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

海洋天然产物片状素D对广泛的癌细胞系表现出潜在的细胞毒性。该化合物对多药耐药（MDR）癌细胞系也有效。我们已经开发了两种不同类型的合成途径，用于层状层天然产品。我们还使用合成类似物进行了结构活性关系研究，并揭示了细胞毒性的结构要求。最近，Bailly及其同事报告说，层状素D的主要作用机理是对拓扑异构酶I的抑制作用，该抑制是众所周知，这是批准的camptotecin型抗肿瘤剂的分子粉。我们与Bailly Group进行了合作，提出了拓扑异构酶I-DNA-LAMELARARIS D三元复合模型。基于此模型，我们设计了1-二核素D和1-取代的1-二甲酰胺素D作为有效的片状素D类似物。在本研究项目中，我们计划为这些类似物开发有效的合成途径……更多并评估它们的抗肿瘤活性。因此，我们使用N-苯甲磺酰氟1-3-3-溴莫洛尔作为密钥反应的N-苯甲磺酰氟1-3-溴莫普罗的调节性层次，在八个步骤中实现了1-核叶状蛋白D的合成。选择性地在1位进行了1-二甲状腺素D的OPothic替代（由异丙基组）选择性地进行，从而提供各种1取1个依赖的O型O蛋白酶保护的1-二十进制1-二足球素D s。在CSF-AG_2O的存在下，OPOTECHECHECHAT-AGAG_2O在CSF-AG_2O的存在下进行了palladium catalylamellararin D进行了钯催化的交叉耦合（Suzuki-Miyaura耦合），以提供其他类型的1-替代的1-替代的1-二核酸盐1-二核酸盐1-二核酸酯。硼硼化物对这些化合物的异丙基脱落产生了1叠定的1-二甲素蛋白D类似物。这些新类似物对广泛的癌细胞系的生物测定正在投资。初步结果表明，1-二甲素蛋白D暴露了针对HELA细胞的潜在细胞毒性，类似于片状素D。