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

海洋天然产物片螺素D对多种癌细胞系表现出强的细胞毒性。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路线，以层状类天然产物。我们还使用合成类似物进行了构效关系研究，并揭示了细胞毒性的结构要求。最近，Bailly及其同事报道了片螺素D的主要作用机制是抑制拓扑异构酶I，已知拓扑异构酶I是批准的Campotecin型抗肿瘤剂的分子靶点。我们与Bailly小组合作提出了拓扑异构酶I-DNA-lamellarin D三元复合物模型。基于此模型，我们设计了1-dearylllamellarin D和1-取代的1-dearylllamellarin D作为有效的片螺素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 ...更多信息 因此，我们以N-苯磺酰基-3-溴吡咯为关键反应，通过区域选择性锂化反应，经八步反应合成了1-脱芳基苦皮素D。O-保护的（异丙基）1-dearylllamellarin D在1-位选择性地进行亲电取代，得到各种1-取代的O-保护的1-dearylllamellarin D s。在CsF-Ag_2 O存在下，O-保护的1-溴-1-脱芳基苦楝素D与硼酸发生Suzuki-Miyaura偶联反应，以高产率得到了其它类型的1-取代O-保护的1-脱芳基苦楝素D。这些化合物的异丙基用硼氢化钠脱保护得到1-取代的1-dearylllamellarin D类似物。这些新的类似物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对Hela细胞具有与lamellarin D相似的细胞毒活性。少

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