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

Abstract

A series of neutral pseudo-octahedral Ru^II 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 Ru^II 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.