Solution equilibria of deferoxamine amides.
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.
Ihnat
Peter M
PM
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center 986025, Omaha, Nebraska 68198-6025, USA. peter.ihnat@pcorp.com
Vennerstrom
Jonathan L
JL
Robinson
Dennis H
DH
D000577:Amides / Q000737:chemistry*; D003676:Deferoxamine / Q000031:analogs & derivatives / Q000737:chemistry*; D004355:Drug Stability; D007477:Ions / Q000737:chemistry; D019999:Pharmaceutical Solutions / Q000737:chemistry
D000577:Amides; D007477:Ions; D019999:Pharmaceutical Solutions; D003676:Deferoxamine