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Artemisinin: Against Malaria, Cancer and Viruses

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (30 November 2017) | Viewed by 94968

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Prof. Dr. Svetlana B. Tsogoeva

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Department of Chemistry and Pharmacy, Friedrich-Alexander-University of Erlangen-Nürnberg, Nikolaus-Fiebiger-Str. 10, 91058 Erlangen, Germany
Interests: asymmetric organocatalysis; domino reactions toward bioactive heterocycles; one-pot processes; natural product hybrids for medicinal chemistry
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Dear Colleagues,

The natural 1,2,4 trioxane sesquiterpene artemisinin, isolated from the Chinese medicinal plant Artemisia annua L. (sweet wormwood) in 1972 by Youyou Tu (Nobel Prize, 2015), has proven to be a versatile antimalarial. In order to improve the pharmacological properties of artemisinin, several semisynthetic derivatives were developed: dihydroartemisinin, artesunic acid, and artemether. All three artemisinin derivatives proved to be highly active against malaria parasites and different cancer cell lines and also against viruses. In addition to the high safety of artemisinin and its derivatives, a high therapeutic tolerance, effectivity and a unique mode of action can be mentioned as the advantages of these compounds. Although the mechanism of action of artemisinin is still not completely understood, it is generally accepted that the endoperoxide linkage within the 1,2,4 trioxane system is essential for its activities. Generation of reactive oxygen species (ROS) and carbon-centered radicals are widely accepted as key intermediates responsible for the antimalarial and anticancer activities of artemisinin and its derivatives. In case of malaria, a disruption of the cellular redox cycling, an inhibition of a calcium-ATPase (SERCA, pFATP6), as well as a depolarization of the mitochondrial potential is discussed further. The advantage of artemisinin and its semi-synthetic analogue artesunic acid as anticancer agents lies not only in their potency as toxic agents to cancer cells, but also in their low toxicity to normal cells.

Over the past decade, a great deal of attention has been paid to the synthesis of new artemisinin derivatives and of a wide variety of atemisinin-derived dimers and hybrids as lead compounds of interest. These new molecular structures demonstrate improved properties compared to their parent compounds (e.g., circumventing multidrug resistance and low bioavailability), making the dimerization/hybridisation concept highly compelling for development of efficient antimalarial, anticancer and antiviral drugs.

The present Special Issue intends to highlight the past and present role of artemisinin and different types of artemisinin-derived compounds for the development of new efficient therapeutics for the treatment of malaria, cancer, and viruses and will consider the future prospects of artemisinin for drug discovery.

Prof. Dr. Svetlana B. Tsogoeva
Guest Editor

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Keywords

artemisinin
antimalarial
anticancer
antiviral
medicinal chemistry
artemisinin’s mode of action
artemisinin-derived hybrids/dimers

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13 pages, 10793 KiB

Open AccessArticle

Treatment of Multidrug-Resistant Leukemia Cells by Novel Artemisinin-, Egonol-, and Thymoquinone-Derived Hybrid Compounds

by Lisa Gruber, Sara Abdelfatah, Tony Fröhlich, Christoph Reiter, Volker Klein, Svetlana B. Tsogoeva and Thomas Efferth

Molecules 2018, 23(4), 841; https://doi.org/10.3390/molecules23040841 - 6 Apr 2018

Cited by 23 | Viewed by 6081

Abstract

Two major obstacles for successful cancer treatment are the toxicity of cytostatics and the development of drug resistance in cancer cells during chemotherapy. Acquired or intrinsic drug resistance is responsible for almost 90% of treatment failure. For this reason, there is an urgent need for new anticancer drugs with improved efficacy against cancer cells, and with less toxicity on normal cells. There are impressive examples demonstrating the success of natural plant compounds to fight cancer, such as Vinca alkaloids, taxanes, and anthracyclines. Artesunic acid (ARTA), a drug for malaria treatment, also exerts cytotoxic activity towards cancer cells. Multidrug resistance often results from drug efflux pumps (ABC-transporters) that reduce intracellular drug levels. Hence, it would be interesting to know, whether ARTA could overcome drug resistance of tumor cells, and in what way ABC-transporters are involved. Different derivatives showing improved features concerning cytotoxicity and pharmacokinetic behavior have been developed. Considering both drug sensitivity and resistance, we chose a sensitive and a doxorubicin-resistant leukemia cell line and determined the killing effect of ARTA on these cells. Molecular docking and doxorubicin efflux assays were performed to investigate the interaction of the derivatives with P-glycoprotein. Using single-cell gel electrophoresis (alkaline comet assay), we showed that the derivatives of ARTA induce DNA breakage and accordingly programmed cell death, which represents a promising strategy in cancer treatment. ARTA activated apoptosis in cancer cells by the iron-mediated generation of reactive oxygen species (ROS). In conclusion, ARTA derivatives may bear the potential to be further developed as anticancer drugs. Full article

(This article belongs to the Special Issue Artemisinin: Against Malaria, Cancer and Viruses)

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2372 KiB

Open AccessArticle

Artesunate Activates the Intrinsic Apoptosis of HCT116 Cells through the Suppression of Fatty Acid Synthesis and the NF-κB Pathway

by Xiao Chen, Yin Kwan Wong, Teck Kwang Lim, Wei Hou Lim, Qingsong Lin, Jigang Wang and Zichun Hua

Molecules 2017, 22(8), 1272; https://doi.org/10.3390/molecules22081272 - 8 Aug 2017

Cited by 35 | Viewed by 9281

Abstract

The artemisinin compounds, which are well-known for their potent therapeutic antimalarial activity, possess in vivo and in vitro antitumor effects. Although the anticancer effect of artemisinin compounds has been extensively reported, the precise mechanisms underlying its cytotoxicity remain under intensive study. In the present study, a high-throughput quantitative proteomics approach was applied to identify differentially expressed proteins of HCT116 colorectal cancer cell line with artesunate (ART) treatment. Through Ingenuity Pathway Analysis, we discovered that the top-ranked ART-regulated biological pathways are abrogation of fatty acid biosynthetic pathway and mitochondrial dysfunction. Subsequent assays showed that ART inhibits HCT116 cell proliferation through suppressing the fatty acid biosynthetic pathway and activating the mitochondrial apoptosis pathway. In addition, ART also regulates several proteins that are involved in NF-κB pathway, and our subsequent assays showed that ART suppresses the NF-κB pathway. These proteomic findings will contribute to improving our understanding of the underlying molecular mechanisms of ART for its therapeutic cytotoxic effect towards cancer cells. Full article

(This article belongs to the Special Issue Artemisinin: Against Malaria, Cancer and Viruses)

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2896 KiB

Open AccessArticle

Artesunate Enhances the Cytotoxicity of 5-Aminolevulinic Acid-Based Sonodynamic Therapy against Mouse Mammary Tumor Cells In Vitro

by Tomohiro Osaki, Yoshihiro Uto, Masahiro Ishizuka, Tohru Tanaka, Nobuyasu Yamanaka, Tsukasa Kurahashi, Kazuo Azuma, Yusuke Murahata, Takeshi Tsuka, Norihiko Itoh, Tomohiro Imagawa and Yoshiharu Okamoto

Molecules 2017, 22(4), 533; https://doi.org/10.3390/molecules22040533 - 27 Mar 2017

Cited by 17 | Viewed by 5656

Abstract

Sonodynamic therapy (SDT) kills tumor cells through the synergistic effects of ultrasound (US) and a sonosensitizer agent. 5-Aminolevulinic acid (5-ALA) has been used as a sonodynamic sensitizer for cancer treatment. However, studies have shown that 5-ALA-based SDT has limited efficacy against malignant tumors. In this study, we examined whether artesunate (ART) could enhance the cytotoxicity of 5-ALA-based SDT against mouse mammary tumor (EMT-6) cells in vitro. In the ART, ART + US, ART + 5-ALA, and ART + 5-ALA + US groups, the cell survival rate correlated with ART concentration, and decreased with increasing concentrations of ART. Morphologically, many apoptotic and necrotic cells were observed in the ART + 5-ALA + US group. The percentage of reactive oxygen species-positive cells in the ART + 5-ALA + US group was also significantly higher than that in the 5-ALA group (p = 0.0228), and the cell death induced by ART + 5-ALA + US could be inhibited by the antioxidant N-acetylcysteine. These results show that ART offers great potential in enhancing the efficacy of 5-ALA-based SDT for the treatment of cancer. However, these results are only based on in vitro studies, and further in vivo studies are required. Full article

(This article belongs to the Special Issue Artemisinin: Against Malaria, Cancer and Viruses)

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988 KiB

Open AccessArticle

Application of the Triazolization Reaction to Afford Dihydroartemisinin Derivatives with Anti-HIV Activity

by Sampad Jana, Shabina Iram, Joice Thomas, Muhammad Qasim Hayat, Christophe Pannecouque and Wim Dehaen

Molecules 2017, 22(2), 303; https://doi.org/10.3390/molecules22020303 - 17 Feb 2017

Cited by 33 | Viewed by 7318

Abstract

Artemisinin and synthetic derivatives of dihydroartemisinin are known to possess various biological activities. Post-functionalization of dihydroartemisinin with triazole heterocycles has been proven to lead to enhanced therapeutic potential. By using our newly developed triazolization strategy, a library of unexplored fused and 1,5-disubstituted 1,2,3-triazole derivatives of dihydroartemisinin were synthesized in a single step. All these newly synthesized compounds were characterized and evaluated for their anti-HIV (Human Immunodeficiency Virus) potential in MT-4 cells. Interestingly; three of the synthesized triazole derivatives of dihydroartemisinin showed activities with half maximal inhibitory concentration (IC₅₀) values ranging from 1.34 to 2.65 µM. Full article

(This article belongs to the Special Issue Artemisinin: Against Malaria, Cancer and Viruses)

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1572 KiB

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Synthetic Approaches to Mono- and Bicyclic Perortho-Esters with a Central 1,2,4-Trioxane Ring as the Privileged Lead Structure in Antimalarial and Antitumor-Active Peroxides and Clarification of the Peroxide Relevance

by Axel G. Griesbeck, Maria Bräutigam, Margarethe Kleczka and Angela Raabe

Molecules 2017, 22(1), 119; https://doi.org/10.3390/molecules22010119 - 11 Jan 2017

Cited by 9 | Viewed by 7373

Abstract

The synthesis of 4-styryl-substituted 2,3,8-trioxabicyclo[3.3.1]nonanes, peroxides with the core structure of the bioactive 1,2,4-trioxane ring, was conducted by a multistep route starting from the aryl methyl ketones 1a–1c. Condensation and reduction/oxidation delivered enals 4a–4c that were coupled with ethyl acetate and reduced to the 1,3-diol substrates 6a–6c. Highly diastereoselective photooxygenation delivered the hydroperoxides 7a–7c and subsequent PPTS (pyridinium-p-toluenesulfonic acid)-catalyzed peroxyacetalization with alkyl triorthoacetates gave the cyclic peroxides 8a–8e. These compounds in general show only moderate antimalarial activities. In order to extend the repertoire of cyclic peroxide structure, we aimed for the synthesis of spiro-perorthocarbonates from orthoester condensation of β-hydroxy hydroperoxide 9 but could only realize the monocyclic perorthocarbonate 10. That the central peroxide moiety is the key structural motif in anticancer active GST (glutathione S-transferase)-inhibitors was elucidated by the synthesis of a 1,3-dioxane 15—with a similar substitution pattern as the pharmacologically active peroxide 11—via a singlet oxygen ene route from the homoallylic alcohol 12. Full article

(This article belongs to the Special Issue Artemisinin: Against Malaria, Cancer and Viruses)

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Review

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17 pages, 1967 KiB

Open AccessReview

Increasing the Strength and Production of Artemisinin and Its Derivatives

by Syed Lal Badshah, Asad Ullah, Nasir Ahmad, Zainab M. Almarhoon and Yahia Mabkhot

Molecules 2018, 23(1), 100; https://doi.org/10.3390/molecules23010100 - 3 Jan 2018

Cited by 29 | Viewed by 10274

Abstract

Artemisinin is a natural sesquiterpene lactone obtained from the Artemisia annua herb. It is widely used for the treatment of malaria. In this article, we have reviewed the role of artemisinin in controlling malaria, spread of resistance to artemisinin and the different methods used for its large scale production. The highest amount of artemisinin gene expression in tobacco leaf chloroplast leads to the production of 0.8 mg/g of the dry weight of the plant. This will revolutionize the treatment and control of malaria in third world countries. Furthermore, the generations of novel derivatives of artemisinin- and trioxane ring structure-inspired compounds are important for the treatment of malaria caused by resistant plasmodial species. Synthetic endoperoxide-like artefenomel and its derivatives are crucial for the control of malaria and such synthetic compounds should be further explored. Full article

(This article belongs to the Special Issue Artemisinin: Against Malaria, Cancer and Viruses)

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12133 KiB

Open AccessReview

Peroxides with Anthelmintic, Antiprotozoal, Fungicidal and Antiviral Bioactivity: Properties, Synthesis and Reactions

by Vera A. Vil’, Ivan A. Yaremenko, Alexey I. Ilovaisky and Alexander O. Terent’ev

Molecules 2017, 22(11), 1881; https://doi.org/10.3390/molecules22111881 - 2 Nov 2017

Cited by 66 | Viewed by 11197

Abstract

The biological activity of organic peroxides is usually associated with the antimalarial properties of artemisinin and its derivatives. However, the analysis of published data indicates that organic peroxides exhibit a variety of biological activity, which is still being given insufficient attention. In the present review, we deal with natural, semi-synthetic and synthetic peroxides exhibiting anthelmintic, antiprotozoal, fungicidal, antiviral and other activities that have not been described in detail earlier. The review is mainly concerned with the development of methods for the synthesis of biologically active natural peroxides, as well as its isolation from natural sources and the modification of natural peroxides. In addition, much attention is paid to the substantially cheaper biologically active synthetic peroxides. The present review summarizes 217 publications mainly from 2000 onwards. Full article

(This article belongs to the Special Issue Artemisinin: Against Malaria, Cancer and Viruses)

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1828 KiB

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Design of Drug Delivery Systems Containing Artemisinin and Its Derivatives

by Blessing Atim Aderibigbe

Molecules 2017, 22(2), 323; https://doi.org/10.3390/molecules22020323 - 20 Feb 2017

Cited by 54 | Viewed by 9807

Abstract

Artemisinin and its derivatives have been reported to be experimentally effective for the treatment of highly aggressive cancers without developing drug resistance, they are useful for the treatment of malaria, other protozoal infections and they exhibit antiviral activity. However, they are limited pharmacologically by their poor bioavailability, short half-life in vivo, poor water solubility and long term usage results in toxicity. They are also expensive for the treatment of malaria when compared to other antimalarials. In order to enhance their therapeutic efficacy, they are incorporated onto different drug delivery systems, thus yielding improved biological outcomes. This review article is focused on the currently synthesized derivatives of artemisinin and different delivery systems used for the incorporation of artemisinin and its derivatives. Full article

(This article belongs to the Special Issue Artemisinin: Against Malaria, Cancer and Viruses)

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4990 KiB

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Synthetic Strategies for Peroxide Ring Construction in Artemisinin

by Vera A. Vil’, Ivan A. Yaremenko, Alexey I. Ilovaisky and Alexander O. Terent’ev

Molecules 2017, 22(1), 117; https://doi.org/10.3390/molecules22010117 - 11 Jan 2017

Cited by 34 | Viewed by 13327

Abstract

The present review summarizes publications on the artemisinin peroxide fragment synthesis from 1983 to 2016. The data are classified according to the structures of a precursor used in the key peroxidation step of artemisinin peroxide cycle synthesis. The first part of the review comprises the construction of artemisinin peroxide fragment in total syntheses, in which peroxide artemisinin ring resulted from reactions of unsaturated keto derivatives with singlet oxygen or ozone. In the second part, the methods of artemisinin synthesis based on transformations of dihydroartemisinic acid are highlighted. Full article

(This article belongs to the Special Issue Artemisinin: Against Malaria, Cancer and Viruses)

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1152 KiB

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Artemisinin and Its Derivatives as a Repurposing Anticancer Agent: What Else Do We Need to Do?

by Zhe Li, Qin Li, Jun Wu, Manyuan Wang and Junxian Yu

Molecules 2016, 21(10), 1331; https://doi.org/10.3390/molecules21101331 - 7 Oct 2016

Cited by 70 | Viewed by 11943

Abstract

Preclinical investigation and clinical experience have provided evidence on the potential anticancer effect of artemisinin and its derivatives (ARTs) in the recent two decades. The major mechanisms of action of ARTs may be due to toxic-free radicals generated by an endoperoxide moiety, cell cycle arrest, induction of apoptosis, and inhibition of tumor angiogenesis. It is very promising that ARTs are expected to be a new class of antitumor drugs of wide spectrum due to their detailed information regarding efficacy and safety. For developing repurposed drugs, many other characteristics of ARTs should be studied, including through further investigations on possible new pathways of anticancer effects, exploration on efficient and specific drug delivery systems-especially crossing biological barriers, and obtaining sufficient data in clinical trials. The aim of this review is to highlight these achievements and propose the potential strategies to develop ARTs as a new class of cancer therapeutic agents. Full article

(This article belongs to the Special Issue Artemisinin: Against Malaria, Cancer and Viruses)

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