Chen, Feng, Romero-Canelón, Isolda, Habtemariam, Abraha, Song, Ji-Inn, Banerjee, Samya, Clarkson, Guy J., Song, Lijiang, Prokes, Ivan and Sadler, Peter J. (2022) Effect of cysteine thiols on the catalytic and anticancer activity of Ru(ii) sulfonyl-ethylenediamine complexes. Dalton Transactions, 51 (11). pp. 4447-4457. doi:10.1039/D1DT03856G ISSN 1477-9226.

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Abstract

We have synthesized a series of novel substituted sulfonyl ethylenediamine (en) RuII arene complexes 1–8 of [(η6-arene)Ru(R1-SO2-EnBz)X], where the arene is benzene, HO(CH2)2O-phenyl or biphenyl (biph), X = Cl or I, and R1 is phenyl, 4-Me-phenyl, 4-NO2-phenyl or dansyl. The ‘piano-stool’ structure of complex 3, [(η6-biph)Ru(4-Me-phenyl-SO2-EnBz)I], was confirmed by X-ray crystallography. The Image ID:d1dt03856g-t1.gif values of their aqua adducts were determined to be high (9.1 to 9.7). Complexes 1–8 have antiproliferative activity against human A2780 ovarian, and A549 lung cancer cells with IC50 values ranging from 4.1 to >50 μM, although, remarkably, complex 7 [(η6-biph)Ru(phenyl-SO2-EnBz)Cl] was inactive towards A2780 cells, but as potent as the clinical drug cisplatin towards A549 cells. All these complexes also showed catalytic activity in transfer hydrogenation (TH) of NAD+ to NADH with sodium formate as hydride donor, with TOFs in the range of 2.5–9.7 h−1. The complexes reacted rapidly with the thiols glutathione (GSH) and N-acetyl-L-cysteine (NAC), forming dinuclear bridged complexes [(η6-biph)2Ru2(GS)3]2− or [(η6-biph)2Ru2(NAC-H)3]2−, with the liberation of the diamine ligand which was detected by LC-MS. In addition, the switching on of fluorescence for complex 8 in aqueous solution confirmed release of the chelated DsEnBz ligand in reactions with these thiols. Reactions with GSH hampered the catalytic TH of NAD+ to NADH due to the decomposition of the complexes. Co-administration to cells of complex 2 [(η6-biph)Ru(4-Me-phenyl-SO2-EnBz)Cl] with L-buthionine sulfoximine (L-BSO), an inhibitor of GSH synthesis, partially restored the anticancer activity towards A2780 ovarian cancer cells. Complex 2 caused a concentration-dependent G1 phase cell cycle arrest, and induced a significant level of reactive oxygen species (ROS) in A2780 human ovarian cancer cells. The amount of induced ROS decreased with increase in GSH concentration, perhaps due to the formation of the dinuclear Ru-SG complex.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry
Divisions:	Faculty of Science, Engineering and Medicine > Science > Chemistry
Library of Congress Subject Headings (LCSH):	Organometallic compounds -- Synthesis, Ethylenediamine, Cysteine, Glutathione, Hydrogenation
Journal or Publication Title:	Dalton Transactions
Publisher:	Royal Society of Chemistry
ISSN:	1477-9226
Official Date:	March 2022
Dates:	Date Event March 2022 Published 28 February 2022 Available 14 January 2022 Accepted
Volume:	51
Number:	11
Page Range:	pp. 4447-4457
DOI:	10.1039/D1DT03856G
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Date of first compliant deposit:	1 March 2022
Date of first compliant Open Access:	1 March 2022
RIOXX Funder/Project Grant:	Project/Grant ID RIOXX Funder Name Funder ID EP/F034210/1 [EPSRC] Engineering and Physical Sciences Research Council http://dx.doi.org/10.13039/501100000266 EP/P030572/1 [EPSRC] Engineering and Physical Sciences Research Council http://dx.doi.org/10.13039/501100000266 EP/M027503/1 [EPSRC] Engineering and Physical Sciences Research Council http://dx.doi.org/10.13039/501100000266 UNSPECIFIED China Scholarship Council http://dx.doi.org/10.13039/501100004543 NF151429 Royal Society http://dx.doi.org/10.13039/501100000288

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