Cyclopeptide Alkaloids: Isolation, Structure Elucidation, Antiplasmodial Activity and AGEs Inhibiting Properties

Date: 16 May 2017

Venue: UAntwerp - Campus Drie Eiken - Building Q - promotiezaal - Universiteitsplein 1 - 2610 Antwerp (Wilrijk) (route: UAntwerpen, Campus Drie Eiken)

Time: 3:00 PM - 5:00 PM

PhD candidate: Emmy Tuenter

Principal investigator: Luc Pieters

Co-principal investigator: Nina Hermans

Short description: Phd defence Emmy Tuenter - Department of Pharmaceutical Sciences


Cyclopeptide Alkaloids: Isolation, Structure Elucidation, Antiplasmodial Activity and AGEs Inhibiting Properties

Cyclopeptide alkaloids are polyamidic, macrocyclic compounds, containing a 13-, 14- or 15-membered ring. This relatively small class of natural products consists of approximately 230 known compounds. Although they occur in various plant families, they are most widely distributed in the Rhamnaceae family, notably the genus Ziziphus.

The aim of this project was to isolate a considerable number of cyclopeptide alkaloids from four selected plant species, and to assess their antiplasmodial activity and AGEs (advanced glycation end products) inhibiting properties; two targets for which previously only few, but promising results were reported, in relation to this class of compounds.

From the root bark of Hymenocardia acida, the known compound hymenocardine was purified, together with three alkaloids which were reported for the first time: hymenocardinol, hymenocardine N‑oxide, and hymenocardine‑H.

Nine cyclopeptide alkaloids, were isolated from roots of Ziziphus oxyphylla: nummularine‑R, along with its new derivatives O‑desmethylnummularine‑R and O‑desmethylnummularine‑R N‑oxide, hemsine‑A, as well as hemsine‑A N‑oxide, ramosine-A, oxyphylline‑C, and two new compounds, oxyphyllines‑E and ‑F. Just like oxyphylline‑C, oxyphyllines‑E and ‑F belong to the relatively rare class of neutral cyclopeptide alkaloids.

Seven cyclopeptide alkaloids were purified from the stem bark of Ziziphus nummularia and Ziziphus spina-christi. Three new compounds were identified: nummularine‑U from Z. nummularia, and spinanines‑B and ‑C from Z. spina-christi, together with the known compounds mauritine‑F, nummularines‑D and ‑E, and amphibine‑D.

Thus, a total of 20 cyclopeptide alkaloids were isolated by means of conventional separation methods as well as semi-preparative HPLC with DAD and ESIMS detection and LC‑DAD‑(HRMS)‑SPE‑NMR. Structure elucidation was done by spectroscopic means.

For 14 of the obtained compounds, antiplasmodial and cytotoxic activities were determined. Overall, the result of spinanine‑B was the most promising (IC50 value of 2.1 ± 0.3 μM against Plasmodium falciparum K1, and no cytotoxic effects against MRC‑5 cells in concentrations up to 64.0 μM). Furthermore, a SAR study was carried out, indicating the most important descriptors (molecular properties) responsible for the activity of the cyclopeptide alkaloids against P. falciparum.

In addition, in vitro and in vivo studies were performed with hymenocardine, to assess its gastro-intestinal stability, absorption and hepatic metabolism. The results indicated that hymenocardine is absorbed unchanged from the gastrointestinal tract, at least in part, and that reduction, and/or the loss of an N-methyl group are the main hepatic biotransformation reactions.

As for the AGEs inhibiting properties of cyclopeptide alkaloids, no solid conclusions could be drawn, since several drawbacks were encountered when applying the most commonly used methods, and further optimization of these methods is required.