Synthesis and solution properties of deferoxamine amides.
The poor membrane permeability and oral bioavailability of the iron chelating agent deferoxamine (DFO) mesylate result from the low octanol/water partition coefficient and high aqueous solubility. With the ultimate aim to improve biomembrane permeability while retaining the iron-binding ability of DFO, a series of more lipophilic amides were prepared by reacting the terminal primary amino group with fatty and aromatic acid chlorides or anhydrides. Octanol/water partition coefficients and equilibrium solubilities of these analogs in solvents, chosen to delineate physicochemical interactions, were determined as a function of temperature. Solid-state properties were evaluated by calorimetry. All DFO amide derivatives had higher melting points, indicating that derivatives formed strong intermolecular interactions in the solid phase. Formamidation of the primary amine of deferoxamine resulted in a 200-fold increase in the octanol/water partition coefficient and reduced aqueous solubility at least 2000-fold compared with the parent molecule. The partition coefficient increased and aqueous solubility decreased 2-fold with the addition of each methylene group in the homologous series of aliphatic amides. Solubilities of the derivatives in water-saturated octanol and hexane showed irregular profiles as a function of increasing aliphatic chain length that were attributed to intermolecular packing in the solid state. The temperature dependence of the partition coefficients was interpreted to indicate that interfacial transfer of the deferoxamine amides was, in part, affected by an apparent diminished ability to form energetically favorable interactions in the water-saturated organic phase.
Ihnat
P M
PM
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska 68198-6025, USA. peter.ihnat@spcorp.com
Vennerstrom
J L
JL
Robinson
D H
DH
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D002152:Calorimetry, Differential Scanning; D002463:Cell Membrane Permeability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D016208:Databases, Factual; D003676:Deferoxamine / Q000138:chemical synthesis* / Q000737:chemistry; D006586:Hexanes; D007502:Iron Chelating Agents / Q000737:chemistry*; D008970:Molecular Weight; D000442:Octanols; D021281:Quantitative Structure-Activity Relationship; D012995:Solubility; D012996:Solutions; D012997:Solvents; D013056:Spectrophotometry, Ultraviolet; D013816:Thermodynamics
D000577:Amides; D006586:Hexanes; D007502:Iron Chelating Agents; D000442:Octanols; D012996:Solutions; D012997:Solvents; D003676:Deferoxamine