Structure-activity relationships for osmium(II) arene phenylazopyridine anticancer complexes functionalised with alkoxy and glycolic substituents

Russell J Needham, Hannah E Bridgewater, Isolda Romero-Canelón, Abraha Habtemariam, Guy J Clarkson, Peter J Sadler

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Abstract

Twenty-four novel organometallic osmium(II) phenylazopyridine (AZPY) complexes have been synthesised and characterised; [Os(η6-arene)(5-RO-AZPY)X]Y, where arene = p-cym or bip, AZPY is functionalized with an alkoxyl (O-R, R = Me, Et, nPr, iPr, nBu) or glycolic (O-{CH2CH2O}nR*, n = 1-4, R* = H, Me, or Et) substituent on the pyridyl ring para to the azo-bond, X is a monodentate halido ligand (Cl, Br or I), and Y is a counter-anion (PF6-, CF3SO3- or IO3-). X-ray crystal structures of two complexes confirmed their 'half-sandwich' structures. Aqueous solubility depended on X, the AZPY substituents, arene, and Y. Iodido complexes are highly stable in water (X = I ⋙ Br > Cl), and exhibit the highest antiproliferative activity against A2780 (ovarian), MCF-7 (breast), SUNE1 (nasopharyngeal), and OE19 (oesophageal) cancer cells, some attaining nanomolar potency and good cancer-cell selectivity. Their activity and distinctive mechanism of action is discussed in relation to hydrophobicity (RP-HPLC capacity factor and Log Po/w), cellular accumulation, electrochemical reduction (activation of azo bond), cell cycle analysis, apoptosis and induction of reactive oxygen species (ROS). Two complexes show ca. 4× higher activity than cisplatin in the National Cancer Institute (NCI) 60-cell line five-dose screen. The COMPARE algorithm of their datasets reveals a strong correlation with one another, as well as anticancer agents olivomycin, phyllanthoside, bouvardin and gamitrinib, but only a weak correlation with cisplatin, indicative of a different mechanism of action.

Original languageEnglish
Article number111154
Number of pages14
JournalJournal of Inorganic Biochemistry
Volume210
Early online date24 Jun 2020
DOIs
Publication statusPublished - 1 Sept 2020
Externally publishedYes

Bibliographical note

This is an open access article under the CC BY license
(http://creativecommons.org/licenses/BY/4.0/).

Funder

ERC (grant nos. 247450 , 324594 ), EPSRC (grant nos. EP/F034210/1 and EP/P030572/1 ), Mike and Enfys Bagguley , (PhD Studentship for HEB), the Wellcome Trust (grant no. 107691/Z/15/Z )

Keywords

  • Organometallic complexes
  • Half sandwich arene complexes
  • Osmium complexes
  • Anticancer
  • Aqueous solubility and stability
  • Mechanism of action

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