Design of novel artemisinin-like derivatives with cytotoxic and anti-angiogenic properties. J Cell Mol Med

Dafra Pharma Research & Development, Slachthuisstraat, Turnhout, Belgium.
Journal of Cellular and Molecular Medicine (Impact Factor: 4.01). 05/2011; 15(5):1122-35. DOI: 10.1111/j.1582-4934.2010.01120.x
Source: PubMed


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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Available from: Gert Fricker, Jul 29, 2014
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    • "As a consequence of this awareness, increased research efforts are focused on new derivatives with innovative applications and improved properties. Major pharmaceutical companies are beginning to take an interest in developing new trioxane compounds [18] [19] [20] [21]. Current analytical techniques describe derivatisation-based methods [22], gas chromatography (GC) [23], thin layer chromatography (TLC) [24], supercritical fluid chromatography (SCFC) [25], spectroscopic [26] and immunological techniques [27] [28], but it is clear that the main-stream methods are mainly based on high performance liquid chromatography (HPLC), coupled to ultra violet (UV), evaporative light scattering detector (ELSD), electron capture detection (ECD) or electrospray ionisation (ESI)–mass spectrometry (MS) detection [29] [30] [31] [32]. "
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    Journal of Pharmaceutical Analysis 02/2014; 4(1):37–52. DOI:10.1016/j.jpha.2013.03.006
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    ABSTRACT: P-Glycoprotein/MDR1 represents an important component of the blood brain barrier and contributes to multidrug resistance. We investigated two derivatives of the anti-malarial artemisinin, SM616 and GHP-AJM-3/23, concerning their ability to interact with P-glycoprotein. The ability of the two compounds to inhibit P-glycoprotein (P-gp) activity was examined in sensitive CCRF-CEM and P-gp over-expressing and multidrug-resistant CEM/ADR5000 cells as well as in porcine brain capillary endothelial cells (PBCEC) by means of calcein-AM assays. Verapamil as well-known P-gp inhibitor was used as control drug. CEM/ADR5000 cells exhibited cross-resistance to GHP-AJM-3/23, but slight collateral sensitivity to SM616. Furthermore, SM616 inhibited calcein efflux both in CEM/ADR5000 and PBCEC, whereas GHP-AJM-3/23 did only increase calcein fluorescence in PBCEC, but not CEM/ADR5000. This may be explained by the fact that CEM/ADR5000 only express P-gp but not other ATP-binding cassette transporters, whereas PBCEC are known to express several ABC transporters and calcein is transported by more than one ABC transporter. Hence, SM616 may be the more specific P-gp inhibitor. In conclusion, the collateral sensitivity of SM616 as well as the inhibition of calcein efflux in both CEM/ADR5000 cells and PBCEC indicate that this compound may be a promising P-gp inhibitor to treat cancer therapy and to overcome the blood brain barrier.
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