Complexes incorporating picolinamide ligands have been reported with a wide variety of metals including copper, nickel, iron, manganese, zinc, cadmium, cobalt, ruthenium, osmium and the lanthanides amongst others.170, 305-311 The McGowan group has extensively researched picolinamide complexes with ruthenium, rhodium, iridium, titanium and copper for application in catalysis and drug discovery.170, 171, 312-314
Ruthenium, rhodium and iridium arene complexes with picolinamide ligands have been investigated for their anti-cancer potential within the McGowan group.
Picolinamide ligands within ruthenium p-cymene complexes were found to adopt different coordination modes (N,N or N,O bound) depending upon the nature of the ligand substituent modulated by temperature and pH (Figure 1.26a and Figure 1.26b). Neutral complexes with N,N bound picolinamide underwent rapid hydrolysis, rapid binding to guanine and significant cytotoxicity (IC50 < 25 μM); in contrast monocationic complexes with N,O bound picolinamide underwent slow hydrolysis, did not bind to DNA and were non-cytotoxic.310The positioning, number and nature
of the substituents on the picolinamide ligand was found to have a significant effect on cytotoxicity.170 Analogous monocationic ruthenium p-cymene complexes with N-methyl picolinamide ligands (N,O bound) are non-toxic.315 Rhodium and iridium Cp* complexes with picolinamide ligands (Figure 1.26c) showed moderate anti-cancer activity (IC50 = 30 - 80 μM), with improvements in activity when the picolinamide ligand is substituted for a ketoiminate ligand (IC50 = 3 - 5 μM).171 Rhodium and iridium picolinamide complexes with functionalised Cp* arene containing hydroxyl tethered arms of various carbon chain lengths displayed cytotoxicity (IC50 = 50 - 130 μM) against a number of different cell lines (Figure 1.26d). Cytotoxicity improved proportionally with carbon chain length, with the most promising results for the 14-carbon tethered Cp* rhodium and iridium picolinamide complexes. The mechanism of action of these complexes may involve disruption of cell anti-oxidant function through inhibition of thioredoxin reductase.316
Figure 1.26: Metal arene picolinamide complexes a) neutral ruthenium p-cymene complexes with N,N-bound picolinamide b) monocationic ruthenium p-cymene complexes with N,O-bound picolinamide c) rhodium and iridium Cp* picolinamide complexes d) rhodium and iridium hydroxyl tethered Cp*
picolinamide complexes
Ruthenium and rhodium coordination complexes with picolinamide ligands have also been investigated for their anti-cancer potential within the McGowan group.
These complexes consist of two picolinamide ligands, one N,N bound and one N,O bound, and two labile halide ligands attached to a ruthenium(III) or rhodium(III)
central ion (Figure 1.27). Ruthenium and rhodium complexes with labile chloride ligands formed a mixture of three geometric isomers: cis-trans-cis, cis-cis-cis and trans-trans-trans. However, when iodide ligands are present only the trans-trans-trans isomer is formed. This is thought to be due to the larger ionic radius of the iodide, compared to the chloride ion, which means that the iodide ions preferentially adopt the trans position to minimise electronic overlap. Ruthenium and rhodium complexes with iodide ligands displayed improved cytotoxicity (IC50 = 1 - 40 μM) compared to the complexes with chloride ligands (IC50 = 5 - 90 μM).
In addition, substitutions in the meta and para positions of the picolinamide aryl ring were associated with improved cytotoxicity. In the chloride complexes, improved cytotoxicity was associated with increased hydrolysis rates. Whereas in the iodide complexes, improved cytotoxicity was associated with decreased hydrolysis rates.312
Figure 1.27: Metal bis-picolinamide bis-halide complexes. Geometric (cis / trans) descriptors are designated in the order: halide ligand, picolinamide pyridyl
ring, picolinamide amide group. M = Ru, Rh
1.9 Objectives
The objective of this research was the exploration of the chemistry and biology of a variety of cobalt picolinamide complexes with different structural features. Metal picolinamide complexes previously investigated contain a number of elements which are thought to be important for anti-cancer activity (Figure 1.28). The planar aromatic pyridyl and aryl rings of the picolinamide ligand provide a potential site for π-π stacking interactions with nucleobases within DNA. The acidic amide proton of the picolinamide ligand provides a potential hydrogen bonding site for interactions with biomolecules. The substituents on the picolinamide aryl ring can affect the hydrophobicity and cellular uptake of the complex and can affect the anti-cancer activity. The presence of a labile halide or pseudohalide ligand allows the possibility of activation by ligand exchange to form more reactive species which may then interact with target biomolecules.
Figure 1.28: Potential cobalt picolinamide complexes including sites of potential variation
There have only been a few reported cobalt picolinamide complexes with even fewer having undergone biological investigation. There are a number of features of cobalt picolinamide complexes which may be varied in order to fully explore the potential of these complexes. The oxidation state of the central cobalt ion may be varied as cobalt(II) and cobalt(III) complexes are stable in biological systems. The number of picolinamide ligands and the nature of the ligand binding to the metal (N,N or N,O coordination) can be varied and will affect the overall charge of the complex and the number of possible isomers. The substituents present on the picolinamide aryl ring can be varied to investigate how differing electronic and steric groups affect the biological activity. Additional ligands may also be varied from labile halide ligands to more stable alternative bidentate ligands. This research aimed to investigate the importance of all of these different structural variations within cobalt picolinamide complexes with respect to the biological activity of the complexes.
1.10 References
1. P. D. Sasieni, J. Shelton, N. Ormiston-Smith, C. S. Thomson and P. B. Silcocks, British Journal of Cancer, 2011, 105, 460-465.
2. Cancer Research UK, Cancer mortality for all cancers combined,
http://www.cancerresearchuk.org/health-professional/cancer-statistics/mortality, Accessed 06/02/2017.
3. A. Aggarwal and R. Sullivan, Journal of Cancer Policy, 2014, 2, 31-39.
4. Cancer Research UK, Cancer incidence statistics,
http://www.cancerresearchuk.org/health-professional/cancer-statistics/incidence, Accessed 06/02/2017.
5. A. Jemal, F. Bray, M. M. Center, J. Ferlay, E. Ward and D. Forman, Ca- A Cancer Journal for Clinicians, 2011, 61, 69-90.
6. Cancer Research UK, Worldwide cancer statistics,
http://www.cancerresearchuk.org/health-professional/cancer-statistics/worldwide-cancer, Accessed 06/02/2017.
7. World Health Organisation, Cancer,
http://www.who.int/mediacentre/factsheets/fs297/en/, Accessed 06/02/2017.
8. A. G. Knudson, Proceedings of the National Academy of Sciences of the United States of America, 1971, 68, 820-823.
9. P. Boffetta and F. Nyberg, British Medical Bulletin, 2003, 68, 71-94.
10. D. Hanahan and R. A. Weinberg, Cell, 2000, 100, 57-70.
11. D. Hanahan and R. A. Weinberg, Cell, 2011, 144, 646-674.
12. S. Mercadante, V. Gebbia, A. Marrazzo and S. Filosto, Cancer Treatment Reviews, 2000, 26, 303-311.
13. H. Suzuki, A. Asakawa, H. Amitani, N. Nakamura and A. Inui, Journal of Gastroenterology, 2013, 48, 574-594.
14. M. von Elstermann, Nature Reviews Cancer, 2008, 8, 410-411.
15. A. Urruticoechea, R. Alemany, J. Balart, A. Villanueva, F. Vinals and G. Capella, Current Pharmaceutical Design, 2010, 16, 3-10.
16. Institute of Medicine, eds. C. M. Pechura and D. P. Rall, National Acadamy Press, Washington, Editon edn., 1993.
17. V. T. DeVita, Jr. and E. Chu, Cancer Research, 2008, 68, 8643-8653.
18. M. Frezza, S. Hindo, D. Chen, A. Davenport, S. Schmitt, D. Tomco and Q. P.
Dou, Current Pharmaceutical Design, 2010, 16, 1813-1825.
19. C. Orvig and M. J. Abrams, Chemical Reviews, 1999, 99, 2201-2203.
20. F. P. Dwyer, E. C. Gyarfas, W. P. Rogers and J. H. Koch, Nature, 1952, 170, 190-191.
21. D. Gaynor and D. M. Griffith, Dalton Transactions, 2012, 41, 13239-13257.
22. C. A. Lipinski, F. Lombardo, B. W. Dominy and P. J. Feeney, Advanced Drug Delivery Reviews, 2001, 46, 3-26.
23. P. Yang and M. L. Guo, Coordination Chemistry Reviews, 1999, 185-6, 189-211.
24. N. Farrell, L. R. Kelland, J. D. Roberts and M. Vanbeusichem, Cancer Research, 1992, 52, 5065-5072.
25. L. R. Kelland, C. F. J. Barnard, K. J. Mellish, M. Jones, P. M. Goddard, M.
Valenti, A. Bryant, B. A. Murrer and K. R. Harrap, Cancer Research, 1994, 54, 5618-5622.
26. A. L. Noffke, A. Habtemariam, A. M. Pizarro and P. J. Sadler, Chemical Communications, 2012, 48, 5219-5246.
27. B. Rosenberg, L. Vancamp, J. E. Trosko and V. H. Mansour, Nature, 1969, 222, 385-386.
28. O. R. Allen, R. J. Knox and P. C. McGowan, Dalton Transactions, 2008, 1293-1295.
29. A. Cuin, A. C. Massabni, G. A. Pereira, C. Q. Fujimura Leite, F. R. Pavan, R.
Sesti-Costa, T. A. Heinrich and C. M. Costa-Neto, Biomedicine &
Pharmacotherapy, 2011, 65, 334-338.
30. B. Desoize, Anticancer Research, 2004, 24, 1529-1544.
31. Z. Liu, A. Habtemariam, A. M. Pizarro, S. A. Fletcher, A. Kisova, O. Vrana, L.
Salassa, P. C. A. Bruijnincx, G. J. Clarkson, V. Brabec and P. J. Sadler, Journal of Medicinal Chemistry, 2011, 54, 3011-3026.
32. I. Ott and R. Gust, Archiv Der Pharmazie, 2007, 340, 117-126.
33. C. Santini, M. Pellei, V. Gandin, M. Porchia, F. Tisato and M. Marzano, Chemical Reviews, 2014, 114, 815-862.
34. S. H. van Rijt, A. F. A. Peacock, R. D. L. Johnstone, S. Parsons and P. J. Sadler, Inorganic Chemistry, 2009, 48, 1753-1762.
35. A. R. Kapdi and I. J. S. Fairlamb, Chemical Society Reviews, 2014, 43, 4751-4777.
36. M. Nath, M. Vats and P. Roy, European Journal of Medicinal Chemistry, 2013, 59, 310-321.
37. E. Wong and C. M. Giandomenico, Chemical Reviews, 1999, 99, 2451-2466.
38. B. Rosenberg, L. Vancamp and T. Krigas, Nature, 1965, 205, 698-699.
39. B. Rosenberg and L. Vancamp, Cancer Research, 1970, 30, 1799-1802.
40. E. Blanchard, Journal of Solid Tumors, 2012, 2, 26-33.
41. National Cancer Institute at the National Institutes of Health, Cancer drug
information - cisplatin,
http://www.cancer.gov/cancertopics/druginfo/cisplatin, Accessed 15/02/2017.
42. J. J. Liu, J. Lu and M. J. McKeage, Current Cancer Drug Targets, 2012, 12, 962-986.
43. B. Crossley, PhD Thesis, The University of Leeds, 2011.
44. A. Eastman, Pharmacology & Therapeutics, 1987, 34, 155-166.
45. A. E. Egger, C. G. Hartinger, H. Ben Hamidane, Y. O. Tsybin, B. K. Keppler and P. J. Dyson, Inorganic Chemistry, 2008, 47, 10626-10633.
46. A. M. J. Fichtinger-Schepman, J. L. Vanderveer, J. H. J. Denhartog, P. H. M.
Lohman and J. Reedijk, Biochemistry, 1985, 24, 707-713.
47. E. R. Jamieson and S. J. Lippard, Chemical Reviews, 1999, 99, 2467-2498.
48. J. J. Roberts and F. Friedlos, Pharmacology & Therapeutics, 1987, 34, 215-246.
49. C. A. Rabik and M. E. Dolan, Cancer Treatment Reviews, 2007, 33, 9-23.
50. M. A. Fuertes, J. Castilla, C. Alonso and J. M. Perez, Current Medicinal Chemistry - Anti-Cancer Agents, 2002, 2, 539-551.
51. T. W. Hambley, Journal of the Chemical Society-Dalton Transactions, 2001, 2711-2718.
52. A. Basu and S. Krishnamurthy, Journal of Nucleic Acids, 2010, 2010, Article ID:
201367.
53. R. A. Alderden, M. D. Hall and T. W. Hambley, Journal of Chemical Education, 2006, 83, 728-734.
54. A. Gelasco and S. J. Lippard, Biochemistry, 1998, 37, 9230-9239.
55. N. J. Wheate, S. Walker, G. E. Craig and R. Oun, Dalton Transactions, 2010, 39, 8113-8127.
56. A. I. Ivanov, J. Christodoulou, J. A. Parkinson, K. J. Barnham, A. Tucker, J.
Woodrow and P. J. Sadler, Journal of Biological Chemistry, 1998, 273, 14721-14730.
57. R. C. Dolman, G. B. Deacon and T. W. Hambley, Journal of Inorganic Biochemistry, 2002, 88, 260-267.
58. R. F. Borch and M. E. Pleasants, Proceedings of the National Academy of Sciences of the United States of America, 1979, 76, 6611-6614.
59. J. P. Fillastre and G. Raguenezviotte, Toxicology Letters, 1989, 46, 163-175.
60. N. Pabla and Z. Dong, Oncotarget, 2012, 3, 107-111.
61. A. S. Jaggi and N. Singh, Toxicology, 2012, 291, 1-9.
62. P. R. Brock, K. R. Knight, D. R. Freyer, K. C. M. Campbell, P. S. Steyger, B. W.
Blakley, S. R. Rassekh, K. W. Chang, B. J. Fligor, K. Rajput, M. Sullivan and E.