Elucidation and Control of the Molecular Mechanism of Action of the Multifunctional Antitumor Agents Lamellarins

海洋天然产物lamellarins是一种多功能抗肿瘤药物，它同时抑制拓扑异构酶I和蛋白激酶（CDKs、GSK-3、Pim 1、DYRK 1A、CLK等）。在本研究中，我们打算通过SAR和对接模拟研究来产生靶向选择性抑制剂。作为结果，我们建立了以下新的事实。激酶选择性（或拓扑异构酶I选择性）抑制剂可以通过将外周氧官能团（OH或OMe）适当排列在片螺素骨架上来产生。以C1-C11单键为中心的限制性旋转生成的16-甲基苦皮素N的两种对映体对蛋白激酶的抑制活性和选择性有很大差异。在C1取代基取代芳环的片螺素N类似物对蛋白激酶表现出良好的选择性，这取决于C1-取代基的结构。

Marine natural products lamellarins are the multifunctional antitumor agents which inhibit both topoisomerase I and protein kinases(CDKs, GSK-3, Pim1, DYRK1A, CLKs, etc). In this research, we intended to produce target-selective inhibitors through SAR and docking simulation studies. As the results, we established following new facts. The kinase-selective(or topo I-selective) inhibitors can be produced by proper arrangement of the peripheral oxygen functionalities(OH or OMe) on the lamellarin skeleton. The inhibitory activity and selectivity of two enantiomers of 16-methyllamellarin N, which are generated by restricted rotation around C1-C11 single bond, on the protein kinases are quite different. The lamellarin N analogues having a substituent at C1 instead of an aromatic ring exhibited good selectivity on the protein kinases depending on the structure of C1-substituent.