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Synthesis and solution properties of deferoxamine amides
P M Ihnat1, J L Vennerstrom, D H Robinson
1Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska 68198-6025, USA. peter.ihnat@spcorp.com
Journal of Pharmaceutical Sciences
|October 24, 2000
Summary
Modifying deferoxamine (DFO) into lipophilic amides significantly enhances its membrane permeability and oral bioavailability. These DFO amide derivatives show improved physicochemical properties for potential therapeutic applications.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Drug Delivery
Background:
- Deferoxamine (DFO) mesylate, an iron chelator, suffers from poor membrane permeability and oral bioavailability due to low lipophilicity and high aqueous solubility.
- Improving these physicochemical properties is crucial for enhancing DFO's therapeutic efficacy.
Purpose of the Study:
- To synthesize novel deferoxamine amide derivatives with enhanced lipophilicity.
- To evaluate the impact of these modifications on membrane permeability and iron-binding capabilities.
Main Methods:
- Synthesis of DFO amide derivatives by reacting the primary amino group with fatty and aromatic acid chlorides/anhydrides.
- Determination of octanol/water partition coefficients and equilibrium solubilities as a function of temperature.
- Evaluation of solid-state properties using calorimetry.
Main Results:
- Formamidation of DFO increased the octanol/water partition coefficient 200-fold and reduced aqueous solubility over 2000-fold.
- Homologous aliphatic amides showed a 2-fold increase in partition coefficient and decrease in solubility per methylene group.
- All derivatives exhibited higher melting points, suggesting strong intermolecular interactions in the solid phase.
Conclusions:
- Lipophilic modification of deferoxamine via amidation effectively improves its physicochemical properties, notably increasing lipophilicity and reducing aqueous solubility.
- These DFO amide derivatives demonstrate potential for enhanced biomembrane permeability while retaining iron-binding capacity.