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

Citation
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
Citations number
37
Categorie Soggetti
Biochemistry & Biophysics","Inorganic & Nuclear Chemistry
Journal title
JOURNAL OF INORGANIC BIOCHEMISTRY
ISSN journal
01620134 → ACNP
Volume
78
Issue
3
Year of publication
2000
Pages
209 - 216
Database
ISI
SICI code
0162-0134(200002)78:3<209:ICOTCA>2.0.ZU;2-0
Abstract
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.