Ligand reactivity of dithiocarbamate and 5,6-dihydroxyindole using a ruthenium(bpy)[,2 '2+] scaffold: S-oxygenation of dithiocarbamate and metalation of melanin precursor

Dithiocarbamates (DTCs) are metal chelating compounds with wide-ranging bioactivity. Within the body, a major pathway of decomposition is S-oxygenation, and the S-oxygenated forms have been shown to have enhanced activity. To understand the possible reactive pathways of S-oxygenation of a metal-bound DTC, a substitutionally inert Ru-DTC was synthesized as a chemical model. Dialkyldithiocarbamates (dmDTC: dimethyl-DTC and diPrDTC: diisopropyl-DTC) were used in the synthesis of Ru(BPY)2(DTC)+. Results indicated that S-oxygenation and/or S-extrusion may occur upon treatment with oxidizing agents under different conditions. Several factors, such as solvent effect, pH, oxidant, temperature, and the presence of catalysis can contribute to these various degrees of sulfur-based oxidation. The isolation and characterization of oxygenated derivatives of Ru(bpy)2(dmDTC)+, Ru(bpy)2(N,N -dimethyldithiocarbamate)+ (1), Ru(bpy) 2(N,N-dimethyldithiocarbamate-sulfinate-S,S )+ (3),Ru(bpy)2(dimethylmonothiocarbamate) + (4), Ru(bpy)2(N,N-dimethyl(peroxydithiocarbamate- S,S)+ (2a), and Ru(bpy)2( N,N-dimethyl(peroxydithiocarbamate-O,S)+ (2b) as well as the diPrDTC derivatives (1', 2'a, 2'b and 3') are described. The highly reactive complex 2a undergoes intramolecular disproportionation and O-atom transfer reaction with PEt3 at room temperature but can be stabilized at -80°C in CDCl3 anerobically. The interconversion of the two stereoisomers, 2a and 2b , is facilitated by photoinduced linkage isomerization and its thermal reverse reaction. The isomerization is an intramolecular process involving a low activation energy barrier. All of these results elucidate the kinetically inert ruthenium complex enhances the likelihood of isolating the intermediate which provides an insight of how DTCs undergo S-oxygenation and S-extrusion in biological systems. This metal binding strategy is further extended to a non-innocent ligand modeling the redox reactivity of melanin. Severe disease such as melanoma and Parkinson's disease are caused by a malfunction of melanin. The melanin precursors 5,6-dihydroxyindole (DHI) and an N-alkylated DHI (rDHI) (r: methyl and isopropyl groups) were used to investigate the redox chemistry of metalation of melanin precursor. The same Ru(bpy)22+ scaffold was incorporated into the ligand in an attempt to decrease the reactivity, and the redox activity was followed by cyclic voltammetry and EPR. The isolation and characterization of these highly sensitive rDHI ligands and its complexes were successfully accomplished to contribute in understanding the nature of human melanin. All Ru complexes were characterized by conventional techniques and were structurally defined by X-ray crystallography.