Synthesis and cytotoxicity of novel artemisinin derivatives containing sulfur atoms

doi:10.1016/j.ejmech.2016.08.015

European Journal of Medicinal Chemistry

Volume 123, 10 November 2016, Pages 763-768

https://doi.org/10.1016/j.ejmech.2016.08.015 Get rights and content

Highlights

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Ten novel artemisinin derivatives containing sulfur atoms were reported for the first time.
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Compounds 4a and 4f showed potent cytotoxicity compared with that of 5-FU.
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A high selectivity of compounds 4a and 4f was observed.

Abstract

Ten novel artemisinin derivatives containing sulfur atoms were designed and synthesized and their structures were confirmed by ¹H NMR, ¹³C NMR and HRMS technologies in this study. All compounds were reported for the first time. The in vitro cytotoxicity against PC-3, SGC-7901, A549 and MDA-MB-435s cancer cell lines was evaluated by MTT assay. Compounds 4a and 4f displayed potent antitumor activity against PC-3, SGC-7901 and A549 cells with IC₅₀ ranging from 1.6 to 30.5 μM, which values are compared to that of 5-FU (IC₅₀ from 6.8 to 42.5 μM). Compounds 4a and 4f showed high specificity towards human lung cancer A549 cells compared to normal human hepatic L-02 cells with selectivity index of 16.1 and 50.1 respectively. Our promising findings indicated that the compounds 4a and 4f could stand as potential lead compounds for further investigation.

Graphical abstract

Introduction

Artemisinin is extracted from the Chinese herb qinghaosu (Artemisia annua or annual wormwood) containing a 1, 2, 4-tiroxane ring system [1], which is a powerful antimalarial drug and has also been proved to possess antiviral [2], [3], [4], [5], [6], immunosuppressive [7], [8], [9] and anticancer [10], [11], [12], [13], [14] activities. Its anticancer activity with strong selectivity [15], [16], reversing multidrug resistance [17] and sensitization radiation and chemotherapy [16], [18] attracts extensive attention. Many artemisinin derivatives have been synthesized as anticancer agents [2], [10], [14], [19], [20], [21], [22], [23], [24], [25], [26], [27]. However, current modification strategies have only focused on the hemiacetal structure of artemisinin due to the difficulty to introduce functionalities on the ring systems by conventional chemical methods. Biotransformation technology successfully solved the above problem. 9α-OH-dihydroartemisinin (9α-OH DHA) with double hydroxyl modification sites was obtained in our previous work [28], which make chemical modification on the ring system come true.

According to the analysis of the elemental composition of U.S. FDA approved drug architectures [29], the sulfur is the fifth most used element beyond C, H, O and N. The appearance of sulfur atom even enhance the cellular uptake percentage and the level of reactive oxygen species (ROS) [30], which is a crucial factor for the antitumor activity of artemisinins [31], [32]. Herein, ten novel artemisinin ester derivatives containing sulfur atoms with alkyl or aromatic side chains were reported and in vitro cytotoxicity against four cancer cell lines (PC-3, SGC-7901, A549 and MDA-MB-435s) was evaluated.

Section snippets

Chemistry

9α-OH DHA was obtained according to our previous work [28], [33]. The synthesis of compounds 3a–3e began with m-bromobenzoic acid (1) and different thiols (2a–2e) in the presence of Pd₂(dba)₃ and Xantphos in 1,4-dioxane, with heating reflux for 6 h under nitrogen. The reaction mixture was acidified with acetic acid to reach pH 3–4 then filtered and concentrated. The crude product was purified by silica gel chromatography to give target compounds (3a–3e) (Scheme 1). The synthesis of compounds 4a–

Conclusions

In conclusion, ten novel artemisinin derivatives containing sulfur atoms were synthesized and evaluated for their cytotoxicity against selected four human cancer cell lines. Compounds 4a and 4f with the p-methoxythiophenyl substituent group on benzoic acid were potent cytotoxicity and high specificity. The structure-activity relationship study revealed that the substitutes on benzoic acid and the length of alkyl carbon chain had an impact on their cytotoxicity. Our results indicated compounds 4a

Materials and measurements

Melting points (mp) were determined in duplicate on an X-4 digital display microscope melting point apparatus. ¹H NMR and ¹³C NMR spectra was obtained in CDCl₃ solution on a Brucker Avance-400 or Brucker 300 spectrophotometer using TMS as the internal standard. High resolution ESI mass spectra were measured on Aglient LC-Q-TOF-MS 6520. Column chromatography was done using silica gel (Qingdao Marine Chemical Co., Ltd., China), or Sephadex LH-20 (GE healthcare, Sweden).

All commercially available

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

This work was supported by the Specialized Research Fund for the Doctoral Program of Higher Education Priority Development Field (No. 20110096130002), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). Authors are also thankful to the Professor Zhou Jia-hong (Nanjing Normal University) for NMR data.

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Short communicationSynthesis and cytotoxicity of novel artemisinin derivatives containing sulfur atoms

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

Conclusions

Materials and measurements

Conflict of interest

Acknowledgments

Bioorg. Med. Chem.

Biochem. Biophys. Res. Commun.

Eur. J. Pharmacol.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Bioorg. Med. Chem.

Bioorg. Med. Chem. Lett.

Eur. J. Pharma. Sci.

Eur. J. Med. Chem.

Exp. Cell. Res.

FEBS Open Bio.

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Eur. J. Med. Chem.

Chin. Med. J.

Short communication
Synthesis and cytotoxicity of novel artemisinin derivatives containing sulfur atoms