Synthesis and Cytotoxicity of Novel 10-Substituted Dihydroartemisinin Derivatives Containing N-Arylphenyl-ethenesulfonamide Groups

Yajing Liu,Zijian Liu,Ping Gong,Peng Li,Jiyue Shi,Bin Mi,Huimin Chen

doi:10.3390/molecules18032864

Yajing Liu, Zijian Liu + Show 5 more

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https://doi.org/10.3390/molecules18032864

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Abstract

The manuscript describes the synthesis of 10-substituted dihydroartemisinin derivatives containing N-aryl phenylethenesulfonamide groups and their in vitro anti-tumor activities against the HT-29, MDA-MB-231, U87MG, H460, A549 and HL-60 cancer cell lines and the normal WI-38 cell line. Most tested compounds showed enhanced cytotoxic activities and good selectivity toward the MDA-MB-231, HT-29 and HL-60 cell lines, with IC50 values in the single-digit μM range as compared with dihydroartemisinin (DHA), and all of them displayed less toxicity towards WI-38 cells. Among them, compounds 3c and 6c with trifluoromethoxy groups on the N-phenyl ring were found to be most active compounds against the six tested cancer cell lines.

Highlights

Artemisinin is a sesquiterpene lactone isolated from the plant Artemesia annua L
Despite the reported neurotoxic and embryotoxic effects in animals occurring at higher doses, application of artemisinins in humans seems to be relatively safe [5]
The stereochemistry of compound 3 had already been determined as 10β by the 1H-NMR coupling constant (J = 3.4 Hz) between 9-H and 10-H and the chemical shift of 10-H (4.77 ppm) [9]

Summary

Introduction

Artemisinin is a sesquiterpene lactone isolated from the plant Artemesia annua L. Artemisinin and its derivatives, such as dihydroartemisinin (DHA) [1], artemether, arteether, and artesunate [2], are widely used currently as front-line antimalarials [3,4]. Despite the reported neurotoxic and embryotoxic effects in animals occurring at higher doses, application of artemisinins in humans seems to be relatively safe [5]. In addition to their well-known antimalarial activity, artemisinin derivatives possess cytotoxic activity against cancer cells by inducing apoptosis [6], but high concentrations are required [7]. The synthesis of new, structurally modified derivatives of artemisinin is essential. The high chemical sensitivity of the artemisinin molecule restricts broad derivatization for library synthesis for further clinical development. The majority of the artemisinin derivatizations were carried out on the

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