Synthesis and evaluation of cytotoxic activities of artemisinin derivatives

Abstract

Artemisinin is a naturally occurring antimalarial agent which has shown potent anticancer activity. In this work, new artemisinin derivatives with the piperazine group were synthesized. The cytotoxic activities of derivatives 5a-5d were evaluated by MTT assay against ten cell lines. The results showed that 5a-5d were more effective in inhibiting cancer cell growth than artemisinin. 5d was the most active against HepG2 and PLC-PRF-5 cells and presented no cytotoxicity on L-02 cells. Hoechst 33342 staining and flow cytometry experiment revealed that 5d could induce HepG2 and PLC-PRF-5 cell apoptosis. Flow cytometry analysis showed that 5d induced the loss of mitochondrial membrane potential (MMP) and increased the levels of intracellular free calcium and reactive oxygen species. 5d also induced cell cycle arrest in G2/M phase in HepG2 cells. According to the results of Western blotting and caspase-3 kit, 5d could significantly increase the content of p53, bax, Apaf-1, and caspase-3 and decrease the protein level of bcl-2, pro-caspase-9, and pro-caspase-3 in HepG2 cells. These findings indicate that 5d activates the mitochondria-mediated apoptotic pathway in HepG2 cells and may merit further investigation as a potential therapeutic agent for hepatocellular carcinoma.

Piperazine skeleton in the structural modification of natural products: a review

“…The structure of compounds 36, which showed the highest activity against hepatocellular carcinoma cells, inspired to improve the oil solubility of the piperazine group into the C10 position. Furthermore, this substrate could induce cell cycle arrest in the G2/M phase and apoptosis in HepG2 cells 61 . Reportedly, Yu et al synthesised twelve artemisinin-piperazine-dithiocarbamate derivatives, all of which had stronger in vitro antitumor activity than dihydroartemisinin.…”

SAHAquines, Novel Hybrids Based on SAHA and Primaquine Motifs, as Potential Cytostatic and Antiplasmodial Agents

“…Such observations prompted us, and others, to design and prepare novel derivatives of known antimalarial drugs and evaluate their cytostatic potential . Our efforts have been focused on primaquine (PQ), which is an old drug with many flaws (e.g., induction of hemolytic anemia in individuals lacking glucose‐6‐phosphate dehydrogenase, quick metabolism, degradation to inactive carboxyprimaquine, altering the treatment outcome in dependence of CYP 2D6 enzyme activity) but is currently the only available Plasmodium hypnozoitocide .…”

“…Such observations prompted us, and others, to design and preparen ovel derivatives of known antimalarial drugs and evaluatet heir cytostaticp otential. [24][25][26][27][28][29][30][31][32][33][34] Our efforts have been focusedo np rimaquine (PQ), which is an old drug with many flaws (e.g.,induction of hemolytic anemia in individuals lacking glucose-6-phosphate dehydrogenase, quick metabolism, degradationt oi nactive carboxyprimaquine, altering the treatment outcomei nd ependence of CYP2 D6 enzymea ctivity) [35] but is currently the only available Plasmodium hypnozoitocide. [36] We previously showed that variousP Qd erivatives of amides, ureas, bis-ureas, semicarbazides, and acylsemicarbazide-type derivatives possessed significant cytostatic activity against a panel of cancerc ell lines or high selectivity towards the breast adenocarcinoma cell line (MCF-7).…”

Cytotoxic Effects of Artemisia annua L. and Pure Artemisinin on the D-17 Canine Osteosarcoma Cell Line

“…The low amount of artemisinin extracted from the plant, its low hydro- and liposolubility, and its limited bioavailability can represent a serious limitation for the standardization and commercialization of the drug. In the last 30 years, several semisynthetic artemisinin derivatives were developed with different strategies, including genetic engineering [1, 4, 5]. Although developed as antimalarials, artemisinin and its semisynthetic derivatives have also been investigated for many other therapeutic properties, such as antiviral, antimicrobial, and anti-inflammatory activities [6].…”