Design and Synthesis of New Antitumor Agents Using Marine Natural Product Lamellarin as A Structural Motif

以海洋天然产物板层素为结构基序设计与合成新型抗肿瘤药物

基本信息

批准号：
18510188
负责人：
IWAO Masatomo
金额：
$ 2.61万
依托单位：
Nagasaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

A marine natural product lamellarin D exhibits potent cytotoxicity against a wide range of cancer cell lines. This compound is also effective for multidrug resistant (MDR)cancer cell lines. We have developed two different types of synthetic routes to lamellarine-class natural products. We have also performed structure-activity relationship studies using synthetic analogues and revealed structural requirements for cytotoxicity. Recently, Bailly and co-workers have reported that the major mechanism of action of lamellarin D is the inhibition of topoisomerase I which is known to be the molecular targent of approved camptotecin-type antitumor agents. We performed collaboration with Bailly group to propose topoisomerase I-DNA-lamellarin D ternary complex model. Based upon this model, we designed 1-dearyllammelarin D and 1-substituted 1-dearyllamellarin D as effective lamellarin D analogues. In the present research project, we planned to develop efficient synthetic routes to these analogues … More and evaluate their antitumor activity.Thus, we have achieved the synthesis of 1-dearyllamellarin D in eight steps using regioselective lithiation of N-benzenesulfony1-3-bromopyrrole as a key reaction. Electrophilic substitutions of the O-protected (by isopropyl group)1-dearyllamellarin D proceeded at the 1-position selectively to give a variety of 1-substituted O-protected 1-dearyllamellarin D s. O-protected 1-bromo-1-dearyllamellarin D underwent palladium-catalyzed cross-coupling (Suzuki-Miyaura coupling)with boronic acids in the presence of CsF-Ag_2O to give the other types of 1-substituted O-protected 1-dearyllamellarin D s in good yields. Deprotection of the isopropyl group of these compounds by boron trichloride gave 1-substituted 1-dearyllamellarin D analogues.The bioassay of these new analogues against a wide range of cancer cell lines is under investigation. A preliminary result indicated 1-dearyllamellarin D exhibited potent cytotoxicity against Hela cells in the level similar to lamellarin D. Less

海洋天然产物板层素 D 对多种癌细胞系具有有效的细胞毒性，我们已经开发了两种不同类型的板层素类天然产物的合成途径。最近，Bailly 及其同事还使用合成类似物进行了结构-活性关系研究，揭示了细胞毒性的结构要求，板层蛋白 D 的主要作用机制是抑制拓扑异构酶。 I 是已批准的喜树碱型抗肿瘤药物的分子靶标，我们与 Bailly 团队合作提出了拓扑异构酶 I-DNA-层片蛋白 D 三元复合物模型，基于该模型，我们设计了 1-脱芳基片层蛋白 D 和 1-脱芳基片层蛋白 D。取代 1-脱芳基片层蛋白 D 作为有效的片层蛋白 D 类似物在本研究项目中，我们计划开发这些类似物的有效合成路线……更多和因此，我们以 N-苯磺酰基 1-3-溴吡咯的区域选择性锂化为关键反应，通过 O-保护（异丙基）1- 的亲电取代，分八步合成了 1-脱芳基片层素 D。 dearyllamellarin D 在 1 位选择性地进行，得到多种 1-取代的 O-保护1-脱芳基片层蛋白 D s - 保护的 1-脱芳基片层蛋白 D s 的异丙基脱保护效果良好。这些化合物通过三氯化硼得到 1-取代的 1-dearyllamellarin D 类似物。这些新类似物针对多种癌细胞系的生物测定正在研究中，初步结果表明 1-dearyllamellarin D 在一定水平上显示出针对 Hela 细胞的有效细胞毒性。与板层蛋白 D 相似。更少