Iron complexes of the cardioprotective agent dexrazoxane (ICRF-187) and its desmethyl derivative, ICRF-154: solid state structure, solution thermodynamics, and DNA cleavage activity
Nk. Diop et al., Iron complexes of the cardioprotective agent dexrazoxane (ICRF-187) and its desmethyl derivative, ICRF-154: solid state structure, solution thermodynamics, and DNA cleavage activity, J INORG BIO, 78(3), 2000, pp. 209-216
This study investigates the solution thermodynamics of the iron complexes o
f dexrazoxane (ICRF-187, (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane), [F
e(ADR-925)] (+ /0), and its desmethyl derivative ICRF-154, [Fe(ICRF-247)H2O
] (+ /0). The solid state structure of [Fe(ICRF -247)H2O](+) is also report
ed. [Fe(ICRF-247)H2O]Br . 0.5NaBr . H2O crystallizes in the P42(1)2 space g
roup with Z = 4, a = 14.9851(8), b = 14.9851(8), c = 8.0825(9) Angstrom and
R = 0.03(2) for 1839 reflections and exhibits a pentagonal bipyramidal geo
metry with a labile water molecule occupying the seventh coordination site;
Potentiometric titrations (FeL = 8.5 mM, 0.1 M NaNO3, 25 degrees C) reveal
stable monomeric complexes (log K-f = 18.2 +/- 0.1, [Fe(ADR-925)] (+), and
17.4 +/- 0.1, [Fe(ICRF-247)H2O] (+)) exist in solution at relatively low p
H. Upon addition of base. the iron-bound water is deprotonated; the pK(a) v
alues for [Fe(ICRF-247)H2O] (+) and [Fe(ADR-925)] (+) are 5.63 +/- 0.07 and
5.84 +/- 0.07, respectively. At higher pH both complexes undergo mu-oxo di
merization characterized by log K-d values of 2.68 +/- 0.07 for [Fe(ICRF-24
7)H2O] (+) and 2.23 +/- 0.07 for [Fe(ADR-925)] (+). In the presence of an o
xidant and reductant, both [Fe(ICRF-247)H2O] (+) and [Fe(ADR-925)] (+) prod
uce hydroxyl radicals that cleave pBR322 plasmid DNA at pH 7 in a metal com
plex concentration-dependent manner. At low metal complex concentrations (
similar to 10(-5) M) where the monomeric form predominates, cleavage by bot
h FeICRF complexes is efficient while at higher concentrations ( similar to
5 X 10(-4) M) DNA cleavage is hindered. This change in reactivity is in pa
rt accounted for by dimer formation. (C) 2000 Elsevier Science Inc. All rig
hts reserved.