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

doi:10.1016/j.jinorgbio.2020.111154

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

University of Warwick

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

113 Downloads (Pure)

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 language	English
Article number	111154
Number of pages	14
Journal	Journal of Inorganic Biochemistry
Volume	210
Early online date	24 Jun 2020
DOIs	https://doi.org/10.1016/j.jinorgbio.2020.111154
Publication status	Published - 1 Sept 2020
Externally published	Yes

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 )

Funding

We thank the 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), and Anglo American Platinum, for their support for this project. We also thank Heraeus for the gift of some osmium, the National Cancer Institute for NCI-60 screening, Wen-Ying Zhang, Dr. Lijiang Song and Dr. Ivan Prokes for assistance with electrochemistry, ICP-OES, ICP-MS, ESI-MS, and NMR, and Dr. Jessica M. Hearn for helpful discussion of NCI data. The authors have no conflicts of interest.

Funders	Funder number
Heraeus
Anglo American Platinum
National Cancer Institute
Wellcome Trust	107691/Z/15/Z
European Research Council	247450, 324594
Engineering and Physical Sciences Research Council	EP/F034210/1, EP/P030572/1

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

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10.1016/j.jinorgbio.2020.111154Licence: CC BY

PublishedFinal published version, 4.21 MBLicence: CC BY

Cite this

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

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.",

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T1 - Structure-activity relationships for osmium(II) arene phenylazopyridine anticancer complexes functionalised with alkoxy and glycolic substituents

AU - Needham, Russell J

AU - Bridgewater, Hannah E

AU - Romero-Canelón, Isolda

AU - Habtemariam, Abraha

AU - Clarkson, Guy J

AU - Sadler, Peter J

N1 - This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).

PY - 2020/9/1

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N2 - 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.

AB - 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.

KW - Organometallic complexes

KW - Half sandwich arene complexes

KW - Osmium complexes

KW - Anticancer

KW - Aqueous solubility and stability

KW - Mechanism of action

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DO - 10.1016/j.jinorgbio.2020.111154

M3 - Article

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SN - 0162-0134

VL - 210

JO - Journal of Inorganic Biochemistry

JF - Journal of Inorganic Biochemistry

M1 - 111154

ER -

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

Abstract

Bibliographical note

Funder

Funding

UN SDGs

Keywords

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