Qinghaosu (artemisinin): Chemistry and pharmacology

Abstract

Qinghaosu and its derivatives are widely used in the world as a new generation of antimalarial drug. Up to now, some important progresses of Qinghaosu research have been made, including synthesis of new Qinghaosu derivatives and analogs, investigation on their bioactivities and mode of actions. The present review briefly describes these efforts made by researchers in China, particularly in this Institute.Keywords: Qinghaosu; artemisinin; structure modification; antimalarial activity; anticancer activity; immunosuppressive activity; mode of action Acta Pharmacologica Sinica (2012) 33: 1141-1146; doi: 10.1038/aps.2012.104; published online 27 Aug 2012On 23rd May 1967, China established National Steering Group on antimalarial drug research, more than 60 institutes and 500 researchers joined in this project. After screening of over 5000 traditional Chinese medicines, Qinghaosu (QHS), an antimalarial principle, was isolated from Artemisia annua L in 1972 [1,2] . At the end of 1975, its unique chemical structure was elucidated, as a sesquiterpene lactone bearing a peroxy group, quite different from that of all known antimalarial drugs [3] .Early pharmacological and clinic studies showed QHS have rapid onset of action, low toxicity and high effect on both drug-resistant and drug-sensitive malaria. However, its shortcomings (poor solubility in water or oil; high rate of parasite recrudescence) needed to be overcome. In 1976, our Institute was charged with this important mission, and a research in relationship between chemical structure and activity immediately started.First of all, the function of peroxy group for antimalarial activity was examined. The negative result of deoxyqinghaosu (Scheme 1) against P berghei in mice demonstrated that the peroxy group was essential. Soon afterwards, it was found that some other simple peroxides including monoterpene ascaridol had no antimalarial activity. These experimental results proved peroxy group to be an essential but not a sufficient factor. At that time, we noted the molecule contained a rare segment -O-C-O-C-O-C=O, and realized that whole molecular skeleton might play an important role for antimalarial activity.When dihydroartemisinin (DHA) was found to be more active than QHS, but was still with poor solubility and lower stability (as a lactol) than QHS, we decided to prepare its derivatives. In 1976-1977, over 50 derivatives of DHA were synthesized (Scheme 1) and evaluated [4,5] .The first 25 compounds (in oil solution) were tested in mice infected chloroquine-resistant P berghei though intramuscular injection [6] . Most of these derivatives showed higher activity than QHS (SD 50 6.20 mg/kg) and DHA (SD 50 3.65 mg/kg). In the ether series, SM 224 (R=CH 3 , SD 50 1.02 mg/kg) is more

Synergistic Inhibition of Delayed Rectifier K+ and Voltage-Gated Na+ Currents by Artemisinin in Pituitary Tumor (GH3) Cells

“…ART is a natural product purified from the sweet woodworm Artemisia annua L., is a sesquiterpenetrioxane lactone containing unusual peroxide bridge [1]. In addition to its antimalarial action, there are a variety of pharmacological effects including cytotoxicity against tumor cells as well as anti-viral and anti-parasitic actions [1,2].…”

“…Numerous reports demonstrated that ART was effective on suppressing tumor growth including pituitary macroadenoma [1][2][3][4][5][6]. A previous study reported the ability of ART in influencing the amplitude of ionic currents in neurons isolated from nodose ganglia [7].…”

Peroxy natural products

“…Its antimalarial activity, structural modification, structure-activity relationships, mode of actions, and use in therapy have been well reviewed. [237][238][239][240] 3.3 Diterpenes: A dolabellane diterpene derivative 401 with the naturally rare peroxy function was identified as a component of the aerial parts of Cleome droserifolia, 241 and additional related peroxide 402 was found from Aglaia odorata. 242 Jatropha integerrima provided a rhamnofolane endoperoxide 2-epicaniojane 403, whose structure was confirmed by X-ray diffraction analysis.…”

Dihydroartemisinin-induced apoptosis in human acute monocytic leukemia cells

“…Artemisinin is an effective drug for treating malaria and belongs to the family of sesquiterpene lactones, which are produced by the Artemisia annua plant (8). Dihydroartemisinin (DHA) is a water-soluble semi-synthetic derivative of artemisinin (9), and it is commercially combined with piperaquine as an effective therapy for malaria with limited side effects (10,11).…”