Chen, Feng, Romero-Canelón, Isolda, Soldevila-Barreda, Joan J., Song, Ji-Inn, Coverdale, James P. C., Clarkson, Guy J., Kasparkova, Jana, Habtemariam, Abraha, Wills, Martin, Brabec, Viktor and Sadler, P. J. (2018) Transfer hydrogenation and antiproliferative activity of tethered half-sandwich organoruthenium catalysts. Organometallics, 37 (10). pp. 1555-1566. doi:10.1021/acs.organomet.8b00132 ISSN 0276-7333.

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Abstract

We report the synthesis and characterization of four neutral organometallic tethered complexes, [Ru(η6-Ph(CH2)3-ethylenediamine-N-R)Cl], where R = methanesulfonyl (Ms, 1), toluenesulfonyl (Ts, 2), 4-trifluoromethylbenzenesulfonyl (Tf, 3), and 4-nitrobenzenesulfonyl (Nb, 4), including their X-ray crystal structures. These complexes exhibit moderate antiproliferative activity toward human ovarian, lung, hepatocellular, and breast cancer cell lines. Complex 2 in particular exhibits a low cross-resistance with cisplatin. The complexes show potent catalytic activity in the transfer hydrogenation of NAD+ to NADH with formate as hydride donor in aqueous solution (310 K, pH 7). Substituents on the chelated ligand decreased the turnover frequency in the order Nb > Tf > Ts > Ms. An enhancement of antiproliferative activity (up to 22%) was observed on coadministration with nontoxic concentrations of sodium formate (0.5–2 mM). Complex 2 binds to nucleobase guanine (9-EtG), but DNA appears not to be the target, as little binding to calf thymus DNA or bacterial plasmid DNA was observed. In addition, complex 2 reacts rapidly with glutathione (GSH), which might hamper transfer hydrogenation reactions in cells. Complex 2 induced a dose-dependent G1 cell cycle arrest after 24 h exposure in A2780 human ovarian cancer cells while promoting an increase in reactive oxygen species (ROS), which is likely to contribute to its antiproliferative activity.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry
Divisions:	Faculty of Science, Engineering and Medicine > Science > Chemistry
Library of Congress Subject Headings (LCSH):	Organoruthenium compounds, Catalysts, Catalysis, Hydrogenation
Journal or Publication Title:	Organometallics
Publisher:	American Chemical Society
ISSN:	0276-7333
Official Date:	23 April 2018
Dates:	Date Event 23 April 2018 Published 16 April 2018 Accepted
Volume:	37
Number:	10
Page Range:	pp. 1555-1566
DOI:	10.1021/acs.organomet.8b00132
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Date of first compliant deposit:	9 October 2018
Date of first compliant Open Access:	9 October 2018
RIOXX Funder/Project Grant:	Project/Grant ID RIOXX Funder Name Funder ID 247450 European Research Council http://viaf.org/viaf/130022607 EP/F034210/1 [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 UNSPECIFIED Bruker-Daltonik GmbH (Bremen) http://viaf.org/viaf/147613499 UNSPECIFIED University of Warwick http://dx.doi.org/10.13039/501100000741 17-09436S Grantová Agentura České Republiky http://dx.doi.org/10.13039/501100001824

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