title: 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)H2O](+/0). The solid state structure of [Fe(ICRF-247)H2O]+ is also reported. [Fe(ICRF-247)H2O]Br x 0.5NaBr x H2O crystallizes in the P42(1)2 space group with Z = 4, a = 14.9851(8), b = 14.9851(8), c = 8.0825(9) A 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 degrees 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 mu-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 (approximately 10(-5) M) where the monomeric form predominates, cleavage by both FeICRF complexes is efficient while at higher concentrations (approximately 5 x 10(-4) M) DNA cleavage is hindered. This change in reactivity is in part accounted for by dimer formation.
authors.affiliation: Department of Chemistry, Kenyon College, Gambier, OH 43022, USA.
authors.forename: N K
authors.initials: NK
authors.lastname: Diop
authors.forename: L K
authors.initials: LK
authors.lastname: Vitellaro
authors.forename: P
authors.initials: P
authors.lastname: Arnold
authors.forename: M
authors.initials: M
authors.lastname: Shang
authors.forename: R A
authors.initials: RA
authors.lastname: Marusak
mesh_terms: D002317:Cardiovascular Agents / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry*; D006868:Hydrolysis; D007501:Iron / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011929:Razoxane / Q000031:analogs & derivatives* / Q000737:chemistry*; D012996:Solutions; D013816:Thermodynamics
chemical_list: D002317:Cardiovascular Agents; D012996:Solutions; D011929:Razoxane; D004247:DNA; D007501:Iron; C000283:1,2-bis(3,5-dioxopiperazin-1-yl)ethane