Synthesis and evaluation of dihydroartemisinin and dihydroartemisitene acetal dimers showing anticancer and antiprotozoal activity

Galal, Ahmed M.; Gul, Waseem; Slade, Desmond; Ross, Samir A.; Feng, Shixia; Hollingshead, Melinda G.; Alley, Michael C.; Kaur, Gurmeet; ElSohly, Mahmoud A.

doi:10.1016/j.bmc.2008.11.050

Cited by 61 publications

(61 citation statements)

References 43 publications

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“…In addition to the antiangiogenic matricryptins endostatin and anastellin, most promastigotes bind to proangiogenic factors such as ECM-1 (36, 39), TEM8 (40), and VEGF (41). The promotion of angiogenesis might provide a favorable environment for Leishmania, since several antileishmanial molecules have antiangiogenic activity (31,32) and since L. donovani promastigotes are able to synthesize their own basic fibroblast growth factor (FGF)-like molecules (42). Furthermore, VEGF is upregulated by the hypoxia-inducible factor HIF-1, which is activated by L. donovani for its survival within host macrophages (43).…”

Section: Discussionmentioning

confidence: 99%

Large-Scale Investigation of Leishmania Interaction Networks with Host Extracellular Matrix by Surface Plasmon Resonance Imaging

et al. 2014

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We have set up an assay to study the interactions of live pathogens with their hosts by using protein and glycosaminoglycan arrays probed by surface plasmon resonance imaging. We have used this assay to characterize the interactions of Leishmania promastigotes with ϳ70 mammalian host biomolecules (extracellular proteins, glycosaminoglycans, growth factors, cell surface receptors). We have identified, in total, 27 new partners (23 proteins, 4 glycosaminoglycans) of procyclic promastigotes of six Leishmania species and 18 partners (15 proteins, 3 glycosaminoglycans) of three species of stationary-phase promastigotes for all the strains tested. The diversity of the interaction repertoires of Leishmania parasites reflects their dynamic and complex interplay with their mammalian hosts, which depends mostly on the species and strains of Leishmania. Stationary-phase Leishmania parasites target extracellular matrix proteins and glycosaminoglycans, which are highly connected in the extracellular interaction network. Heparin and heparan sulfate bind to most Leishmania strains tested, and 6-O-sulfate groups play a crucial role in these interactions. Numerous Leishmania strains bind to tropoelastin, and some strains are even able to degrade it. Several strains interact with collagen VI, which is expressed by macrophages. Most Leishmania promastigotes interact with several regulators of angiogenesis, including antiangiogenic factors (endostatin, anastellin) and proangiogenic factors (ECM-1, VEGF, and TEM8 [also known as anthrax toxin receptor 1]), which are regulated by hypoxia. Since hypoxia modulates the infection of macrophages by the parasites, these interactions might influence the infection of host cells by Leishmania.

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Section: Discussionmentioning

confidence: 99%

Large-Scale Investigation of Leishmania Interaction Networks with Host Extracellular Matrix by Surface Plasmon Resonance Imaging

et al. 2014

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“…For example, not all dimers tested were found to have an effective antiproliferative effect on cancer cells and those that do also have different potencies towards different cancer cell lines (e.g. 23,133,136). In our recent study [137], we tested two artemisinin-dimers synthesized in our laboratories and found that one was slight but significantly more potent effect than the other both in vitro and in vivo.…”

Section: Artemisinin Dimers and Trimersmentioning

confidence: 97%

“…Galal et al [136] reported that daily subcutaneous injection (25-50 mg/ kg/day) of a dimer caused a significant growth delay of HL-60 human leukemia xenografts in the mouse. However, one of the dimer tested was found to be toxic to animals.…”

Section: Artemisinin Dimers and Trimersmentioning

confidence: 98%

Development of artemisinin compounds for cancer treatment

2012

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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.

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“…The formation of two important intermediates (7,8) were confirmed by 1 H-NMR spectral and LC-MS data, The formation of the title compounds, were evidenced by 1 H-NMR spectrum, IR, LC-MS and element analysis data, which were explained in experimental part.…”

mentioning

confidence: 75%

“…Some of them showed excellent anti-tumor activity toward different cancer cell lines in vitro. [3][4][5][6][7][8][9] Also, several studies demonstrated that artemisinin analogues were effective to many drug-and radiation-resistant cancer cell lines due to their multiple mechanisms. 10,11) The main mode likely involves a similar metalinduced free-radical formation leading to induce apoptosis in cancer cells and inhibit the tumor angiogenesis.…”

Section: )mentioning

confidence: 99%

Design, Synthesis and Antitumor Activity of Novel Artemisinin Derivatives Using Hybrid Approach

Xie

Zhai

Ren

et al. 2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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Despite cancer chemotherapy has entered a new era of molecularly targeted therapeutics and some forms of cancer have been successfully treated by modern therapies, the successful treatment of cancer remains a significant challenge in the future because chemotherapy is limited by the drug resistance and adverse side effects.1) In order to develop more effective and reliable anticancer agents that circumvent these limitations, the search for novel anti-tumor agents has turned to natural products, in particular plants used in traditional folk medicines. 2)In recent years, artemisinin and its derivatives have been widely studied for their anticancer activities. Some of them showed excellent anti-tumor activity toward different cancer cell lines in vitro. [3][4][5][6][7][8][9] Also, several studies demonstrated that artemisinin analogues were effective to many drug-and radiation-resistant cancer cell lines due to their multiple mechanisms. 10,11) The main mode likely involves a similar metalinduced free-radical formation leading to induce apoptosis in cancer cells and inhibit the tumor angiogenesis. [12][13][14][15][16] Recently, considerable attention has been focused on chalcones, which are a class of privileged structures that are easily prepared and have a wide range of biological properties, [17][18][19][20][21] which makes them an attractive pharmacophoric scaffold. An area of particular interest is their potential as antitumor agents, for which several modes of action have been proposed. The key mechanism is the inhibition of tubulin polymerization, while also including the inhibition of angiogenesis and the induction of apoptosis. [22][23][24] Chalcones and artemisinin analogues represent two classes of natural products, whose antitumor effects appear to be consistent via different molecular mechanisms. As the application of hybrid strategy to synthesize artemisinin analogues are continuously emerging, 9,25) it is reasonable to combine their structure analogues to form a single molecular framework with a linker, which would allow us to find more potent anti-tumor agents, in which these 'merge' pharmacophore may be addressing the active site of different targets and offering the possibility to overcome drug resistance. Intrigued by these observations, we designed and synthesized two new series of novel artemisinin derivatives by replacement of oxygen at C-10 with nitrogen, in which the substituted chalcone group is bonded to the artemisinin nucleus through an oxyacetyl linkage.Chemistry The synthetic routes of compounds are outlined in Chart 1. Separable diastereomeric mixture of 10b-azidodihydroartemisinin (2) and 10a-azidodihydroartemisinin (3) were obtained by treating 1 with trimethylsilyl chloride, sodium azide and sodium iodide at room temperature for 28 h, according to ref 6. The a and b isomers appeared as two distinct spots on TLC and were separated by column chromatography, with b-isomers as the major products. The reduction of azido compounds (2, 3) with Staudinger reaction afforded the correspondin...

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Synthesis and evaluation of dihydroartemisinin and dihydroartemisitene acetal dimers showing anticancer and antiprotozoal activity

Cited by 61 publications

References 43 publications

Large-Scale Investigation of Leishmania Interaction Networks with Host Extracellular Matrix by Surface Plasmon Resonance Imaging

Large-Scale Investigation of Leishmania Interaction Networks with Host Extracellular Matrix by Surface Plasmon Resonance Imaging

Development of artemisinin compounds for cancer treatment

Design, Synthesis and Antitumor Activity of Novel Artemisinin Derivatives Using Hybrid Approach

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