Fu, Y. (Ying), Habtemariam, Abraha, Basri, Aida M. B. H., Braddick, Darren, Clarkson, Guy J. and Sadler, P. J.. (2011) Structure–activity relationships for organometallic osmium arene phenylazopyridine complexes with potent anticancer activity. Dalton Transactions, Vol.40 (No.40). p. 10553. ISSN 1477-9226

Full text not available from this repository.

Abstract

We report the synthesis and characterisation of 32 half sandwich phenylazopyridine OsII arene complexes [Os(η6-arene)(phenylazopyridine)X]+ in which X is chloride or iodide, the arene is p-cymene or biphenyl and the pyridine and phenyl rings contain a variety of substituents (F, Cl, Br, I, CF3, OH or NO2). Ten X-ray crystal structures have been determined. Cytotoxicity towards A2780 human ovarian cancer cells ranges from high potency at nanomolar concentrations to inactivity. In general the introduction of an electron-withdrawing group (e.g. F, Cl, Br or I) at specific positions on the pyridine ring significantly increases cytotoxic activity and aqueous solubility. Changing the arene from p-cymene to biphenyl and the monodentate ligand X from chloride to iodide also increases the activity significantly. Activation by hydrolysis and DNA binding appears not to be the major mechanism of action since both the highly active complex [Os(η6-bip)(2-F-azpy)I]PF6 (9) and the moderately active complex [Os(η6-bip)(3-Cl-azpy)I]PF6 (23) are very stable and inert towards aquation. Studies of octanol–water partition coefficients (log P) and subcellular distributions of osmium in A2780 human ovarian cancer cells suggested that cell uptake and targeting to cellular organelles play important roles in determining activity. Although complex 9 induced the production of reactive oxygen species (ROS) in A2780 cells, the ROS level did not appear to play a role in the mechanism of anticancer activity. This class of organometallic osmium complexes has new and unusual features worthy of further exploration for the design of novel anticancer drugs.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry
Divisions:	Faculty of Science > Chemistry
Library of Congress Subject Headings (LCSH):	Structure-activity relationships (Biochemistry), Osmium compounds, Organometallic compounds, Antineoplastic agents
Journal or Publication Title:	Dalton Transactions
Publisher:	Royal Society of Chemistry
ISSN:	1477-9226
Date:	2011
Volume:	Vol.40
Number:	No.40
Page Range:	p. 10553
Identification Number:	10.1039/c1dt10937e
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	European Research Council (ERC), Engineering and Physical Sciences Research Council (EPSRC), European Regional Development Fund (ERDF), Advantage West Midlands (AWM)
Grant number:	247450 (ERC)
References:	1 B. Rosenberg, L. Vancamp, J. E. Trosko and V. H. Mansour, Nature, 1969, 222, 385–386. 2 C. G. Hartinger and P. J. Dyson, Chem. Soc. Rev., 2009, 38, 391–401. 3 G. Gasser, I. Ott and N. Metzler-Nolte, J. Med. Chem., 2011, 54, 3–25. 4 H. Elizabeth, V. Anne, T. Laurent, J. Gerard and A. Christian, ´ Angew. Chem., 2006, 118, 291–296. 5 R. E. Morris, R. E. Aird, P. del Socorro Murdoch, H. Chen, J. Cummings, N. D. Hughes, S. Parsons, A. Parkin, G. Boyd, D. I. Jodrell and P. J. Sadler, J. Med. Chem., 2001, 44, 3616–3621. 6 R. E. Aird, J. Cummings, A. A. Ritchie, M. Muir, R. E. Morris, H. Chen, P. J. Sadler and D. I. Jodrell, Br. J. Cancer, 2002, 86, 1652–1657. 7 H. Chen, J. A. Parkinson, S. Parsons, R. A. Coxall, R. O. Gould and P. J. Sadler, J. Am. Chem. Soc., 2002, 124, 3064–3082. 8 C. Scolaro, A. Bergamo, L. Brescacin, R. Delfino, M. Cocchietto, G. Laurenczy, T. J. Geldbach, G. Sava and P. J. Dyson, J. Med. Chem., 2005, 48, 4161–4171. 9 K. V. Kong, W. K. Leong and L. H. K. Lim, Chem. Res. Toxicol., 2009, 22, 1116–1122. 10 L. K. Filak, G. Muhlgassner, F. Bacher, A. Roller, M. Galanski, M. A. ¨ Jakupec, B. K. Keppler and V. B. Arion, Organometallics, 2011, 30, 273–283. 11 M. Hanif, A. A. Nazarov, C. G. Hartinger, W. Kandioller, M. A. Jakupec, V. B. Arion, P. J. Dyson and B. K. Keppler, Dalton Trans., 2010, 39, 7345–7352. 12 W.-X. Ni, W.-L. Man, M. T.-W. Cheung, R. W.-Y. Sun, Y.-L. Shu, Y.-W. Lam, C.-M. Che and T.-C. Lau, Chem. Commun., 2011, 47, 2140–2142. 13 A. F. A. Peacock and P. J. Sadler, Chem.–Asian J., 2008, 3, 1890–1899. 14 A. Bergamo, A. Masi, A. F. A. Peacock, A. Habtemariam, P. J. Sadler and G. Sava, J. Inorg. Biochem., 2010, 104, 79–86. 15 K. Kien Voon, L. Weng Kee, N. Swee Phyaw, N. Thanh Hung and H. K. L. Lina, ChemMedChem, 2008, 3, 1269–1275. 16 A. Dorcier, W. H. Ang, S. Bolano, L. Gonsalvi, L. Juillerat-Jeannerat, G. Laurenczy, M. Peruzzini, A. D. Phillips, F. Zanobini and P. J. Dyson, Organometallics, 2006, 25, 4090–4096. 17 A. F. A. Peacock, S. Parsons and P. J. Sadler, J. Am. Chem. Soc., 2007, 129, 3348–3357. 18 J. Maksimoska, D. S. Williams, G. Ekin Atilla-Gokcumen, K. S. M. Smalley, P. J. Carroll, R. D. Webster, P. Filippakopoulos, S. Knapp, M. Herlyn and E. Meggers, Chem.–Eur. J., 2008, 14, 4816–4822. 19 B. Cebrian-Losantos, A. A. Krokhin, I. N. Stepanenko, R. Eichinger, ´ M. A. Jakupec, V. B. Arion and B. K. Keppler, Inorg. Chem., 2007, 46, 5023–5033. 20 D. J. Ward and H. Sheppeard, Rheumatology, 1980, 19, 25–29. 21 F. E. Berglof, Scand. J. Rheumatol., 1959, 5, 70–74. 22 C. J. Menkes, Rheumatology, 1979, 18, 65–77. 23 Platinum, Gold, and Other Metal Chemotherapeutic Agents (ACS symposium series), ed. C. Hinckley, C. N. Bemiller, L. J. E. Strack and L. D. Russell, American Chemical Society, 1983, vol. 209. 24 Y. Fu, A. Habtemariam, A. M. Pizarro, S. H. van Rijt, D. J. Healey, P. A. Cooper, S. D. Shnyder, G. J. Clarkson and P. J. Sadler, J. Med. Chem., 2010, 53, 8192–8196. 25 S. D. Shnyder, Y. Fu, A. Habtemariam, S. H. van Rijt, P. A. Cooper, P. M. Loadman and P. J. Sadler, Med. Chem. Commun., 2011, 2, 666– 668. 26 S. J. Dougan, A. Habtemariam, S. E. McHale, S. Parsons and P. J. Sadler, Proc. Natl. Acad. Sci. U. S. A., 2008, 105, 11628–11633. 27 S. H. van Rijt, A. Mukherjee, A. M. Pizarro and P. J. Sadler, J. Med. Chem., 2010, 53, 840–849. 28 D. F. Veber, S. R. Johnson, H.-Y. Cheng, B. R. Smith, K. W. Ward and K. D. Kopple, J. Med. Chem., 2002, 45, 2615–2623. 29 Y. C. Martin, J. Med. Chem., 1981, 24, 229–237. 30 K. Birchall, V. J. Gillet, P. Willett, P. Ducrot and C. Luttmann, J. Chem. Inf. Model., 2009, 49, 1330–1346. 31 G. A. Patani and E. J. LaVoie, Chem. Rev., 1996, 96, 3147–3176. 32 J. E. Liebmann, S. M. Hahn, J. A. Cook, C. Lipschultz, J. B. Mitchell and D. C. Kaufman, Cancer Res., 1993, 53, 2066–2070. 33 S. H. van Rijt, A. J. Hebden, T. Amaresekera, R. J. Deeth, G. J. Clarkson, S. Parsons, P. C. McGowan and P. J. Sadler, J. Med. Chem., 2009, 52, 7753–7764. 34 M. J. McKeage, S. J. Berners-Price, P. Galettis, R. J. Bowen, W. Brouwer, L. Ding, L. Zhuang and B. C. Baguley, Cancer Chemother. Pharmacol., 2000, 46, 343–350. 35 B. Halliwell and M. Whiteman, Br. J. Pharmacol., 2004, 142, 231– 255. 36 H. Wang and J. A. Joseph, Free Radical Biol. Med., 1999, 27, 612– 616. 37 A. Gomes, E. Fernandes and J. L. F. C. Lima, J. Biochem. Biophys. Methods, 2005, 65, 45–80. 38 R. F. Ozols, K. G. Louie, J. Plowman, B. C. Behrens, R. L. Fine, D. Dykes and T. C. Hamilton, Biochem. Pharmacol., 1987, 36, 147–153. 39 O. I. Aruoma, B. Halliwell, B. M. Hoey and J. Butler, Free Radical Biol. Med., 1989, 6, 593–597. 40 S. J. Dougan, M. Melchart, A. Habtemariam, S. Parsons and P. J. Sadler, Inorg. Chem., 2006, 45, 10882–10894. 41 C. A. Hunter and J. K. M. Sanders, J. Am. Chem. Soc., 1990, 112, 5525–5534. 42 O. Novakova, H. Chen, O. Vrana, A. Rodger, P. J. Sadler and V. Brabec, Biochemistry, 2003, 42, 11544–11554. 43 W. Hu, Q. Luo, X. Ma, K. Wu, J. Liu, Y. Chen, S. Xiong, J. Wang, P. J. Sadler and F. Wang, Chem.–Eur. J., 2009, 15, 6586–6594. 44 D. Trachootham, J. Alexandre and P. Huang, Nat. Rev. Drug Discovery, 2009, 8, 579–591. 45 L. K. Hosking, R. D. H. Whelan, S. A. Shellard, P. Bedford and B. T. Hill, Biochem. Pharmacol., 1990, 40, 1833–1842. 46 Z. H. Siddik, Oncogene, 2003, 22, 7265–7279. 47 H. H. Bailey, R. T. Mulcahy, K. D. Tutsch, R. Z. Arzoomanian, D. Alberti, M. B. Tombes, G. Wilding, M. Pomplun and D. R. Spriggs, J. Clin. Oncol., 1994, 12, 194–205. 48 T. C. Hamilton, M. A. Winker, K. G. Louie, G. Batist, B. C. Behrens, T. Tsuruo, K. R. Grotzinger, W. M. McKoy, R. C. Young and R. F. Ozols, Biochem. Pharmacol., 1985, 34, 2583–2586. 49 H. Maeda, S. Hori, H. Ohizumi, T. Segawa, Y. Kakehi, O. Ogawa and A. Kakizuka, Cell Death Differ., 2004, 11, 737–746. 50 E. A. Meyer, R. K. Castellano and F. Diederich, Angew. Chem., Int. Ed., 2003, 42, 1210–1250. 51 J. A. Platts, D. E. Hibbs, T. W. Hambley and M. D. Hall, J. Med. Chem., 2001, 44, 472–474. 52 M. Groessl, E. Reisner, C. G. Hartinger, R. Eichinger, O. Semenova, A. R. Timerbaev, M. A. Jakupec, V. B. Arion and B. K. Keppler, J. Med. Chem., 2007, 50, 2185–2193. 53 F. Yu, J. Megyesi and P. M. Price, Am. J. Physiol.: Renal Physiol., 2008, 295, F44–52. 54 E. R. Jamieson and S. J. Lippard, Chem. Rev., 1999, 99, 2467–2498. 55 A. F. A. Peacock, A. Habtemariam, S. A. Moggach, A. Prescimone, S. Parsons and P. J. Sadler, Inorg. Chem., 2007, 46, 4049–4059. 56 CrysAlis PRO, Oxford Diffraction Ltd., Abington, Oxfordshire, U.K., 2007. 57 G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr., 1990, 46, 467–473. 58 G. M. Sheldrick, SHELX97, Programs for Crystal Structure Analysis (Release 97-92), University of Gottingen, Germany, 1997. ¨ 59 V. Vichai and K. Kirtikara, Nat. Protoc., 2006, 1, 1112–1116.
URI:	http://wrap.warwick.ac.uk/id/eprint/39548

Request changes to a record

Actions (login required)

View Item