33:5404–5410CrossRefGoogle Scholar
  34. 34.
    Yang D, van Boom SSGE, Reedijk J, van Boom JH, Farrell N, Wang AHJ (1995) Nat Struct Biol 2:577–578CrossRefGoogle Scholar
  35. 35.
    Wheate NJ, Collins JG (2005) Curr Med Chem Anticancer Agents 5:267–279CrossRefGoogle Scholar
  36. 36.
    Wheate NJ, Collins JG (2003) Coord Chem Rev 241:133–145CrossRefGoogle Scholar
  37. 37.
    Brabec V, Kašpárková J, Vrána O, Nováková O, Cox JW, Qu Y, Farrell N (1999) Biochemistry 38:6781–6790CrossRefGoogle Scholar
  38. 38.
    McGregor TD, Bousfield W, Qu Y, Farrell N (2002) J Inorg Biochem 91:212–219CrossRefGoogle Scholar
  39. 39.
    Gao J, Woolley FR, Zingaro RA (2005) J Med Chem 48:7192–7197CrossRefGoogle Scholar
  40. 40.
    Martinez R, Chacon-Garcia L (2005) Curr Med Chem 12:127–151CrossRefGoogle Scholar
  41. 41.
    Khan QA, Kohlhagen G, Marshall R, Austin CA, Kalena GP, Kroth H, Sayer JM, Jerina DM, Pommier Y (2003) Proc Natl Acad Sci 100:12498–12503CrossRefGoogle Scholar
  42. 42.
    Bolognese A, Correale G, Manfra M, Lavecchia A, Mazzoni O, Novellino E, Colla PL, Sanna G, Loddo R (2004) J Med Chem 47:849–858CrossRefGoogle Scholar
  43. 43.
    Ang D, Harper BW, Cubo L, Mendoza O, Vilar R, Aldrich-Wright JR (2016) Chem Eur J 22:2317–2325CrossRefGoogle Scholar
  44. 44.
    Harper BWJ, Aldrich-Wright JR (2015) Dalton Trans 44:87–96CrossRefGoogle Scholar
  45. 45.
    Yamada M, Tanaka Y, Yoshimoto Y, Kuroda S, Shimao I (1992) Bull Chem Soc Jpn 65:1006–1011CrossRefGoogle Scholar
  46. 46.
    Armstrong LG, Lindoy LF (1975) Inorg Chem 14:1322–1326CrossRefGoogle Scholar
  47. 47.
    Wang F, Chen H, Parsons S, Oswald ID, Davidson JE, Sadler PJ (2003) Chem Eur J 9:5810–5820CrossRefGoogle Scholar
  48. 48.
    Bancroft DP, Lepre CA, Lippard SJ (1990) J Am Chem Soc 112:6860–6871CrossRefGoogle Scholar
  49. 49.
    Miller SE, House DA (1989) Inorg Chim Acta 161:131–137CrossRefGoogle Scholar
  50. 50.
    Batchelor LK, Păunescu E, Soudani M, Scopelliti R, Dyson PJ (2017) Inorg Chem 56:9617–9633CrossRefGoogle Scholar
  51. 51.
    Mendoza-Ferri MG, Hartinger CG, Eichinger RE, Stolyarova N, Severin K, Jakupec MA, Nazarov AA, Keppler BK (2008) Organometallics 27:2405–2407CrossRefGoogle Scholar

Copyright information

© Society for Biological Inorganic Chemistry (SBIC) 2019

Authors and Affiliations

  1. 1.Department of ChemistryLoyola CollegeChennaiIndia

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