Paik Ik-Hyeon, Xie Suji, Shapiro Theresa A, Labonte Tanzina, Narducci Sarjeant Amy A, Baege Astrid C, Posner Gary H
Department of Chemistry, The Johns Hopkins University, Baltimore, Maryland 21218-2685, USA.
J Med Chem. 2006 May 4;49(9):2731-4. doi: 10.1021/jm058288w.
In only two steps and in 63% overall yield, naturally occurring 1,2,4-trioxane artemisinin (1) was converted into C-10-carba trioxane conjugated diene dimer 4. This new dimer was then transformed easily in one additional 4 + 2-cycloaddition step into phthalate dimer 5, and further modification led to bis-benzyl alcohol dimer 7 and its phosphorylated analogues 8 and 9. Bis-benzyl alcohol dimer 7 is the most antimalarially active in vitro, 10 times more potent than artemisinin (1). Bis-benzyl alcohol dimer 7 is approximately 1.5 times more orally efficacious in rodents than the antimalarial drug sodium artesunate and is about 37 times more efficacious than sodium artesunate via subcutaneous administration. Both dimers 5 and 7 are thermally stable neat even at 60 degrees C for 24 h. Phthalate dimer 5 is very highly growth inhibitory but not cytotoxic toward several human cancer cell lines; both dimers 5 and 7 very efficiently and selectively kill human cervical cancer cells in vitro in a dose-dependent manner with no cytotoxic effects on normal cervical cells.
只需两步，总产率为63%，天然存在的1,2,4 - 三氧杂环己烷青蒿素（1）就被转化为C - 10 - 碳杂三氧杂环己烷共轭二烯二聚体4。然后，这个新的二聚体在另外一步4 + 2环加成反应中很容易地转化为邻苯二甲酸酯二聚体5，进一步修饰得到双苄醇二聚体7及其磷酸化类似物8和9。双苄醇二聚体7在体外具有最强的抗疟活性，比青蒿素（1）强10倍。双苄醇二聚体7在啮齿动物中的口服疗效比抗疟药青蒿琥酯钠高约1.5倍，通过皮下给药比青蒿琥酯钠有效约37倍。二聚体5和7即使在60℃下纯态放置24小时也热稳定。邻苯二甲酸酯二聚体5对几种人类癌细胞系具有很强的生长抑制作用但无细胞毒性；二聚体5和7在体外均能非常高效且选择性地以剂量依赖方式杀死人类宫颈癌细胞，对正常宫颈细胞无细胞毒性作用。
