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Abstract
Organometallic complexes have the potential to behave as catalytic drugs. We investigate here Rh(III) complexes of general formula [(Cpx)Rh(N,N′)(Cl)], where N,N′ is ethylenediamine (en), 2,2′-bipyridine (bpy), 1,10-phenanthroline (phen) or N-(2-aminoethyl)-4-(trifluoromethyl)benzenesulfonamide (TfEn), and Cpx is pentamethylcyclopentadienyl (Cp*), 1-phenyl-2,3,4,5-tetramethylcyclopentadienyl (CpxPh) or 1-biphenyl-2,3,4,5-tetramethyl cyclopentadienyl (CpxPhPh). These complexes can reduce NAD+ to NADH using formate as a hydride source under biologically-relevant conditions. The catalytic activity decreased in the order of N,N-chelated ligand bpy > phen > en with Cp* as the η5-donor. The en complexes (1–3) became more active with extension to the CpX ring, whereas the activity of the phen (7–9) and bpy (4–6) compounds decreased. [Cp*Rh(bpy)Cl]+ (4) showed the highest catalytic activity, with a TOF of 37.4±2h−1. Fast hydrolysis of the chlorido complexes 1–10 was observed by 1H NMR (<10min at 310K). The pKa* values for the aqua adducts were determined to be ca. 8–10. Complexes 1–9 also catalysed the reduction of pyruvate to lactate using formate as the hydride donor. The efficiency of the transfer hydrogenation reactions was highly dependent on the nature of the chelating ligand and the Cpx ring. Competition reactions between NAD+ and pyruvate for reduction by formate catalysed by 4 showed a preference for reduction of NAD+. The antiproliferative activity of complex 3 towards A2780 human ovarian cancer cells increased by up to 50% when administered in combination with non-toxic doses of formate, suggesting that transfer hydrogenation can induce reductive stress in cancer cells.
Highlights
Transfer hydrogenation reactions for the reduction of ketones, imines or C_C double bonds have been intensively studied in recent years [1,2,3,4]
The aim of the present work was to synthesise a series of Rh(III) Cp* catalysts which can carry out transfer hydrogenation reactions in cells
Ruthenium(II), rhodium (III) and Iridium (III) half sandwich complexes have previously been reported to catalyse the reduction of NAD+ via transfer hydrogenation using sodium formate as a hydride source [22,23,24]
Summary
Transfer hydrogenation reactions for the reduction of ketones, imines or C_C double bonds have been intensively studied in recent years [1,2,3,4]. Precious metal complexes containing Ru, Rh or Ir are often effective as transfer hydrogenation catalysts, and half-sandwich organometallic complexes in particular have achieved high conversions, turnover frequencies (TOF) and enantio-selectivities [1,2,3,4]. Catalytic activity and enantio-selectivity depend on the choice of appropriate chiral ligands, on the substrate, the hydride donor, and on the reaction conditions [1,2,3,5,6,7]. Organo-Ru(II) and -Ir(III) complexes can catalyse hydride transfer reactions under biologically-relevant conditions (pH 7.2, 310 K, aqueous media) [12,13,14,15,16,17].
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