公开(公告)号：EP1042328A1

公开(公告)日：2000-10-11

申请号：EP98952736.1

申请日：1998-10-22

申请人： Novartis AG ,  The Scripps Research Institute

发明人： NICOLAOU, Kyriacos, C. ,  VANDELFT, Floris ,  HOSOKAWA, Seijiro ,  KIM, Sanghee ,  LI, Tianhu ,  OHSHIMA, Takashi ,  PFEFFERKORN, Jeff ,  VOURLOUMIS, Dionisios ,  XU, Jin-You ,  WINSSINGER, Nicolas

IPC分类号： C07D493/08 ,  A61K31/34

CPC分类号： C07D493/08

摘要： Sarcodictyin A and B, eleutherobin, and bioactive analogs (A) thereof synthesized using solid phase and solution phase chemistries. The synthetic method employs an attachment of common precursors, e.g., compounds 1880 or 200, on a solid support for generating conjugates 230 and 240, followed by standard chemical manipulations. A combinatorial library of sarcodictyins and eleutherobin analogs is constructed with modified C-8 ester, C-15 ester and C-4 ketal functionalities and is screened for activity with respect to tubulin polymerization and cytotoxic activity against tumor cells, including Taxol-resistant lines. Compounds 600, 610, 630, 660-700, 730, 760, 850, and 920 are identified to be of equal or superior biological activities as compared to their corresponding natural product.

摘要翻译： Sarcodictyin A和B，eleutherobin和使用固相和液相化学法合成的生物活性类似物（A）。 该合成方法使用常规前体（例如化合物1880或200）附着在固体载体上以产生偶联物230和240，接着进行标准化学操作。 用修饰的C-8酯，C-15酯和C-4缩酮官能团构建sarcodictyins和eleutherobin类似物的组合文库，并针对微管蛋白聚合和针对肿瘤细胞（包括紫杉醇抗性品系）的细胞毒活性筛选活性。 与其相应的天然产物相比，化合物600,610,630,660-700,730,760,850和920被鉴定为具有相同或更高的生物活性。