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.
J Nat Prod. 2017 Apr 28;80(4):879-886. doi: 10.1021/acs.jnatprod.6b00600. Epub 2017 Mar 2.
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.
异甘草素（1）具有多种体外生物活性。然而，其较差的水溶性限制了其在后续体内实验中的应用。为了能够在不使用有毒载体或共溶剂的情况下将 1 用于体内研究，本研究采用了依赖分子中酚基团可用性的磷酸前药策略。在这项研究中，在 1 的 C-4 位置添加了一个磷酸基团，得到了水溶性更好的前药 2 和其铵盐 3，与 2 相比，3 具有更高的稳定性。本文报道了磷酸前药 3 的合成、表征、在生物介质中的溶解度和稳定性，并与 1 进行了比较，以及其在体内抗炎特性方面的新结果。如设计的那样，前药 3 的溶解度优于母体天然产物 1（9.6mg/mL 与 3.9μg/mL 相比）。作为一种铵盐，前药 3 作为固体和在水溶液中也具有极好的稳定性，而与其磷酸前体 2 相反。
