Transfer Hydrogenation and Antiproliferative Activity
of Tethered Half-Sandwich Organoruthenium Catalysts
Version 2 2018-06-04, 23:44
Version 1 2018-04-23, 18:20
Posted on 2018-06-04 - 23:44
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.
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Chen, Feng; Romero-Canelón, Isolda; Soldevila-Barreda, Joan J.; Song, Ji-Inn; Coverdale, James P. C.; Clarkson, Guy J.; et al. (2018). Transfer Hydrogenation and Antiproliferative Activity
of Tethered Half-Sandwich Organoruthenium Catalysts. ACS Publications. Collection. https://doi.org/10.1021/acs.organomet.8b00132
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AUTHORS (11)
FC
Feng Chen
IR
Isolda Romero-Canelón
JS
Joan J. Soldevila-Barreda
JS
Ji-Inn Song
JC
James P. C. Coverdale
GC
Guy J. Clarkson
JK
Jana Kasparkova
AH
Abraha Habtemariam
MW
Martin Wills
VB
Viktor Brabec
PS
Peter J. Sadler