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

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.

• Authors: Feng Chen , Joan J Soldevila-Barreda , Isolda Romero-Canelón , James P C Coverdale , Ji-Inn Song , Guy J Clarkson , Jana Kasparkova , Abraha Habtemariam , Viktor Brabec , Juliusz A Wolny , Volker Schünemann , Peter J Sadler
• Journal: Dalton transactions (Cambridge, England : 2003) (Dalton Trans) Vol. 47 Issue 21 Pg. 7178-7189 (May 29 2018) ISSN: 1477-9234 [Electronic] England
• PMID: 29651471 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Coenzymes
• Ethylenediamines
• Formates
• Organometallic Compounds
• Reactive Oxygen Species
• Sulfonamides
• NAD
• Ruthenium

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Biocatalysis
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Coenzymes (metabolism)
• Crystallography, X-Ray
• Drug Screening Assays, Antitumor
• Ethylenediamines (chemistry, pharmacology)
• Formates (chemistry, metabolism)
• Humans
• Hydrogen-Ion Concentration
• Hydrogenation (drug effects)
• Models, Molecular
• Molecular Structure
• NAD (metabolism)
• Organometallic Compounds (chemical synthesis, chemistry, pharmacology)
• Quantum Theory
• Reactive Oxygen Species (analysis, metabolism)
• Ruthenium (chemistry, pharmacology)
• Sulfonamides (chemistry, pharmacology)