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

Ndeye Khady Diop, Lizabeth K. Vitellaro, Paul Arnold, Maoyu Shang, Rosemary A. Marusak

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25 Scopus citations

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)H2O]+/0. The solid state structure of [Fe(ICRF-247)H2O]+ is also reported. [Fe(ICRF-247)H2O]Br · 0.5NaBr · H2O crystallizes in the P4212 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 NaNO3, 25 °C) reveal stable monomeric complexes (log Kf = 18.2 ± 0.1, [Fe(ADR-925)]+, and 17.4 ± 0.1, [Fe(ICRF-247)H2O]+) exist in solution at relatively low pH. Upon addition of base, the iron-bound water is deprotonated; the pKa values 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 μ-oxo dimerization characterized by log Kd values of 2.68 ± 0.07 for [Fe(ICRF-247)H2O]+ and 2.23 ± 0.07 for [Fe(ADR-925)]+. In the presence of an oxidant and reductant, both [Fe(ICRF-247)H2O]+ 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 (∼5×10-4M) DNA cleavage is hindered. This change in reactivity is in part accounted for by dimer formation.

Original languageEnglish (US)
Pages (from-to)209-216
Number of pages8
JournalJournal of Inorganic Biochemistry
Volume78
Issue number3
DOIs
StatePublished - Feb 29 2000
Externally publishedYes

Bibliographical note

Funding Information:
The authors gratefully acknowledge the Research Corporation Award CC3833 (R.A.M.), HHMI Award 71196-504202 Teacher Summer Research Fellowship (P.A.), and Kenyon College Science Scholar Research Funds (N.K.D., L.K.V.) for generous monetary support of this work. Thanks are also expressed to Dr Anthony Imondi (Battelle, Columbus, OH) for samples of ADR-925, to Dr R.J. Motekaitis (Texas A&M University, College Station, TX) for help with stability constant determination, and to Ken Eward (BioGrafx, Mt. Vernon, OH) for graphics artwork.

Keywords

  • ADR-925
  • DNA cleavage
  • Dexrazoxane
  • ICRF-154
  • Iron chelates

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