权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

海洋天然产物海带多糖D对多种癌细胞具有很强的细胞毒性。这种化合物对多药耐药(MDR)癌细胞株也有效。我们已经开发了两种不同类型的合成路线，以获得片状天然产品。我们还使用合成类似物进行了构效关系研究，揭示了细胞毒性的结构要求。最近，Bailly和他的同事们报道了海带多糖D的主要作用机制是抑制拓扑异构酶I，而拓扑异构酶I是已知的喜树碱类抗肿瘤药物的分子靶标。我们与Bailly小组合作，提出了拓扑异构酶I-DNA-层粘连蛋白D三元复合体模型。基于这一模型，我们设计了1-脱芳基薄荷糖苷D和1-取代1-脱芳基薄荷糖苷D作为有效的海带多糖D类似物。在目前的研究项目中，我们计划开发这些类似物…的有效合成路线因此，我们以N-苯磺酰基-3-溴吡咯的区域选择性锂化法为关键反应，实现了1-脱芳基薄层糖素D的八步合成。O-保护(异丙基)1-脱芳基海带多糖D的亲电取代选择性地在1-位进行，得到一系列1-取代O-保护的1-脱芳基海带多糖D S。O-保护的1-溴-1-脱芳基海带多糖D在CSF-Ag_2O存在下与钯催化的交叉偶联(Suzuki-Miyaura偶联)得到其他类型的1-取代O-保护的1-脱芳基海带多糖D S。用三氯化硼去保护这些化合物的异丙基，得到1-取代的1-脱芳基薄荷糖苷D类似物。这些新类似物对多种癌细胞的生物活性正在研究中。初步结果表明，1-脱芳基海带菌素D对Hela细胞有较强的细胞毒作用，与海带菌素D相似。