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Structure–activity relationships for organometallic osmium arene phenylazopyridine complexes with potent anticancer activity

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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 (No.40). pp. 10553-10562. ISSN 1477-9226

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Official URL: http://dx.doi.org/10.1039/c1dt10937e

Abstract

We report the synthesis and characterisation of 32 half sandwich phenylazopyridine Os(II) arene complexes [Os(eta(6)-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, CF(3), OH or NO(2)). 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(eta(6)-bip)(2-F-azpy)I]PF(6) (9) and the moderately active complex [Os(eta(6)-bip)(3-Cl-azpy)I]PF(6) (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 R Medicine > RM Therapeutics. Pharmacology
Divisions:	Faculty of Science > Chemistry
Library of Congress Subject Headings (LCSH):	Drugs -- Structure-activity relationships, Antineoplastic agents -- Development, Aromatic compounds -- Therapeutic use, Osmium compounds -- Therapeutic use, Complex compounds -- Synthesis, Organometallic compounds -- Therapeutic use
Journal or Publication Title:	Dalton Transactions
Publisher:	Royal Society of Chemistry
ISSN:	1477-9226
Date:	2011
Number:	No.40
Page Range:	pp. 10553-10562
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), Advantage West Midlands (AWM), European Regional Development Fund (ERDF)
Grant number:	247450 (ERC)
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URI:	http://wrap.warwick.ac.uk/id/eprint/39639