Isolation and Structure Elucidation by LC-DAD-MS and LC-DAD-SPE-NMR of Cyclopeptide Alkaloids from the Roots of Ziziphus oxyphylla and Evaluation of Their Antiplasmodial Activity

Abstract

Nine cyclopeptide alkaloids (1-9), of which five (compounds 2, 3, 5, 8, and 9) are described herein for the first time, were isolated from roots of Ziziphus oxyphylla by means of conventional separation methods as well as semipreparative HPLC with DAD and ESIMS detection and LC-DAD-SPE-NMR. Structure elucidation was done by spectroscopic means. Nummularine-R (1), a previously known constituent from this species, was isolated along with its new derivatives O-desmethylnummularine-R (2) and O-desmethylnummularine-R N-oxide (3). In addition, the known compounds hemsine-A (4) and ramosine-A (6), as well as hemsine-A N-oxide (5), were isolated. Moreover, oxyphylline-C (7), a known constituent of Z. oxyphylla stems, was obtained, and two new compounds were identified, oxyphyllines-E (8) and -F (9). Just like oxyphylline-C, oxyphyllines-E and -F belong to the relatively rare class of neutral cyclopeptide alkaloids. The antiplasmodial activity and cytotoxicity of compounds 1, 2, 4, 6, and 9 were evaluated, and the most promising activity was found for O-desmethylnummularine-R (2), which exhibited an IC value of 3.2 ± 2.6 μM against Plasmodium falciparum K1, whereas an IC value of >64.0 μM was evident for its cytotoxicity against MRC-5 cells.

Antiplasmodial Activity, Cytotoxicity and Structure-Activity Relationship Study of Cyclopeptide Alkaloids

“…The in vitro antiplasmodial activity against P. falciparum strain K1 and the cytotoxicity against MRC-5 cells was determined for ten cyclopeptide alkaloids, isolated from the stem bark of Ziziphus nummularia , Ziziphus spina-christi , Ziziphus jujuba , and the root of Hovenia dulcis , all belonging to the Rhamnaceae family, and the results are shown in Table 1 . The results that were previously reported for cyclopeptide alkaloids isolated from the root bark of H. acida (Phyllanthaceae) and the roots of Z. oxyphylla (Rhamnaceae) [ 6 , 7 ] are also included in this table. The highest antiplasmodial activity was found for spinanine-B ( 3 ), with an IC 50 value of 2.1 μM and without cytotoxic effects in concentrations of 64.0 μM or less.…”

“…The extraction, isolation, and structure elucidation of 17 of the 19 cyclopeptide alkaloids included in this manuscript were reported previously [ 6 , 7 , 10 , 11 ]. The isolation procedure of adouetine-X and fragulanine is briefly described here:…”

“…Nummularine-B was found to be moderately active (IC 50 value of 10.3 μM) against Plasmodium falciparum , but not mauritine-L and nummularine-B methiodide [ 5 ]. Our research group has previously reported the antiplasmodial activity of cyclopeptide alkaloids from Hymenocardia acida and Ziziphus oxyphylla [ 6 , 7 ]. Based on these results, some preliminary conclusions concerning their SAR (structure-activity relationship) were drawn, but given the fact that the number of compounds tested in each of these studies was relatively small, it was not possible to draw definite conclusions.…”

“…In the present paper, the antiplasmodial and cytotoxic activities of ten cyclopeptide alkaloids are reported, of which only the antiplasmodial activity of nummularine-B was reported previously [ 5 ]. These results were then combined with previous data obtained by our group in the same test conditions for nine other cyclopeptide alkaloids from H. acida and Z. oxyphylla [ 6 , 7 ], in order to perform a SAR study, and to identify the molecular characteristics that can account for high antiplasmodial activity.…”

Alkaloids from Plants with Antimalarial Activity: A Review of Recent Studies

“…Compound 45 together with others shows high and specific activities against P. falciparum [39] Evidence-Based Complementary and Alternative Medicine A new alkaloid, tavoyanine A (56), and other known alkaloids, roemerine (57), laurolitsine (58), boldine (59), and sebiferine (60) Aporphine alkaloids (56)(57)(58)(59) and morphinandienone (60) Leaf 1.10. Quinoline Alkaloids.…”