Abstract
Natural products have made remarkable contributions to drug discovery and therapy. In this work we exploited various biochemical approaches to investigate the mode of action of 16-α-hydroxy-cleroda-3,13 (14)-Z-dien-15,16-olide (HDK-20), which we recently isolated from Polyalthia longifolia, on Trypanosoma brucei bloodstream trypomastigotes. HDK20 at concentrations ≥ EC50 (0.4 μg/ml) was trypanocidal, with its effect irreversible after only a brief exposure time (<1 h). Fluorescence microscopic assessment of DNA configuration revealed severe cell cycle defects after 8 h of incubation with the compound, the equivalent of a single generation time. This was accompanied by DNA fragmentation as shown by Terminal deoxynucleotidyl transferase dUTP Nick-End Labelling (TUNEL) assays. HDK-20 also induced a fast and profound depolarisation of the parasites’ mitochondrial membrane potential and depleted intracellular ATP levels of T. brucei. Overall, HDK20 showed a multi-target mechanism of action, which provides a biochemical explanation for the promising anti-trypanosomatid activity in our previous report.
Highlights
Action of these reported bioactive extracts or bioactive principles is rarely, if ever, determined[11]
In the 4 × EC50 group (1.6 μg/mL), the cell population was sterilized after 12 h, regardless whether the cells were exposed for 1 h or continuously to the compound (significantly different from control at 4 h (P < 0.01) and 8 h (P < 0.05) for continuous and pulsed exposure, respectively)
We have previously reported the promising activity of HDK20 against T. brucei[12] and here report an investigation of the cellular and biochemical effects this natural compound, isolated from the Nigerian medicinal plant Polyalthia longifolia[12], exerts on the parasites
Summary
Action of these reported bioactive extracts or bioactive principles is rarely, if ever, determined (e.g., triptolide; curcumin)[11]. A comprehensive understanding of the interaction of a drug lead with its molecular target is especially helpful for the process of drug development, for the reason that it allows the use of medicinal chemistry approaches for optimization, and in some cases a more suitable clinical trial design. This is crucial for the development of new and efficient chemotherapy that will replace the current inefficient drugs. We report on a detailed investigation of the mode of action of a clerodane (16-α-hyroxy-cleroda-3,13 (14)-Z-dien-15,16-olide, HDK-20; Fig. 1) previously isolated from Polyalthia longifolia[12] on Trypanosoma brucei trypomastigotes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
