微管蛋白聚合抑制剂OXi8006的合成新方法  

Synthesis of a Tubulin Assembly Inhibitors OXi8006

作　　者：刘春廷[1,2] 毕凯健 畅婉琳[2] 叶霁[2] 张卫东[1,2] 孙青龑[2] 

机构地区：[1]江西中医药大学药学院,南昌330004 [2]第二军医大学药学院,上海200433

出　　处：《有机化学》2015年第2期484-489,共6页Chinese Journal of Organic Chemistry

基　　金：国家自然科学基金(No.81230090);上海市重点学科建设(No.B906)资助项目~~

摘　　要：2-(3'-羟基-4'-甲氧基苯基)-3-(3",4",5"-三甲氧基苯甲酰基)-6-甲氧基吲哚(OXi8006)能够有效抑制微管蛋白聚合,而表现出良好抗癌活性.目前报道的OXi8006全合成路线较长、总收率低,且反应条件苛刻.为了更高效地合成该化合物,从而为进一步的活性和构效关系研究提供原料.以廉价易得的异香兰素为起始原料,先合成芳基乙炔,再与3,4,5-三甲氧基苯甲醛通过亲核加成、氧化反应获得二芳基炔酮、二芳基炔酮再与邻碘代苯胺通过杂迈克尔加成和分子内Heck反应构建出OXi8006的主体结构——2-芳基-3-芳酰基取代吲哚,从而缩短了合成路线,并使总收率提高到20%.2-（3＇-Hydroxy-4＇-methoxyphenyl）-3-（3＂,4＂,5＂-trimethoxybenzoyl）-6-methoxyindole（OXi8006） was found to be a strong inhibitors of tubulin assembly and showed excellent anticancer activity（IC50=1.1 μmol/L）. Reported synthetic method of OXi8006 suffered from some drawbacks, such as long steps and low overall yields. Therefore, developing more efficient and practical protocols to synthesize OXi8006 is highly desirable. Firstly, we prepared aryl acetylene from commercially available isovanillin in three steps. Then the aryl acetylene was converted to diaryl acetylene ketone by reacting with3,4,5-trimethoxybenzaldehyde via nucleophilic addition and oxidation reaction. The key step of 2-aryl-3-aroyl-indole construction was carried out between diaryl acetylenic ketone and o-iodo aniline by performing aza-Michael addition and subsequent intramolecular Heck reaction. The yield of developed synthesis over six steps is 20%.

关 键 词：微管蛋白聚合抑制剂 OXi8006 杂迈克尔加成 HECK反应 

分 类 号：O621.3[理学—有机化学]