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 M and SI > 380 with respect to the human dermal fibroblasts (HDF). In comparison, artemisone has an IC50 of 0.26 M, 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.

Facile Preparation of N-Glycosylated 10-Piperazinyl Artemisinin Derivatives and Evaluation of Their Antimalarial and Cytotoxic Activities / Y. Wu, S. Parapini, I. Williams, P. Misiano, H. Wong, D. Taramelli, N. Basilico, R. Haynes. - In: MOLECULES. - ISSN 1420-3049. - 23:7(2018 Jul 13), pp. 1713.1-1713.19. [10.3390/molecules23071713]

Facile Preparation of N-Glycosylated 10-Piperazinyl Artemisinin Derivatives and Evaluation of Their Antimalarial and Cytotoxic Activities

S. Parapini
Co-primo
;
P. Misiano;D. Taramelli;N. Basilico
;
2018

Abstract

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 M and SI > 380 with respect to the human dermal fibroblasts (HDF). In comparison, artemisone has an IC50 of 0.26 M, 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.
Settore MED/04 - Patologia Generale
Settore MED/07 - Microbiologia e Microbiologia Clinica
Settore MED/46 - Scienze Tecniche di Medicina di Laboratorio
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/582107
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