TY - JOUR
T1 - Facile preparation of N-glycosylated 10-piperazinyl artemisinin derivatives and evaluation of their antimalarial and cytotoxic activities
AU - Wu, Yuet
AU - Parapini, Silvia
AU - Williams, Ian D.
AU - Misiano, Paola
AU - Wong, Ho Ning
AU - Taramelli, Donatella
AU - Basilico, Nicoletta
AU - Haynes, Richard K.
N1 - Publisher Copyright:
© 2018 by the authors.
PY - 2018/7
Y1 - 2018/7
N2 - According to the precepts that C-10 amino-artemisinins display optimum biological activities for the artemisinin drug class, and that attachment of a sugar enhances specificity of drug delivery, polarity and solubility so as to attenuate toxicity, we assessed the effects of attaching sugars to N-4 of the dihydroartemisinin (DHA)-piperazine derivative prepared in one step from DHA and piperazine. N-Glycosylated DHA-piperazine derivatives were obtained according to the Kotchetkov reaction by heating the DHA-piperazine with the sugar in a polar solvent. Structure of the D-glucose derivative is secured by X-ray crystallography. The D-galactose, L-rhamnose and D-xylose derivatives displayed IC50 values of 0.58–0.87 nM against different strains of Plasmodium falciparum (Pf) and selectivity indices (SI) >195, on average, with respect to the mouse fibroblast WEHI-164 cell line. These activities are higher than those of the amino-artemisinin, artemisone (IC50 0.9–1.1 nM). Notably, the D-glucose, D-maltose and D-ribose derivatives were the most active against the myelogenous leukemia K562 cell line with IC50 values of 0.78–0.87 µM and SI > 380 with respect to the human dermal fibroblasts (HDF). In comparison, artemisone has an IC50 of 0.26 µM, and a SI of 88 with the same cell lines. Overall, the N-glycosylated DHA-piperazine derivatives display antimalarial activities that are greatly superior to O-glycosides previously obtained from DHA.
AB - According to the precepts that C-10 amino-artemisinins display optimum biological activities for the artemisinin drug class, and that attachment of a sugar enhances specificity of drug delivery, polarity and solubility so as to attenuate toxicity, we assessed the effects of attaching sugars to N-4 of the dihydroartemisinin (DHA)-piperazine derivative prepared in one step from DHA and piperazine. N-Glycosylated DHA-piperazine derivatives were obtained according to the Kotchetkov reaction by heating the DHA-piperazine with the sugar in a polar solvent. Structure of the D-glucose derivative is secured by X-ray crystallography. The D-galactose, L-rhamnose and D-xylose derivatives displayed IC50 values of 0.58–0.87 nM against different strains of Plasmodium falciparum (Pf) and selectivity indices (SI) >195, on average, with respect to the mouse fibroblast WEHI-164 cell line. These activities are higher than those of the amino-artemisinin, artemisone (IC50 0.9–1.1 nM). Notably, the D-glucose, D-maltose and D-ribose derivatives were the most active against the myelogenous leukemia K562 cell line with IC50 values of 0.78–0.87 µM and SI > 380 with respect to the human dermal fibroblasts (HDF). In comparison, artemisone has an IC50 of 0.26 µM, and a SI of 88 with the same cell lines. Overall, the N-glycosylated DHA-piperazine derivatives display antimalarial activities that are greatly superior to O-glycosides previously obtained from DHA.
KW - Anti-tumour activities
KW - Antimalarial activities
KW - Artemisinins
KW - Artemisone
KW - N-glycosides
KW - Piperazine
UR - http://www.scopus.com/inward/record.url?scp=85052725234&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052725234&partnerID=8YFLogxK
U2 - 10.3390/molecules23071713
DO - 10.3390/molecules23071713
M3 - Article
C2 - 30011856
AN - SCOPUS:85052725234
SN - 1420-3049
VL - 23
SP - 1
EP - 19
JO - Molecules
JF - Molecules
IS - 7
M1 - 1713
ER -