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

Dafra Pharma Research & Development, Slachthuisstraat, Turnhout, Belgium.
Journal of Cellular and Molecular Medicine (Impact Factor: 4.75). 05/2011; 15(5):1122-35. DOI: 10.1111/j.1582-4934.2010.01120.x
Source: PubMed

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.

  • Source
    [Show abstract] [Hide abstract]
    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.
    Natural Products and Bioprospecting. 2(2).
  • [Show abstract] [Hide abstract]
    ABSTRACT: Artemisinin contains an endoperoxide moiety that can react with iron to form cytotoxic free radicals. Cancer cells contain significantly more intracellular free iron than normal cells and it has been shown that artemisinin and its analogs selectively cause apoptosis in many cancer cell lines. In addition, artemisinin compounds have been shown to have anti-angiogenic, anti-inflammatory, anti-metastasis, and growth inhibition effects. These properties make artemisinin compounds attractive cancer chemotherapeutic drug candidates. However, simple artemisinin analogs are less potent than traditional cancer chemotherapeutic agents and have short plasma half-lives, and would require high dosage and frequent administration to be effective for cancer treatment. More potent and target-selective artemisinin-compounds are being developed. These include artemisinin dimers and trimers, artemisinin hybrid compounds, and tagging of artemisinin compounds to molecules that are involved in the intracellular iron-delivery mechanism. These compounds are promising potent anticancer compounds that produce significantly less side effect than traditional chemotherapeutic agents.
    Investigational New Drugs 08/2012; · 3.50 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Artemisinin, a constituent of Artemisia annua L., is a well-known antimalarial drug. Artemisinin-type drugs also inhibit cancer growth in vitro and in vivo. Herbal extracts of A. annua inhibit the growth of cancer cell lines. Here, we report on the use of capsules containing powder of Herba Artemisiae annuae to treat pet sarcoma. The surgical tumor removal as standard treatment was supplemented by adjuvant therapy with A. annua. One cat and one dog with fibrosarcoma survived 40 and 37 months, respectively, without tumor relapse. Two other dogs suffering from fibrosarcoma and hemangioendothelial sarcoma also showed complete remission and are still alive after 39 and 26 months, respectively. A. annua was well tolerated without noticeable side effects. These four cases indicate that A. annua may be a promising herbal drug for cancer therapy.
    Natural products and bioprospecting. 01/2014; 4:113-118.


Available from
Jul 29, 2014