Discovery of sinomenine/8-Bis(benzylthio)octanoic acid hybrids as potential anti-leukemia drug candidate via mitochondrial pathway.

Traditional Chinese medicine Qingfengteng primarily acquired from the dried canes of Sinomenium acutum (Thunb.) Rehd. et Wils. var. cinereum Rehd. et Wils. and S. acutum (Thunb.) Rehd. et Wils. For the therapeutic treatment of rheumatism, acute arthritis, and rheumatoid arthritis based on Qingfengteng, sinomenine hydrochloride was recently made the principal active ingredient in various dosage forms. 8-Bis(benzylthio)octanoic acid (CPI-613) was an orphan medicine that the FDA and EMA approved orphan for the treatment of certain resistant malignancies. Its unique mode of action and minimal toxicity toward normal tissues made for an apt pharmacophore. In order to expand the field of sinomenine anticancer structures, sinomenine/8-Bis(benzylthio)octanoic acid derivatives were designed and synthesized. Among them, target hybrids e4 stood out for having notable cytotoxic effects against cancer cell lines, especially for K562 cells, with IC50 values of 2.45 µM and high safety. In-depth investigations demonstrated that e4 caused apoptosis by stopping the cell cycle at G1 phase, and doing so by altering the morphology of the nucleus and causing membrane potential of the in mitochondria to collapse. These results indicated e4 exerted an antiproliferative effect through apoptosis induction via mitochondrial pathway.

Synthesis of sinomenine derivatives with potential anti-leukemia activity.

In recent years, with sinomenine hydrochloride as the main ingredient, Qingfengteng had been formulated as various dosage forms for clinical treatment. Subsequent findings confirmed a variety of biological roles for sinomenine. Here, 15 H2S-donating sinomenine derivatives were synthesized. Target hybrids a11 displayed substantial cytotoxic effects on cancer cell lines, particularly against K562 cells, with an IC50 value of 1.36 µM. In-depth studies demonstrated that a11 arrested cell cycle at G1 phase, induced apoptosis via both morphological changes in nucleus and membrane potential collapse in mitochondria. These results indicated a11 exerted an antiproliferative effect through apoptosis induction via mitochondrial pathway.