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

doi:10.1016/S0162-0134(00)00013-1

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

Research output: Contribution to journal › Article › peer-review

26 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 K_f = 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 pK_a 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 K_d 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 language	English (US)
Pages (from-to)	209-216
Number of pages	8
Journal	Journal of Inorganic Biochemistry
Volume	78
Issue number	3
DOIs	https://doi.org/10.1016/S0162-0134(00)00013-1
State	Published - Feb 29 2000
Externally published	Yes

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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10.1016/S0162-0134(00)00013-1

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Iron complexes of the cardioprotective agent dexrazoxane (ICRF-187) and its desmethyl derivative, ICRF-154: Solid state structure, solution thermodynamics, and DNA cleavage activity. / Diop, Ndeye Khady; Vitellaro, Lizabeth K.; Arnold, Paul et al.
In: Journal of Inorganic Biochemistry, Vol. 78, No. 3, 29.02.2000, p. 209-216.

Research output: Contribution to journal › Article › peer-review

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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 · 0.5NaBr · H2O crystallizes in the P4212 space group with Z = 4, a = 14.9851(8), b = 14.9851(8), c = 8.0825(9) {\AA} 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.",

keywords = "ADR-925, DNA cleavage, Dexrazoxane, ICRF-154, Iron chelates",

author = "Diop, {Ndeye Khady} and Vitellaro, {Lizabeth K.} and Paul Arnold and Maoyu Shang and Marusak, {Rosemary A.}",

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. ",

year = "2000",

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day = "29",

doi = "10.1016/S0162-0134(00)00013-1",

language = "English (US)",

volume = "78",

pages = "209--216",

journal = "Journal of Inorganic Biochemistry",

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TY - JOUR

T1 - Iron complexes of the cardioprotective agent dexrazoxane (ICRF-187) and its desmethyl derivative, ICRF-154

T2 - Solid state structure, solution thermodynamics, and DNA cleavage activity

AU - Diop, Ndeye Khady

AU - Vitellaro, Lizabeth K.

AU - Arnold, Paul

AU - Shang, Maoyu

AU - Marusak, Rosemary A.

N1 - 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.

PY - 2000/2/29

Y1 - 2000/2/29

N2 - 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.

AB - 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.

KW - ADR-925

KW - DNA cleavage

KW - Dexrazoxane

KW - ICRF-154

KW - Iron chelates

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U2 - 10.1016/S0162-0134(00)00013-1

DO - 10.1016/S0162-0134(00)00013-1

M3 - Article

C2 - 10805177

AN - SCOPUS:0034136253

SN - 0162-0134

VL - 78

SP - 209

EP - 216

JO - Journal of Inorganic Biochemistry

JF - Journal of Inorganic Biochemistry

IS - 3

ER -

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

Bibliographical note

Keywords

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