Cytotoxicity of Artemisinin-Related Endoperoxides to Ehrlich Ascites Tumor Cells

A series of artemisinin-related endoperoxides was tested for cytotoxicity to Ehrlich ascites tumor (EAT) cells using the microculture tetrazolium (MTT) assay. Artemisinin [1] had an IC50 value of 29.8 microM. Derivatives of dihydroartemisinin [2], being developed as antimalarial drugs (artemether [3...

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Bibliographic Details
Published in:	Journal of natural products (Washington, D.C.) Vol. 56; no. 6; pp. 849 - 856
Main Authors:	Woerdenbag, Herman J, Moskal, Tamara A, Pras, Niesko, Malingré, Theo M, El-Feraly, Farouk S, Kampinga, Harm H, Konings, Antonius W. T
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 01-06-1993 Glendale, AZ American Society of Pharmacognosy
Subjects:	AGENTES ANTINEOPLASTICOS Animals ANTINEOPLASTIC AGENTS Antineoplastic Agents, Phytogenic - chemistry Antineoplastic Agents, Phytogenic - pharmacology ANTIPROTOZOAIRE ANTIPROTOZOAL AGENTS ARTEMISIA ARTEMISIA ANNUA Artemisinins Biological and medical sciences Carcinoma, Ehrlich Tumor - pathology Cell Survival - drug effects Chemical Phenomena Chemistry, Physical Cisplatin - pharmacology Doxorubicin - pharmacology DRUGS FITOTOXICIDAD General aspects LACTONAS LACTONE LACTONES Medical sciences MEDICAMENT MEDICAMENT CYTOSTATIQUE MEDICAMENTOS MEDICAMENTOS CONTRA PROTOZOARIOS MOLECULAR STRUCTURE NEOPLASMAS NEOPLASME NEOPLASMS PEROXIDES Peroxides - chemistry Peroxides - pharmacology PEROXIDOS PEROXYDE Pharmacology. Drug treatments PHYTOTOXICITE PHYTOTOXICITY QINGHAOSU SESQUITERPENES Sesquiterpenes - chemistry Sesquiterpenes - pharmacology SESQUITERPENOIDE SESQUITERPENOIDS SESQUITERPENOS STRUCTURE Structure-Activity Relationship Tetrazolium Salts Tumor Cells, Cultured Antineoplastic agent Endoperoxide Ehrlich ascites tumor Cytotoxicity In vitro Biological activity Tumor cell
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Summary:	A series of artemisinin-related endoperoxides was tested for cytotoxicity to Ehrlich ascites tumor (EAT) cells using the microculture tetrazolium (MTT) assay. Artemisinin [1] had an IC50 value of 29.8 microM. Derivatives of dihydroartemisinin [2], being developed as antimalarial drugs (artemether [3], arteether [4], sodium artesunate [5], artelinic acid [6], and sodium artelinate [7]), exhibited a somewhat more potent cytotoxicity. Their IC50 values ranged from 12.2 to 19.9 microM. The presence of an exocyclic methylene fused to the lactone ring, as for artemisitene [9], led to higher cytotoxicity than 1. From the two epimeric 11-hydroxyartemisinin derivatives, the R form 12 showed a considerably higher cytotoxicity than the S form 13. Opening of the lactone ring of 1 dramatically reduced the cytotoxicity. The ether dimer 8 of 2 was the most potent cytotoxic agent, its IC50 being 1.4 microM. The variations in cytotoxicity between the structurally related compounds mostly correlated well with the theoretical capacity of radical formation and stabilization. In some cases lipophilicity or the presence of an electrophilic moiety seemed to have a determinant influence on cytotoxicity. The artemisinin-related endoperoxides showed cytotoxicity to EAT cells at higher concentrations than those needed for in vitro antimalarial activity, as reported in the literature.
Bibliography:	F60 9411848 Q60 ark:/67375/TPS-JTM5GRKR-P istex:4748AFA9EEEFE5126FAE3ECDED5DB9CC10B7B561
ISSN:	0163-3864 1520-6025
DOI:	10.1021/np50096a007