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。

公开(公告)号：EP0944634A1

公开(公告)日：1999-09-29

申请号：EP97953808.0

申请日：1997-12-12

申请人： Novartis AG ,  The Scripps Research Institute

发明人： NICOLAOU, Costa, Kyriacos ,  HE, Yun ,  NINKOVIC, Sacha ,  PASTOR, Joaquin ,  ROSCHANGAR, Frank ,  SARABIA, Francisco ,  VALLBERG, Hans ,  VOURLOUMIS, Dionisios ,  WINSSINGER, Nicolas ,  YANG, Zhen ,  KING, Nigel, Paul ,  FINLAY, Maurice, Raymond, Verschoyle

IPC分类号： A61K31 ,  A61P35 ,  C07D313 ,  C07D405 ,  C07D407 ,  C07D409 ,  C07D413 ,  C07D417 ,  C07D493

CPC分类号： C07D417/06 ,  C07D313/00 ,  C07D493/04

摘要： Epothilone A, epothilone B, analogs of epothilone and libraries of epothilone analogs are synthesized. Epothilone A and B are known anticancers agents that derive their anticancer activity by the prevention of mitosis through the induction and stabilization of microtubulin assembly. The analogs of epothilone are novel. Several of the analogs are demonstrated to have a superior cytotoxic activity as compared to epothilone A or epothilone B as demonstrated by their enhanced ability to induce the polymerization and stabilization of microtubules.

摘要翻译： 埃坡霉素A，埃坡霉素B，埃坡霉素类似物和埃坡霉素类似物文库被合成。 埃坡霉素A和B是已知的抗癌剂，其通过诱导和稳定微管蛋白组装来预防有丝分裂来衍生它们的抗癌活性。 埃博霉素的类似物是新颖的。 证明几种类似物与埃坡霉素A或埃坡霉素B相比具有优异的细胞毒性活性，如它们增强的诱导聚合作用和稳定微管的能力所证明的。