Solution equilibria of deferoxamine amides

Peter M. Ihnat, Jonathan L. Vennerstrom, Dennis H. Robinson

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The physico-chemical solution properties of deferoxamine were modified by acylating the terminal amino group with short-chain aliphatic, succinic, and methylsulphonic moieties. The analog iron(III)-binding constants and stabilities under physiological conditions were determined to confirm that the iron binding ability of the parent molecule was retained following modification. The proton dissociation constants of the lipophilic deferoxamine analogs were determined by potentiometric titration and nonlinear least-squares analysis. However, because the iron(III) binding complex is fully formed below pH 2, the metal-ligand equilibria could not be studied using potentiometric methods. The iron binding constants of the deferoxamine analogs were determined by spectrophotometrically following the proton-dependent exchange of iron with EDTA in the pH range of 4.0 to 6.5 and solving mass balance equations. The proton dissociation constants and the iron binding constants of the lipophilic deferoxamine analogs were comparable to those of deferoxamine. However, at physiological conditions, the iron-binding complex of the most lipophilic butylamide derivative was slightly less stable and the succinamide derivative complex was slightly more stable. Like deferoxamine, the hydroxamate groups of the analogs were unhindered and free to form a 1:1 coordination complex with iron(III). Consequently, changes in aqueous solvation, conformation, and steric interference, imparted by the modifications at the terminal amino group of deferoxamine, may have affected the stabilities of the iron(III) complex and the efficiency of iron binding.

Original languageEnglish (US)
Pages (from-to)1733-1741
Number of pages9
JournalJournal of Pharmaceutical Sciences
Volume91
Issue number7
DOIs
StatePublished - Jan 1 2002

Fingerprint

Deferoxamine
Amides
Iron
Protons
Derivatives
Coordination Complexes
Solvation
Succinic Acid
Least-Squares Analysis
Titration
Edetic Acid
Conformations
Metals
Ligands
Molecules

Keywords

  • Analogs
  • Deferoxamine
  • Ionization constants
  • Lipophilicity
  • Stability constant

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Solution equilibria of deferoxamine amides. / Ihnat, Peter M.; Vennerstrom, Jonathan L.; Robinson, Dennis H.

In: Journal of Pharmaceutical Sciences, Vol. 91, No. 7, 01.01.2002, p. 1733-1741.

Research output: Contribution to journalArticle

Ihnat, Peter M. ; Vennerstrom, Jonathan L. ; Robinson, Dennis H. / Solution equilibria of deferoxamine amides. In: Journal of Pharmaceutical Sciences. 2002 ; Vol. 91, No. 7. pp. 1733-1741.
@article{427b85edb2764c8fab7e5835884d4f29,
title = "Solution equilibria of deferoxamine amides",
abstract = "The physico-chemical solution properties of deferoxamine were modified by acylating the terminal amino group with short-chain aliphatic, succinic, and methylsulphonic moieties. The analog iron(III)-binding constants and stabilities under physiological conditions were determined to confirm that the iron binding ability of the parent molecule was retained following modification. The proton dissociation constants of the lipophilic deferoxamine analogs were determined by potentiometric titration and nonlinear least-squares analysis. However, because the iron(III) binding complex is fully formed below pH 2, the metal-ligand equilibria could not be studied using potentiometric methods. The iron binding constants of the deferoxamine analogs were determined by spectrophotometrically following the proton-dependent exchange of iron with EDTA in the pH range of 4.0 to 6.5 and solving mass balance equations. The proton dissociation constants and the iron binding constants of the lipophilic deferoxamine analogs were comparable to those of deferoxamine. However, at physiological conditions, the iron-binding complex of the most lipophilic butylamide derivative was slightly less stable and the succinamide derivative complex was slightly more stable. Like deferoxamine, the hydroxamate groups of the analogs were unhindered and free to form a 1:1 coordination complex with iron(III). Consequently, changes in aqueous solvation, conformation, and steric interference, imparted by the modifications at the terminal amino group of deferoxamine, may have affected the stabilities of the iron(III) complex and the efficiency of iron binding.",
keywords = "Analogs, Deferoxamine, Ionization constants, Lipophilicity, Stability constant",
author = "Ihnat, {Peter M.} and Vennerstrom, {Jonathan L.} and Robinson, {Dennis H.}",
year = "2002",
month = "1",
day = "1",
doi = "10.1002/jps.10168",
language = "English (US)",
volume = "91",
pages = "1733--1741",
journal = "Journal of Pharmaceutical Sciences",
issn = "0022-3549",
publisher = "John Wiley and Sons Inc.",
number = "7",

}

TY - JOUR

T1 - Solution equilibria of deferoxamine amides

AU - Ihnat, Peter M.

AU - Vennerstrom, Jonathan L.

AU - Robinson, Dennis H.

PY - 2002/1/1

Y1 - 2002/1/1

N2 - The physico-chemical solution properties of deferoxamine were modified by acylating the terminal amino group with short-chain aliphatic, succinic, and methylsulphonic moieties. The analog iron(III)-binding constants and stabilities under physiological conditions were determined to confirm that the iron binding ability of the parent molecule was retained following modification. The proton dissociation constants of the lipophilic deferoxamine analogs were determined by potentiometric titration and nonlinear least-squares analysis. However, because the iron(III) binding complex is fully formed below pH 2, the metal-ligand equilibria could not be studied using potentiometric methods. The iron binding constants of the deferoxamine analogs were determined by spectrophotometrically following the proton-dependent exchange of iron with EDTA in the pH range of 4.0 to 6.5 and solving mass balance equations. The proton dissociation constants and the iron binding constants of the lipophilic deferoxamine analogs were comparable to those of deferoxamine. However, at physiological conditions, the iron-binding complex of the most lipophilic butylamide derivative was slightly less stable and the succinamide derivative complex was slightly more stable. Like deferoxamine, the hydroxamate groups of the analogs were unhindered and free to form a 1:1 coordination complex with iron(III). Consequently, changes in aqueous solvation, conformation, and steric interference, imparted by the modifications at the terminal amino group of deferoxamine, may have affected the stabilities of the iron(III) complex and the efficiency of iron binding.

AB - The physico-chemical solution properties of deferoxamine were modified by acylating the terminal amino group with short-chain aliphatic, succinic, and methylsulphonic moieties. The analog iron(III)-binding constants and stabilities under physiological conditions were determined to confirm that the iron binding ability of the parent molecule was retained following modification. The proton dissociation constants of the lipophilic deferoxamine analogs were determined by potentiometric titration and nonlinear least-squares analysis. However, because the iron(III) binding complex is fully formed below pH 2, the metal-ligand equilibria could not be studied using potentiometric methods. The iron binding constants of the deferoxamine analogs were determined by spectrophotometrically following the proton-dependent exchange of iron with EDTA in the pH range of 4.0 to 6.5 and solving mass balance equations. The proton dissociation constants and the iron binding constants of the lipophilic deferoxamine analogs were comparable to those of deferoxamine. However, at physiological conditions, the iron-binding complex of the most lipophilic butylamide derivative was slightly less stable and the succinamide derivative complex was slightly more stable. Like deferoxamine, the hydroxamate groups of the analogs were unhindered and free to form a 1:1 coordination complex with iron(III). Consequently, changes in aqueous solvation, conformation, and steric interference, imparted by the modifications at the terminal amino group of deferoxamine, may have affected the stabilities of the iron(III) complex and the efficiency of iron binding.

KW - Analogs

KW - Deferoxamine

KW - Ionization constants

KW - Lipophilicity

KW - Stability constant

UR - http://www.scopus.com/inward/record.url?scp=0035998960&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035998960&partnerID=8YFLogxK

U2 - 10.1002/jps.10168

DO - 10.1002/jps.10168

M3 - Article

C2 - 12115836

AN - SCOPUS:0035998960

VL - 91

SP - 1733

EP - 1741

JO - Journal of Pharmaceutical Sciences

JF - Journal of Pharmaceutical Sciences

SN - 0022-3549

IS - 7

ER -