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

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.

Cytotoxicity and mode of action of four naturally occuring flavonoids from the genus Dorstenia: gancaonin Q, 4-hydroxylonchocarpin, 6-prenylapigenin, and 6,8-diprenyleriodictyol.

Several flavonoid-like compounds were found to possess good antiproliferative properties. Herein, we examined the ability of four naturally occuring and biologically active flavonoids from the genus Dorstenia, gancaonin Q (1), 6-prenylapigenin (2), 6,8-diprenyleriodictyol (3), and 4-hydroxylonchocarpin ( 4), to inhibit the proliferation of a panel of fourteen cancer cell lines including leukemia and solid cancer cells, as well as AML12 normal hepatocytes. The study was extended to the analysis of cell cycle distribution, apoptosis induction, and caspase 3/7 activity and the antiangiogenic properties of the four compounds. The results of the cytotoxicity assays showed that more than 50 % inhibition of proliferation was obtained with compound 1 on all the fourteen studied cancer cell lines, with IC (50) values below 20 µg/mL. Compounds 2, 4, and 3 showed selective activity, with IC (50) values below 20 µg/mL being noted on 57.15 %, 71.42 %, and 85.71 % of the fourteen cancer cell lines, respectively. None of the compounds exhibited more than 50 % inhibition against AML12 normal hepatocytes cells at 20 µg/mL. IC (50) values below or around 4 µg/mL were recorded on 28.57 % of the tested cell lines for both compound 1 and 4 and 21.43 % for compound 3, which appeared to be the best cytotoxic compounds. This study indicates that caspase 3/7 activation is one of the modes of induction of apoptosis for compounds 1, 3, and 4 in CCRF-CEM cells. The results of the antiangiogenic assay indicated that compounds 1, 3, and 4 were also able to inhibit the growth of blood capillaries on the chorioallantoic membrane of quail eggs, the best effect being noted for compound 4 (54.1 % inhibition). The results of the present work provide evidence of the cytotoxic potential of the four studied flavonoids and supportive data for further investigations.

Cytotoxicity of artesunic acid homo- and heterodimer molecules toward sensitive and multidrug-resistant CCRF-CEM leukemia cells.

A novel approach to circumvent multidrug resistance is hybridization of natural products in dimers. We analyzed homodimers of two artesunic acid molecules and heterohybrids of artesunic acid and betulin in human CCRF-CEM and multidrug-resistant P-glycoprotein-overexpressing CEM/ADR5000 leukemia cells. Multidrug-resistant cells were not cross-resistant to the novel compounds. Collateral sensitivity was observed for artesunic acid homodimer. Artesunic acid and artesunic acid homodimer induced G0/G1 cell cycle arrest, apoptosis, and formation of reactive oxygen species.