TY - JOUR
T1 - Half-sandwich rhodium(III) transfer hydrogenation catalysts:
T2 - Reduction of NAD + and pyruvate, and antiproliferative activity
AU - Soldevila-Barreda, Joan J.
AU - Habtemariam, Abraha
AU - Romero-canelón, Isolda
AU - Sadler, Peter J.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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 ± 2 h− 1. Fast hydrolysis of the chlorido complexes 1–10 was observed by 1H NMR (< 10 min at 310 K). 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.
AB - 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 ± 2 h− 1. Fast hydrolysis of the chlorido complexes 1–10 was observed by 1H NMR (< 10 min at 310 K). 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.
KW - NADH
KW - NAD+
KW - pyruvate
KW - transfer-hydrogenation
KW - anticancer
KW - organo-rhodium
U2 - 10.1016/j.jinorgbio.2015.10.008
DO - 10.1016/j.jinorgbio.2015.10.008
M3 - Article
SN - 0162-0134
VL - 153
SP - 322
EP - 333
JO - Journal of Inorganic Biochemistry
JF - Journal of Inorganic Biochemistry
ER -