Orally active, hydrolytically stable, semisynthetic, antimalarial trioxanes in the artemisinin family

被引:91
作者
Posner, GH [1 ]
Parker, MH
Northrop, J
Elias, JS
Ploypradith, P
Xie, SJ
Shapiro, TA
机构
[1] Johns Hopkins Univ, Sch Arts & Sci, Dept Chem, Baltimore, MD 21218 USA
[2] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21218 USA
关键词
D O I
10.1021/jm980529v
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
In only three chemical operations, natural trioxane lactone artemisinin (1) was converted into a series of C-10 carbon-substituted 10-deoxoartemisinin compounds 4-9. The three steps involved lactone reduction, replacement of the anomeric lactol OH by F using diethylaminosulfur trifluoride, and finally boron trifluoride-promoted substitution of F by aryl, heteroaryl, and acetylide nucleophiles. All of these C-10 nonacetal, chemically robust, enantiomerically pure compounds 4-9 have high antimalarial potencies in vitro against Plasmodium falciparum malaria parasites, and furans 5a and 5b and pyrrole 7a are antimalarially potent also in vivo even when administered to rodents orally.
引用
收藏
页码:300 / 304
页数:5
相关论文
共 45 条
[31]  
POSNER GH, 1985, TETRAHEDRON LETT, V26, P1823, DOI 10.1016/S0040-4039(00)94747-6
[32]   Antimalarial cyclic peroxy ketals [J].
Posner, GH ;
O'Dowd, H ;
Ploypradith, P ;
Cumming, JN ;
Xie, S ;
Shapiro, TA .
JOURNAL OF MEDICINAL CHEMISTRY, 1998, 41 (12) :2164-2167
[33]   EVIDENCE FOR FE(IV)=O IN THE MOLECULAR MECHANISM OF ACTION OF THE TRIOXANE ANTIMALARIAL ARTEMISININ [J].
POSNER, GH ;
CUMMING, JN ;
PLOYPRADITH, P ;
CHANG, HO .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1995, 117 (21) :5885-5886
[35]   Orally active antimalarial 3-substituted trioxanes: New synthetic methodology and biological evaluation [J].
Posner, GH ;
Cumming, JN ;
Woo, SH ;
Ploypradith, P ;
Xie, SJ ;
Shapiro, TA .
JOURNAL OF MEDICINAL CHEMISTRY, 1998, 41 (06) :940-951
[36]   SYNTHESIS AND ANTIMALARIAL ACTIVITIES OF 12-BETA-ALLYLDEOXOARTEMISININ AND ITS DERIVATIVES [J].
PU, YM ;
ZIFFER, H .
JOURNAL OF MEDICINAL CHEMISTRY, 1995, 38 (04) :613-616
[37]  
Robert A, 1998, CHEM-EUR J, V4, P1287, DOI 10.1002/(SICI)1521-3765(19980710)4:7<1287::AID-CHEM1287>3.0.CO
[38]  
2-J
[39]  
Shimizu M, 1998, SYNTHESIS-STUTTGART, P799
[40]   Copper(I) catalyzed conjugate addition of Grignard reagents to acrylic acids: Homologation of artemisinic acid and subsequent conversion to 9-substituted artemisinin analogs [J].
Vroman, JA ;
Khan, IA ;
Avery, MA .
TETRAHEDRON LETTERS, 1997, 38 (35) :6173-6176