Developing iron nitrosyl complexes as NO donor prodrugs

Abstract

A novel class of water-soluble iron nitrosyl complexes has been developed for use as NO donor prodrugs. To elaborate these NO prodrugs various water-soluble ligands were used such as P(CH₂OH)₃, 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane (PTA), 1,2-bis[bis(hydroxymethyl)phosphino]ethane (HMPE), 1,2-bis[bis(hydroxymethyl)phosphino]benzene (TMBz), cysteamine, cysteamine hydrochloride, L-cysteine ethyl ester hydrochloride (LCEE) and pyrimidine-2-thiol (pyrim). The mononuclear complexes Fe(NO)₂P(CH₂OH)₃Cl 1, Fe(NO)₂(P(CH₂OH)₃)₂2, Fe(NO)₂(PTA)₂3, Fe(NO)₂HMPE 4, Fe(NO)₂TMBz 5, [Fe(NO)₂pyrimI] 10, [Fe(NO)₃P(CH₂OH)₃][X] (X = PF₆, SbF₆, BF₄) 11–13 and the dinuclear species [Fe(NO)₂S(CH₂)₂NH₃Cl]₂6a, [Fe(NO)₂S(CH₂)₂NH₃I₂] 6b, [Fe(NO)₂LCEE]₂8 and [Fe(NO)₂pyrim]₂9 were obtained. Complexes 1, 2, 4, 6a, 6b, 11, 12 and 13 are water-soluble. 1, 2 and 4 were identified as nitroxyl and 6a, 6b, 11, 12 and 13 as nitric oxide donors by applying an EPR NO-trap assay. To determine the amount of nitric oxide which was released from the nitric oxide donors, an additional electrochemical methodology was used. The equilibrium release or the trapping concentration of NO was also studied by a UV-vis method, which allowed the rate constant of NO release to be determined.