Highly potent artemisinin-derived dimers and trimers: Synthesis and evaluation of their antimalarial, antileukemia and antiviral activities

Reiter, Christoph; Fröhlich, Tony; Gruber, Lisa; Hutterer, Corina; Marschall, Manfred; Voigtländer, Cornelia; Friedrich, Oliver; Kappes, Barbara; Efferth, Thomas; Tsogoeva, Svetlana B.

doi:10.1016/j.bmc.2015.07.048

Cited by 99 publications

(74 citation statements)

References 52 publications

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“…Prevention and clinical interventions for HCMV disease are limited, since cross-resistance to all approved anti-HCMV drugs is increasingly observed31. As alternatives to standard drugs2332, our ongoing search for highly active hybrid molecules333435, which exceed their parent compounds in activity against HCMV, resulted in synthesis of new artesunic acid–quinazoline hybrids 8 and 9 (Fig. 7a and Supplementary Methods).…”

Section: Resultsmentioning

confidence: 99%

“…6) as coupling partners, since their fluorescence properties were considered beneficial for biological investigations. Artesunic acid on the other hand was selected because it proved to be a valuable building block in order to get highly bioactive compounds with just a few chemical transformations and also because of its promising pharmacological properties233235.…”

Section: Resultsmentioning

confidence: 99%

“…This new metal-free 10-step sequence, with only a single work up procedure and starting from simple and readily available compounds, results in new functionalized quinazolines of type E (Fig. 1b), which exceed the antiviral potency of the clinical reference drug ganciclovir23. Furthermore, selected fluorescent quinazolines were applied for synthesis of first artesunic acid–quinazoline hybrids, which are, remarkably, also fluorescent and display superior potency against HCMV ( EC 50 down to 0.1±0.0 μM) compared to that of their parent quinazolines ( EC 50 down to 4.6±0.9 μM) and artesunic acid ( EC 50 3.8±0.4 μM), as well as ganciclovir ( EC 50 2.6±0.5 μM).…”

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confidence: 99%

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Facile access to potent antiviral quinazoline heterocycles with fluorescence properties via merging metal-free domino reactions

et al. 2017

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Most of the known approved drugs comprise functionalized heterocyclic compounds as subunits. Among them, non-fluorescent quinazolines with four different substitution patterns are found in a variety of clinically used pharmaceuticals, while 4,5,7,8-substituted quinazolines and those displaying their own specific fluorescence, favourable for cellular uptake visualization, have not been described so far. Here we report the development of a one-pot synthetic strategy to access these 4,5,7,8-substituted quinazolines, which are fluorescent and feature strong antiviral properties (EC50 down to 0.6±0.1 μM) against human cytomegalovirus (HCMV). Merging multistep domino processes in one-pot under fully metal-free conditions leads to sustainable, maximum efficient and high-yielding organic synthesis. Furthermore, generation of artesunic acid–quinazoline hybrids and their application against HCMV (EC50 down to 0.1±0.0 μM) is demonstrated. Fluorescence of new antiviral hybrids and quinazolines has potential applications in molecular imaging in drug development and mechanistic studies, avoiding requirement of linkage to external fluorescent markers.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Facile access to potent antiviral quinazoline heterocycles with fluorescence properties via merging metal-free domino reactions

et al. 2017

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“…It is therefore unsurprising that artemisinin has become the subject of increasing scrutiny for its possible application in cancer. Accumulating evidence demonstrates that artemisinin induces cytotoxicity in a wide range of cancers in vitro and in vivo . Known examples include liver, gastric, colorectal, lung, breast, cervical, ovarian, and esophageal cancers among others .…”

Section: Introductionmentioning

confidence: 99%

Targeting autophagy enhances the anticancer effect of artemisinin and its derivatives

Sun

Yan

Zou

et al. 2019

Medicinal Research Reviews

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Artemisinin and its derivatives, with their outstanding clinical efficacy and safety, represent the most effective and impactful antimalarial drugs. Apart from its antimalarial effect, artemisinin has also been shown to exhibit selective anticancer properties against multiple cancer types both in vitro and in vivo. Specifically, our previous studies highlighted the therapeutic effects of artemisinin on autophagy regulation. Autophagy is a well‐conserved degradative process that recycles cytoplasmic contents and organelles in lysosomes to maintain cellular homeostasis. The deregulation of autophagy is often observed in cancer cells, where it contributes to tumor adaptation to nutrient‐deficient tumor microenvironments. This review discusses recent advances in the anticancer properties of artemisinin and its derivatives via their regulation of autophagy, mitophagy, and ferritinophagy. In particular, we will discuss the mechanisms of artemisinin activation in cancer and novel findings regarding the role of artemisinin in regulating autophagy, which involves changes in multiple signaling pathways. More importantly, with increasing failure rates and the high cost of the development of novel anticancer drugs, the strategy of repurposing traditional therapeutic Chinese medicinal agents such as artemisinin to treat cancer provides a more attractive alternative. We believe that the topics covered here will be important in demonstrating the potential of artemisinin and its derivatives as safe and potent anticancer agents.

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“…These two derivatives are valuable starting materials for artemisinin‐based compounds because they already contain functional groups (alcohol and carboxylic acid function) that are useful for chemical transformations. Recently, we applied artesunic acid ( 2 a ) and dihydroartemisinin ( 2 b ) for the synthesis of four novel artemisinin‐derived compounds: two dimers and two trimers, which were screened for their potency against malaria, leukemia, and HCMV . Trimer 3 (Figure ) turned out to be the most bioactive compound out of the four and it surpassed the monomer artesunic acid by a factor of 35 in terms of antileukemia (EC 50 0.002 μ m ) and by a factor of 95 in terms of anticytomegaloviral activity (EC 50 0.04 μ m ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Artemisinin‐Derived Dimers, Trimers and Dendrimers: Investigation of Their Antimalarial and Antiviral Activities Including Putative Mechanisms of Action

Fröhlich

Hahn

Belmudes

et al. 2018

Chemistry A European J

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Generation of dimers, trimers and dendrimers of bioactive compounds is an approach that has recently been developed for the discovery of new potent drug candidates. Herein, we present the synthesis of new artemisinin-derived dimers and dendrimers and investigate their action against malaria parasite Plasmodium falciparum 3D7 strain and human cytomegalovirus (HCMV). Dimer 7 was the most active compound (EC 1.4 nm) in terms of antimalarial efficacy and was even more effective than the standard drugs dihydroartemisinin (EC 2.4 nm), artesunic acid (EC 8.9 nm) and chloroquine (EC 9.8 nm). Trimer 4 stood out as the most active agent against HCMV in vitro replication and exerted an EC value of 0.026 μm, representing an even higher activity than the two reference drugs ganciclovir (EC 2.60 μm) and artesunic acid (EC 5.41 μm). In addition, artemisinin-derived dimer 13 and trimer 15 were for the first time both immobilized on TOYOPEARL AF-Amino-650M beads and used for mass spectrometry-based target identification experiments using total lysates of HCMV-infected primary human fibroblasts. Two major groups of novel target candidates, namely cytoskeletal and mitochondrial proteins were obtained. Two putatively compound-binding viral proteins, namely major capsid protein (MCP) and envelope glycoprotein pUL132, which are both essential for HCMV replication, were identified.

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Highly potent artemisinin-derived dimers and trimers: Synthesis and evaluation of their antimalarial, antileukemia and antiviral activities

Cited by 99 publications

References 52 publications

Facile access to potent antiviral quinazoline heterocycles with fluorescence properties via merging metal-free domino reactions

Facile access to potent antiviral quinazoline heterocycles with fluorescence properties via merging metal-free domino reactions

Targeting autophagy enhances the anticancer effect of artemisinin and its derivatives

Synthesis of Artemisinin‐Derived Dimers, Trimers and Dendrimers: Investigation of Their Antimalarial and Antiviral Activities Including Putative Mechanisms of Action

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