Stereochemistry-Dependent Cytotoxicity of Some Artemisinin Derivatives

• Published in: Journal of natural products (Washington, D.C.) Vol. 60; no. 4; pp. 325 - 330
• Main Authors: Beekman, Aäron C, Barentsen, Adriaan R. W, Woerdenbag, Herman J, Van Uden, Wim, Pras, Niesko, Konings, Antonius W. T, El-Feraly, Farouk S, Galal, Ahmed M, Wikström, Håkan V
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.04.1997; Amer Chemical Soc; American Society of Pharmacognosy
• Subjects: Antineoplastic agents; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; ARTEMISIA; ARTEMISIA ANNUA; Artemisinins; Biological and medical sciences; Cell Cycle - drug effects; CHEMICAL STRUCTURE; CHEMISTRY; Chemistry, Medicinal; CHIMIE; CYTOTOXIC COMPOUNDS; DOSAGE EFFECTS; Drug Screening Assays, Antitumor; ESTRUCTURA QUIMICA; Flow Cytometry; General aspects; Humans; Life Sciences & Biomedicine; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Plant Sciences; QUIMICA; Science & Technology; Sesquiterpenes - chemistry; Sesquiterpenes - pharmacology; Stereoisomerism; STRUCTURE CHIMIQUE; Structure-Activity Relationship; SUBSTANCE TOXIQUE; SUSTANCIAS TOXICAS; Tetrazolium Salts; Thiazoles; TOXIC SUBSTANCES; TOXICIDAD; TOXICITE; TOXICITY; Tumor Cells, Cultured; QINGHAOSU; ANTIMALARIAL DRUG; Antineoplastic agent; Stereoisomer; Artemisinin; Cytotoxicity; Lactone; Tetracyclic compound; Oxygen heterocycle; In vitro; Acetal; Peracetal; Structure activity relation; Sesquiterpenes; Established cell line; Ehrlich ascites tumor; Dimer; Tumor cell; Organic peroxide
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/np9605495

We determined the cytotoxicity of some artemisinin derivatives against EN2 tumor cells using the MTT assay. Artemisinin (1) was clearly more cytotoxic than deoxyartemisinin (2), which lacks the endoperoxide bridge. Ether-linked dimers of dihydroartemisinin with defined stereochemistry were found to differ in the extent of cytotoxic effect on EN2 cells. The nonsymmetrical dimer (3) was more cytotoxic than the symmetrical dimer (4). The nonsymmetrical dimer of dihydrodeoxyartemisinin (5) lacking the endoperoxide bridges was also effective in the MTT assay, although less cytotoxic than 3 and 4. Similarly, the symmetrical dimer (6) was less effective than 5. Epoxides of artemisitene also showed that stereochemistry was an important factor for cytotoxicity. The results suggested that the endoperoxide bridge was not crucial for cytotoxicity to the tumor cells, but contributed to the cytotoxic effect apparently exerted by the ether linkage of the dimers. Flow cytometry data indicated that the dimers 3 and 4 caused an accumulation of the cells in the G1-phase of the cell cycle. In contrast, artemisinin (1) caused a slight increase of S-phase cells.