One-Step Semisynthesis of Oleacein and the Determination as a 5‑Lipoxygenase Inhibitor

The dialdehydes oleacein (<b>2</b>) and oleocanthal (<b>4</b>) are closely related to oleuropein (<b>1</b>) and ligstroside (<b>3</b>), the two latter compounds being abundant iridoids of <i>Olea europaea</i>. By exploiting oleuropein isolated from the plant leaf extract, an efficient procedure has been developed for a one-step semisynthesis of oleacein under Krapcho decarbomethoxylation conditions. Highlighted is the fact that 5-lipoxygenase is a direct target for oleacein with an inhibitory potential (IC₅₀: 2 μM) more potent than oleocanthal (<b>4</b>) and oleuropein (<b>1</b>). This enzyme catalyzes the initial steps in the biosynthesis of pro-inflammatory leukotrienes. Taken together, the methodology presented here offers an alternative solution to isolation or total synthesis for the procurement of oleacein, thus facilitating the further development as a potential anti-inflammatory agent

Natural-Based Indirubins Display Potent Cytotoxicity toward Wild-Type and T315I-Resistant Leukemia Cell Lines

Drug resistance in chronic myelogenous leukemia (CML) requires the development of new CML chemotherapeutic drugs. Indirubin, a well-known mutikinase inhibitor, is the major active component of “Danggui Longhui Wan”, a Chinese traditional medicine used for the treatment of CML symptoms. An in-house collection of indirubin derivatives was screened at 1 μM on wild-type and imatinib-resistant T315I mutant CML cells. Herein are reported that only 15 analogues of the natural 6-bromoindirubin displayed potent cytotoxicity in the submicromolar range. Kinase assays in vitro show that eight out of the 15 active molecules strongly inhibited both <i>c</i>-Src and Abl oncogenic kinases in the nanomolar range. Most importantly, these eight molecules blocked the activity of T315I mutant Abl kinase at the submicromolar level and with analogue <b>22</b> exhibiting inhibitory activity at the low nanomolar range. Docking calculations suggested that active indirubins might inhibit T315I Abl kinase through an unprecedented binding to both active and Src-like inactive conformations. Analogue <b>22</b> is the first derivative of a natural product identified as an inhibitor of wild-type and imatinib-resistant T315I mutant Abl kinases