Iron complexes of the cardioprotective agent dexrazoxane (ICRF-187) and its desmethyl derivative, ICRF-154: solid state structure, solution thermodynamics, and DNA cleavage activity

Abstract

This study investigates the solution thermodynamics of the iron complexes of dexrazoxane (ICRF-187, (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane), [Fe(ADR-925)] +/0, and its desmethyl derivative ICRF-154, [Fe(ICRF-247)H 2O] +/0. The solid state structure of [Fe(ICRF-247)H 2O] + is also reported. [Fe(ICRF-247)H 2O]Br·0.5NaBr·H 2O crystallizes in the P42 12 space group with Z=4, a=14.9851(8), b=14.9851(8), c=8.0825(9) Å and R=0.03(2) for 1839 reflections and exhibits a pentagonal bipyramidal geometry with a labile water molecule occupying the seventh coordination site. Potentiometric titrations (FeL=8.5 mM, 0.1 M NaNO 3, 25 °C) reveal stable monomeric complexes (log K f=18.2±0.1, [Fe(ADR-925)] +, and 17.4±0.1, [Fe(ICRF-247)H 2O] +) exist in solution at relatively low pH. Upon addition of base, the iron-bound water is deprotonated; the p K a values for [Fe(ICRF-247)H 2O] + and [Fe(ADR-925)] + are 5.63±0.07 and 5.84±0.07, respectively. At higher pH both complexes undergo μ-oxo dimerization characterized by log K d values of 2.68±0.07 for [Fe(ICRF-247)H 2O] + and 2.23±0.07 for [Fe(ADR-925)] +. In the presence of an oxidant and reductant, both [Fe(ICRF-247)H 2O] + and [Fe(ADR-925)] + produce hydroxyl radicals that cleave pBR322 plasmid DNA at pH 7 in a metal complex concentration-dependent manner. At low metal complex concentrations (∼10 −5 M) where the monomeric form predominates, cleavage by both FeICRF complexes is efficient while at higher concentrations (∼5×10 −4 M) DNA cleavage is hindered. This change in reactivity is in part accounted for by dimer formation.