title: Synthesis and Characterization of a Phosphate Prodrug of Isoliquiritigenin.
abstract: Isoliquiritigenin (1) possesses a variety of biological activities in vitro. However, its poor aqueous solubility limits its use for subsequent in vivo experimentation. In order to enable the use of 1 for in vivo studies without the use of toxic carriers or cosolvents, a phosphate prodrug strategy was implemented relying on the availability of phenol groups in the molecule. In this study, a phosphate group was added to position C-4 of 1, leading to the more water-soluble prodrug 2 and its ammonium salt 3, which possesses increased stability compared to 2. Herein are reported the synthesis, characterization, solubility, and stability of phosphate prodrug 3 in biological medium in comparison to 1, as well as new results on its anti-inflammatory properties in vivo. As designed, the solubility of prodrug 3 was superior to that of the parent natural product 1 (9.6 mg/mL as opposed to 3.9 μg/mL). Prodrug 3 as an ammonium salt was also found to possess excellent stability as a solid and in aqueous solution, as opposed to its phosphoric acid precursor 2.
authors.affiliation: Institut de Pharmacologie de Sherbrooke, ‡Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, and §X-ray Crystallography Platform, Department of Chemistry, Université de Sherbrooke , 3001,12e Avenue Nord, Sherbrooke, QC, Canada.
authors.forename: Kumaraswamy
authors.initials: K
authors.lastname: Boyapelly
authors.affiliation: Institut de Pharmacologie de Sherbrooke, ‡Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, and §X-ray Crystallography Platform, Department of Chemistry, Université de Sherbrooke , 3001,12e Avenue Nord, Sherbrooke, QC, Canada.
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Bonin
authors.affiliation: Institut de Pharmacologie de Sherbrooke, ‡Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, and §X-ray Crystallography Platform, Department of Chemistry, Université de Sherbrooke , 3001,12e Avenue Nord, Sherbrooke, QC, Canada.
authors.forename: Hussein
authors.initials: H
authors.lastname: Traboulsi
authors.affiliation: Institut de Pharmacologie de Sherbrooke, ‡Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, and §X-ray Crystallography Platform, Department of Chemistry, Université de Sherbrooke , 3001,12e Avenue Nord, Sherbrooke, QC, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Cloutier
authors.affiliation: Institut de Pharmacologie de Sherbrooke, ‡Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, and §X-ray Crystallography Platform, Department of Chemistry, Université de Sherbrooke , 3001,12e Avenue Nord, Sherbrooke, QC, Canada.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Phaneuf
authors.affiliation: Institut de Pharmacologie de Sherbrooke, ‡Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, and §X-ray Crystallography Platform, Department of Chemistry, Université de Sherbrooke , 3001,12e Avenue Nord, Sherbrooke, QC, Canada.
authors.forename: Daniel
authors.identifier: 0000-0002-0223-6362
authors.initials: D
authors.lastname: Fortin
authors.affiliation: Institut de Pharmacologie de Sherbrooke, ‡Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, and §X-ray Crystallography Platform, Department of Chemistry, Université de Sherbrooke , 3001,12e Avenue Nord, Sherbrooke, QC, Canada.
authors.forename: André M
authors.initials: AM
authors.lastname: Cantin
authors.affiliation: Institut de Pharmacologie de Sherbrooke, ‡Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, and §X-ray Crystallography Platform, Department of Chemistry, Université de Sherbrooke , 3001,12e Avenue Nord, Sherbrooke, QC, Canada.
authors.forename: Martin V
authors.initials: MV
authors.lastname: Richter
authors.affiliation: Institut de Pharmacologie de Sherbrooke, ‡Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, and §X-ray Crystallography Platform, Department of Chemistry, Université de Sherbrooke , 3001,12e Avenue Nord, Sherbrooke, QC, Canada.
authors.forename: Eric
authors.identifier: 0000-0002-5305-8762
authors.initials: E
authors.lastname: Marsault
mesh_terms: D000818:Animals; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D006035:Glycyrrhiza / Q000737:chemistry; D015394:Molecular Structure; D010755:Organophosphates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D014867:Water
chemical_list: D047188:Chalcones; C000621493:Isoliquiritigenin phosphate ammonium salt; D010755:Organophosphates; D011355:Prodrugs; D000644:Quaternary Ammonium Compounds; D014867:Water; C040920:isoliquiritigenin