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. 2011 May;15(5):1122-35.
doi: 10.1111/j.1582-4934.2010.01120.x. Epub 2010 Jul 12.

Design of novel artemisinin-like derivatives with cytotoxic and anti-angiogenic properties

Shahid Soomro  1 , Tobias Langenberg, Anne Mahringer, V Badireenath Konkimalla, Cindy Horwedel, Pavlo Holenya, Almut Brand, Canan Cetin, Gert Fricker, Mieke Dewerchin, Peter Carmeliet, Edward M Conway, Herwig Jansen, Thomas Efferth
Affiliations

Design of novel artemisinin-like derivatives with cytotoxic and anti-angiogenic properties

Shahid Soomro et al. J Cell Mol Med. 2011 May.

Abstract

Artemisinins are plant products with a wide range of medicinal applications. Most prominently, artesunate is a well tolerated and effective drug for treating malaria, but is also active against several protozoal and schistosomal infections, and additionally exhibits anti-angiogenic, anti-tumorigenic and anti-viral properties. The array of activities of the artemisinins, and the recent emergence of malaria resistance to artesunate, prompted us to synthesize and evaluate several novel artemisinin-like derivatives. Sixteen distinct derivatives were therefore synthesized and the in vitro cytotoxic effects of each were tested with different cell lines. The in vivo anti-angiogenic properties were evaluated using a zebrafish embryo model. We herein report the identification of several novel artemisinin-like compounds that are easily synthesized, stable at room temperature, may overcome drug-resistance pathways and are more active in vitro and in vivo than the commonly used artesunate. These promising findings raise the hopes of identifying safer and more effective strategies to treat a range of infections and cancer.

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Figures

fig 1
fig 1
Structure of artemisinin, DHA and artesunate.
fig 2
fig 2
Conversion of DHA into esters.
fig 3
fig 3
Conversion of DHA into ether and amine.
fig 4
fig 4
Synthetic scheme of compounds 3, 4 and 5. Reagents and conditions: (A) NaBH4, THF; (B) BF3.OEt2/Et3SiH, CH2Cl2; (C) BF3.OEt2, CH2Cl2; (D) i. BH3, THF; ii. 3 M NaOHaq, H2O2 30%, THF.
fig 5
fig 5
Inhibition of calcein ametoxymethylester efflux from human leukaemia CCRF/CEM and CEM/Adr5000 cells by different concentrations of the testing substances – derivatives of artesunate. The intracellular accumulation of calcein inside the cells is measured by using FACS analysis. The points indicate mean values of fluorescent effect, vertical lines show standard error calculated on the base of two independent experiment replicates. The effect corresponds to a control of cells which were treated only with calcein.
fig 6
fig 6
(A) High-magnification micrographs of porcine brain capillaries incubated with substance 8. (first row) negative control (capillaries stained only with NBD-CSA in the same time course); (second row) (1) transmitted light image of several capillaries; (2) confocal fluorescent micrograph of several capillaries; in addition to the capillary endothelium, these vessels may contain pericytes within the wall of the capillary and blood cells within the lumen; (3) overlay of 1 and 2 (B)Transport of the P-gp substrate NBD-CSA into porcine brain capillary lumens in the absence of control and presence of testing substances.
fig 7
fig 7
Artemisinin derivatives inhibit angiogenesis in vivo. Lateral views of the trunk region of zebrafish embryos are shown at 48 hrs after fertilization (hpf) (head to the left) that were treated with 1% DMSO (A, control) or artemisinin derivatives (B–D) from 19–48 hpf. (A) At 48 hpf, several blood vessels can clearly be distinguished in the trunk of the embryo: dorsal aorta (DA), posterior cardinal vein (PCV), ISVs, dorsal longitudinal anastomosing vessel (DLAV). (B) In an embryo treated with 25 μg/ml of compound 9, the ISVs are stunted (arrowheads) and the DLAV has not formed. (C, D) Compound 11 has a dose-dependent effect on blood vessel formation. At 1 μg/ml, ISVs are thin and the DLAV is incomplete (asterisks). At the higher dose of 5 μg/ml, several ISVs are severely reduced and the DLAV has many gaps (asterisks).
fig 8
fig 8
Inhibition of VEGF-driven HUVEC proliferation. Optical density (OD) as a measure of viable cells at various concentrations of compounds 7, 10 and artemisinin, expressed as percentage of control (VEGF) treated HUVECs. Increasing levels of artemisinin-like compounds strongly inhibit proliferation/survival of HUVECs even in the presence of VEGF. Error bars = S.E.M.
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