Cryptotanshinone and tanshinone IIA from <i>Salvia milthorrhiza</i> Bunge (Danshen) as a new class of potential pancreatic lipase inhibitors

Salvia miltiorrhiza Bunge extract was investigated for the first time for its inhibitory activity against pancreatic lipase (PL), an important enzyme involved in the digestion of dietary fats. It showed a concentration-dependent activity with an IC50 value of 3.54 ± 0.22 mg/mL. Two compounds, cryptotanshinone and tanshinone IIA (the major lipophilic constituents of S. miltiorrhiza), have been selected as potential ligands of PL. Cryptotanshinone showed a higher lipase inhibitory activity (IC50 = 6.86 ± 0.43 µM) compared to the parent tanshinone IIA. Molecular docking studies were undertaken to establish whether a direct interaction of the principal constituents of the S. miltiorrhiza extract with the human pancreatic lipase could be evoked. All these findings provided new insights into the understanding of the interactions between natural constituents of S. miltiorrhiza extract and PL, also suggesting that cryptotanshinone could be used as lead compound for the development of efficacious PL inhibitors.</p

Interaction of letrozole and its degradation products with aromatase: chemometric assessment of kinetics and structure-based binding validation

Letrozole is one of the most prescribed drugs for the treatment of breast cancer in post-menopausal women, and it is endowed with selective peripheral aromatase inhibitory activity. The efficacy of this drug is also a consequence of its long-lasting activity, likely due to its metabolic stability. The reactivity of cyano groups in the letrozole structure could, however, lead to chemical derivatives still endowed with residual biological activity. Herein, the chemical degradation process of the drug was studied by coupling multivariate curve resolution and spectrophotometric methodologies in order to assess a detailed kinetic profile. Three main derivatives were identified after drug exposure to different degradation conditions, consisting of acid-base and oxidative environments and stressing light. Molecular docking confirmed the capability of these compounds to accommodate into the active site of the enzyme, suggesting that the sustained inhibitory activity of letrozole may be at least in part attributed to the degradation compounds.</p