First In Vitro Human Islet Assessment of Oleanolic Acid (OA) and Its Serine Conjugate: Enhanced Solubility with Comparable Effects

Oleanolic acid (OA) is a natural pentacyclic triterpenoid with reported hypoglycemic, hepatoprotective, antidiabetic, and anti-inflammatory activities. However, its limited aqueous solubility restricts its formulation and potential biomedical applications. To address this limitation, we designed a hydrophilic OA derivative, <b>1a</b>, by introducing an amino acid fragment at the C-28 position. We established a reverse-phase high-performance liquid chromatography (HPLC)-based method to measure the octanol-water partition coefficient (Log P<i>_ow</i>) of OA and <b>1a</b>. Under neutral conditions, <b>1a</b> showed a markedly reduced Log P<i>_ow</i> value (2.91 ± 0.02) compared with OA (4.30 ± 0.01), confirming substantially improved hydrophilicity. The biological compatibility of OA and <b>1a</b> was further evaluated using in vitro human islet cultures. Both compounds maintained high islet viability (approximately 90%). In addition, islets pre-treated with <b>1a</b> exhibited viability, purity, and insulin expression levels comparable to those observed with OA treatment, indicating that the C-28 modification preserved OA's biological properties while improving solubility. Overall, this proof-of-concept study demonstrates that C-28 amino-functionalization can improve the physicochemical properties of OA without compromising its compatibility with human islets. The HPLC-based Log P<i>_ow</i> method established here provides a practical analytical tool for future structure-activity investigations of OA derivatives, and the improved solubility of <b>1a</b> may facilitate its use in human islet preparation workflows.