pH-Dependent Degradation of Andrographolide. Product Identification, Kinetics, and In Vitro Anti-inflammatory Activity and Cytotoxicity Assessment

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Abstract
Andrographolide (1) is a labdane type diterpene lactone abundant in the leaves of Andrographis paniculata. To further explore the stability of this important metabolite, the thermal degradation kinetics of 1 at pH values pH 2.0, pH 6.0, and pH 8.0 were each modeled at three temperatures ranging between 50 and 85°C. The calculated values of the activation energies (Ea), shelf-life (t90%), and rate constant ( k ) were determined for andrographolide by Arrhenius equation. The results indicated that the pHs degradation of 1 followed the first-order reaction kinetics. The optimum pH for andrographolide stability was between pH 2.0 and pH 4.0. The major degradation products in the pH 2.0 and pH 6.0 solutions were isolated and analyzed spectroscopically in comparison with known compounds. Two degradation products, isoandrographolide (2) and 8,9-didehydroandrographolide (3), were formed under acidic conditions, whereas the three degradation products formed under basic conditions were 15- seco -andrographolide (4), 14-deoxy-15-methoxyandrographolide (5), and 14-deoxy-11,14-dehydroandrographolide (6). Anti-inflammatory and cytotoxicity assessment of the degradation products indicated a consistent lowering of the biological effects compared with 1, which has implications for the sustained bioactivity of formulated products.

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