Acid Degradation Products of Qinghaosu and Their Structure-Activity Relationships

Abstract

Treatment of qinghaosu (1) with acid yielded 1'2.4'-trioxanes (5 and 8).endoperoxides (6 and 9), and diketones (7 and 10).Structures of 5, 6, 7, 8, 9, and 10 were assigned based on their physical and spectral data.Structureactivity correlation among these compounds indicated the steric requirement of the 1',2'.4',-trioxanering system as found in 1 for potent antimalarial activity.Qinghaosu (artemisinin or arteannuin, I ) , a sesquiterpene lactone endoperoxide isolated from the Chinese drug "Qing Hao" (Artemisia annua ~.),1,2 has recently been used clinically as a new type of antimalarial agent with rapid action and low toxicity against chloroquine-resistant Plasmodium falciparum.In order to investigate the structure-activity relationships, we have previously reported on the synthesis of I-related componds, including the l0,2',4'-trioxane lactone (-C-0-0-C-0-C-0-CO-, 2).3 1',2',4'-trioxane (-C-0-0-C-0-, 3a and 3b),3,4 and endoperoxide (-C-0-0-C-, 415 ring systems.2 ' .a me..^' " ' H 6 .--$P" 4 1 3H'E -1. HSince these compounds (2, 3a, 3b and 4) were found to be 30-100 times less active than 1 in the in vitro antimalarial assay against the chloroquine-resistant P. falciparum,6 it indicates that the antimalarial activity of I-related analogs may be affected significantly by the steric environment of the 1',2',4'-trioxane ring among these molecules.The ethane bridge between C-1 and C-4 of 1 might play an important role with this respect.We report herein on the synthesis of C-IIC-4 ethane bridge-bearing 1',2',4'-trioxanes (5 and 8) , endoperoxides (6 and 91, and diketones (7 and 10) by acidic degradation of 1.Treatment of 1 with an acid [p-toluenesulfonic acid monohydrate(p-TsOH.H20) or 14% hydrogen chloride (HC1)-MeOH] in anhydrous methyl alcohol (MeOH) gave three products: MT-I (5, 5.5 %).7 MT-11 (6, 20.4 %),7 and MT-111 (7, 3.9 %).7 These products were purified by silica gel column chromatography.The I H -and 13c-nmr spectra of MT-I and MT-I1 were assigned on the basis of I H -~H COSY and IH-1%-COSY spectra as well as decoupling experiments between each proton signal.The 1H-and