Artemisinin-derived hybrids and their anticancer activity

doi:10.1016/j.ejmech.2020.112044

European Journal of Medicinal Chemistry

Volume 188, 15 February 2020, 112044

https://doi.org/10.1016/j.ejmech.2020.112044 Get rights and content

Highlights

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The anticancer activity of artemisinin-derived hybrids is summarized.
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The structure-activity relationships are discussed.
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The mechanism of action is included.

Abstract

The emergence of drug-resistance and the low specificity of anticancer agents are the major challenges in the treatment of cancer and can result in many side effects, creating an urgent demand to develop novel anticancer agents. Artemisinin-derived compounds, bearing a peroxide-containing sesquiterpene lactone moiety, could form free radicals with high reactivity and possess diverse pharmaceutical properties including in vitro and in vivo anticancer activity besides their typical antimalarial activity. Hybrid molecules have the potential to improve the specificity and overcome the drug resistance, therefore hybridization of artemisinin skeleton with other anticancer pharmacophores may provide novel anticancer candidates with high specificity and great potency against drug-resistant cancers. The review outlines the recent advances of artemisinin-derived hybrids as potential anticancer agents, and the structure-activity relationships are also discussed to provide an insight for rational designs of novel hybrids with high activity.

Graphical abstract

This review emphasizes the recent advances of artemisinin-derived hybrids as potential anticancer agents, and the structure-activity relationships are also discussed to provide an insight for rational designs of more effective candidates.

Introduction

Cancer is the second leading cause of death throughout the world and accounts for more than 18 million new cases and 9.6 million deaths in 2018 [[1], [2], [3]]. Many cancers could be cured if appropriate treatment is provided. Anticancer agents are critical for cancer treatment, but the emergence of drug-resistance and the low specificity of most anticancer agents currently used are the major challenges in the treatment of cancer [[4], [5], [6]]. Therefore, it is urgent to explore novel anticancer candidates with high specificity and great potency against drug-resistant cancers.

Artemisinin-derived compounds like dihydroartemisinin and artesunate, bear a peroxide-containing sesquiterpene lactone moiety and could form highly reactive free radicals in the presence of ferrous ion (Fe^II). Artemisinin derivatives are the fundamental drugs for artemisinin-based combination therapy of various malaria [[7], [8], [9]]. Besides their typical antimalarial activity, artemisinin-derived compounds also possess other pharmaceutical properties such as antibacterial [10,11], anti-tubercular [12,13], antiviral [14,15], and anticancer [16,17] activities, so artemisinin moiety represents a useful pharmacophore in the discovery of novel drugs. Moreover, artemisinin-derived compounds also have the capacity to promote the calcium-p38 apoptotic pathway, facilitate apoptosis by suppressing sarcoplasmic/endoplasmic reticulum calcium ATPase activity, induce iron-dependent endoplasmic reticulum stress in cancer cells, and inhibit translationally controlled tumor protein-dependent cancer cell migration, invasion, and metastasis [[18], [19], [20], [21]]. Therefore, artemisinin-derived compounds are promising anticancer candidates.

Artemisinin has some shortcomings such as short half-life, poor solubility as well as limited bioavailability, resulting in relatively low activity towards cancer cells and making it not effective enough to assure cancer treatment [22]. Hybridization could not only prolong the half-life, improve the solubility, and increase the bioavailability, but also reduce the side effects, enhance the activity, and overcome the drug-resistance [[23], [24], [25], [26]]. Obviously, hybridization of artemisinin moiety with other anticancer pharmacophores may provide novel anticancer candidates with favorable physicochemical characteristics, high specificity as well as great potency against both drug-sensitive and drug-resistant cancers.

In recent years, numerous of artemisinin-derived hybrids (Fig. 1) have been screened for their anticancer activity, and some of them exhibited excellent in vitro and in vivo activity against both drug-sensitive and drug-resistant cancers, revealing their potential as putative anticancer drugs. This review outlines the recent advances of artemisinin-derived hybrids as potential anticancer agents, and the structure-activity relationships (SARs) are also discussed so as to provide an insight for rational designs of more effective candidates.

Section snippets

Artemisinin-chalcone hybrids

Chalcones, the principal precursors for the biosynthesis of flavonoids and isoflavonoids, are ubiquitous in nature [27,28]. Chalcone derivatives are active against various cancer cell lines including multidrug-resistant phenotype, and could induce cancer cells apoptosis through the mitochondrial pathway, including the increase of the reactive oxygen species (ROS) level, the loss of mitochondrial membrane potential, the release of cytochrome c, the down-regulation of Bcl-2, the up-regulation of

Artemisinin-coumarin hybrids

Coumarin derivatives have the ability to exert diverse anticancer mechanisms like angiogenesis inhibition, aromatase inhibition, kinase inhibition and telomerase inhibition, and some of them such as irosustat have been under clinical trials for the treatment of various cancers. Coumarins have been considered as useful scaffolds for the development of novel anticancer chemotherapeutic agents [34,35], and incorporation of coumarin into artemisinin motif provides a useful strategy to develop new

Artemisinin-ferrocene hybrids

Ferrocene derivatives possess a sandwich-like structure, and incorporation of ferrocene scaffold into heterocyclic compounds could provide novel hybrids with favorable chemical and physiochemical properties [40,41]. Some ferrocene-containing compounds like ferroquine are now under clinical trials for the treatment of various diseases [42], so ferrocene derivatives constitute versatile and interesting scaffolds for the development of novel drugs.

The artemisinin-ferrocene hybrid 17a (Fig. 4, IC₅₀

Artemisinin-phosphate hybrids

The artemisinin-phosphate hybrids 19a,b (Fig. 5, IC₅₀: 3.82–68.4 μM) showed moderate activity against HeLa and HCT116 cancer cells, while the bis-artemisinin-phosphate hybrids 20a,b (Fig. 5, IC₅₀: 0.04–18.56 μM) exhibited improved activity, implying introduction of the second artemisinin moiety was beneficial for the activity [45]. Partial hydrolysis of diphenylphosphate to the monophenylphosphate ester led to great loss of activity, which may be attributed to the diminished ability of the

Artemisinin-quinoline hybrids

Quinoline derivatives, as an important class of bioactive heterocyclic compounds in the field of pharmaceuticals, have exhibited a variety of biological properties [52,53]. Quinoline derivatives hold great potency against eukaryotic Type II topoisomerases and demonstrate potential activity against cancer cell lines, and some quinoline derivatives such as voreloxin, AT-3639 and quarfloxin have already been used in clinics or under clinical trials for the treatment of various cancers [2,54].

Artemisinin-steroid hybrids

Steroids, an important class of natural products, are conventional secondary metabolites and constitute a judicious choice as potential anticancer leads [64,65]. Many steroid-containing compounds such as aromasin, exemestane, fulvestrant and galeterone have been successfully applied in clinics [66], so steroids are pharmacologically important scaffolds for the development of novel anticancer agents.

The artemisinin-steroid hybrids 31 (Fig. 7, IC₅₀: 0.192 and 7.159 μM), 32 (Fig. 7, IC₅₀:

Artemisinin-1,2,3-triazole hybrids

1,2,3-Triazole, which can be achieved readily by “click chemistry” through azide-alkyne cycloaddition, is one of fundamental building blocks in different bioactive compounds [71,72]. It has the ability to form various non-covalent interactions such as hydrophobic interactions, and hydrogen bonds with different biological targets, leading to diverse pharmaceutical properties [73]. Many 1,2,3-triazole-containing compounds like cefatrizine and carboxyamidotriazole have already been used in clinics

Miscellaneous artemisinin hybrids

The α-configurated artemisinin-pyrazole hybrids 56 (Fig. 9, GI₅₀: 0.019–1.42 μM) and their β-configurated analogs 57 (Fig. 9, GI₅₀: 0.018–0.92 μM), as well as the corresponding pyrazoline derivatives 58 (Fig. 9, GI₅₀: 0.035–1.23 μM) and 59 (Fig. 9, GI₅₀: 0.026–0.50 μM) showed great potency against MDA-MB-231, MCF-7 and doxorubicin-resistant MCF-7/Adr cancer cell lines, and the GI₅₀ values were in nanomolar level against MCF-7 and doxorubicin-resistant MCF-7/Adr cancer cell lines [84,85]. It was

Conclusion

Anticancer agents represent a major strategy in the control and treatment of cancers, but the main challenges are the emergence of drug-resistance and the low specificity of anticancer agents which result in many side effects. Thus, it is urgent to develop novel anticancer agents with excellent activity against both drug-susceptible and drug-resistant cancers and low side effects.

Artemisinin-derived compounds, especially artemisinin-based hybrids,displayed promising in vitro and in vivo

Acknowledgment

This study was supported by the research grant from Natural Science Foundation of Shandong Province, China (Grant No.ZR2019BA015).

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Review articleArtemisinin-derived hybrids and their anticancer activity

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Artemisinin-chalcone hybrids

Artemisinin-coumarin hybrids

Artemisinin-ferrocene hybrids

Artemisinin-phosphate hybrids

Artemisinin-quinoline hybrids

Artemisinin-steroid hybrids

Artemisinin-1,2,3-triazole hybrids

Miscellaneous artemisinin hybrids

Conclusion

Acknowledgment

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Eur. J. Med. Chem.

Eur. J. Med. Chem.

Microb. Pathog.

Int. J. Antimicrob. Agents

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Bioorg. Med. Chem.

Bioorg. Med. Chem.

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Biomed. Pharmacother.

Eur. J. Med. Chem.

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Bioorg. Chem.

Eur. J. Med. Chem.

Drug Discov. Today

Bioorg. Med. Chem. Lett

Bioorg. Med. Chem. Lett

Bioorg. Med. Chem.

Eur. J. Med. Chem.

Bioorg. Med. Chem. Lett

Eur. J. Med. Chem.

Cancer Lett.

Cancer Lett.

Bioorg. Chem.

Bioorg. Med. Chem. Lett

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Cancer: key facts

Cancer control: knowledge into action

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Coumarin-containing hybrids and their anticancer activities

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Artemisinin-a gift from traditional Chinese medicine to the world (Nobel lecture)

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Artemisinin as an anticancer drug: recent advances in target profiling and mechanisms of action

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Review article
Artemisinin-derived hybrids and their anticancer activity