Antiplasmodial Activity, Cytotoxicity and Structure-Activity Relationship Study of Cyclopeptide Alkaloids.
Cyclopeptide alkaloids are polyamidic, macrocyclic compounds, containing a 13-, 14-, or 15-membered ring. The ring system consists of a hydroxystyrylamine moiety, an amino acid, and a β-hydroxy amino acid; attached to the ring is a side chain, comprised of one or two more amino acid moieties. In vitro antiplasmodial activity was shown before for several compounds belonging to this class, and in this paper the antiplasmodial and cytotoxic activities of ten more cyclopeptide alkaloids are reported. Combining these results and the IC50 values that were reported by our group previously, a library consisting of 19 cyclopeptide alkaloids was created. A qualitative SAR (structure-activity relationship) study indicated that a 13-membered macrocyclic ring is preferable over a 14-membered one. Furthermore, the presence of a β-hydroxy proline moiety could correlate with higher antiplasmodial activity, and methoxylation (or, to a lesser extent, hydroxylation) of the styrylamine moiety could be important for displaying antiplasmodial activity. In addition, QSAR (quantitative structure-activity relationship) models were developed, using PLS (partial least squares regression) and MLR (multiple linear regression). On the one hand, these models allow for the indication of the most important descriptors (molecular properties) responsible for the antiplasmodial activity. Additionally, predictions made for interesting structures did not contradict the expectations raised in the qualitative SAR study.
Natural Products & Food Research and Analysis (NatuRA), Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Emmy.Tuenter@uantwerpen.be.
Emmy
E
Tuenter
Department of Analytical Chemistry and Pharmaceutical Technology, Center for Pharmaceutical Research (CePhaR), Vrije Universiteit Brussel-VUB, Laarbeeklaan 103, B-1090 Brussels, Belgium. Karen.Segers@vub.ac.be.
Karen
K
Segers
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea. mumyung2@snu.ac.kr.
Kyo Bin
KB
Kang
Department of Analytical Chemistry and Pharmaceutical Technology, Center for Pharmaceutical Research (CePhaR), Vrije Universiteit Brussel-VUB, Laarbeeklaan 103, B-1090 Brussels, Belgium. Johan.Viaene@vub.ac.be.
Johan
J
Viaene
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Korea. shsung@snu.ac.kr.
Sang Hyun
SH
Sung
Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Paul.Cos@uantwerpen.be.
Paul
P
Cos
Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Louis.Maes@uantwerpen.be.
Louis
L
Maes
Department of Analytical Chemistry and Pharmaceutical Technology, Center for Pharmaceutical Research (CePhaR), Vrije Universiteit Brussel-VUB, Laarbeeklaan 103, B-1090 Brussels, Belgium. yvanvdh@vub.ac.be.
Yvan Vander
YV
Heyden
Natural Products & Food Research and Analysis (NatuRA), Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Luc.Pieters@uantwerpen.be.
Luc
L
Pieters
D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010456:Peptides, Cyclic / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship
D000470:Alkaloids; D000962:Antimalarials; D010456:Peptides, Cyclic
SAR; antiplasmodial activity; cyclopeptide alkaloids; cytotoxicity