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Effect of sulfonamidoethylenediamine substituents in RuII arene anticancer catalysts on transfer hydrogenation of coenzyme NAD+ by formate

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Abstract

A series of neutral pseudo-octahedral RuII sulfonamidoethylenediamine complexes [(η6-p-cym)Ru(N,N′)Cl] where N,N′ is N-(2-(R1,R2-amino)ethyl)-4-toluenesulfonamide (TsEn(R1,R2)) R1,R2 = Me,H (1); Me,Me (2); Et,H (3); benzyl,H (Bz, 4); 4-fluorobenzyl,H (4-F-Bz, 5) or naphthalen-2-ylmethyl,H (Naph, 6), were synthesised and characterised including the X-ray crystal structure of 3. These complexes catalyse the reduction of NAD+ regioselectively to 1,4-NADH by using formate as the hydride source. The catalytic efficiency depends markedly on the steric and electronic effects of the N-substitutent, with turnover frequencies (TOFs) increasing in the order: 1 < 2 < 3, 6 < 4, 5, achieving a TOF of 7.7 h−1 for 4 with a 95% yield of 1,4-NADH. The reduction rate was highest between pH* (deuterated solvent) 6 and 7.5 and improved with an increase in formate concentration (TOF of 18.8 h−1, 140 mM formate). The calculations suggested initial substitution of an aqua ligand by formate, followed by hydride transfer to RuII and then to NAD+, and indicated specific interactions between the aqua complex and both NAD+ and NADH, the former allowing a preorganisation involving interaction between the aqua ligand, formate anion and the pyridine ring of NAD+. The complexes exhibited antiproliferative activity towards A2780 human ovarian cancer cells with IC50 values ranging from 1 to 31 μM, the most potent complex, [(η6-p-cym)Ru(TsEn(Bz,H))Cl] (4, IC50 = 1.0 ± 0.1 μM), having a potency similar to the anticancer drug cisplatin. Co-administration with sodium formate (2 mM), increased the potency of all complexes towards A2780 cells by 20–36%, with the greatest effect seen for complex 6.

Graphical abstract: Effect of sulfonamidoethylenediamine substituents in RuII arene anticancer catalysts on transfer hydrogenation of coenzyme NAD+ by formate

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Publication details

The article was received on 01 Feb 2018, accepted on 05 Mar 2018 and first published on 13 Apr 2018


Article type: Paper
DOI: 10.1039/C8DT00438B
Citation: Dalton Trans., 2018, Advance Article
  • Open access: Creative Commons BY license
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    Effect of sulfonamidoethylenediamine substituents in RuII arene anticancer catalysts on transfer hydrogenation of coenzyme NAD+ by formate

    F. Chen, J. J. Soldevila-Barreda, I. Romero-Canelón, J. P. C. Coverdale, J. Song, G. J. Clarkson, J. Kasparkova, A. Habtemariam, V. Brabec, J. A. Wolny, V. Schünemann and P. J. Sadler, Dalton Trans., 2018, Advance Article , DOI: 10.1039/C8DT00438B

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