Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, USA.
J Am Chem Soc. 2010 Jan 13;132(1):371-83. doi: 10.1021/ja908626k.
Nakiterpiosin and nakiterpiosinone are two related C-nor-D-homosteroids isolated from the sponge Terpios hoshinota that show promise as anticancer agents. We have previously described the asymmetric synthesis and revision of the relative configuration of nakiterpiosin. We now provide detailed information on the stereochemical analysis that supports our structure revision and the synthesis of the originally proposed and revised nakiterpiosin. In addition, we herein describe a refined approach for the synthesis of nakiterpiosin, the first synthesis of nakiterpiosinone, and preliminary mechanistic studies of nakiterpiosin's action in mammalian cells. Cells treated with nakiterpiosin exhibit compromised formation of the primary cilium, an organelle that functions as an assembly point for components of the Hedgehog signal transduction pathway. We provide evidence that the biological effects exhibited by nakiterpiosin are mechanistically distinct from those of well-established antimitotic agents such as taxol. Nakiterpiosin may be useful as an anticancer agent in those tumors resistant to existing antimitotic agents and those dependent on Hedgehog pathway responses for growth.
纳基萜烯辛因和纳基萜烯辛酮是两种从海绵 Terpios hoshinota 中分离出的相关 C-去甲-D-同甾体，具有作为抗癌剂的潜力。我们之前已经描述了纳基萜烯辛因的不对称合成和相对构型的修订。现在，我们提供了支持我们结构修订的立体化学分析的详细信息，并合成了最初提出和修订的纳基萜烯辛因。此外，我们还描述了纳基萜烯辛因的精细合成方法、纳基萜烯辛酮的首次合成以及纳基萜烯辛因在哺乳动物细胞中作用的初步机制研究。用纳基萜烯辛因处理的细胞表现出初级纤毛形成受损，初级纤毛是 Hedgehog 信号转导途径组件的组装点。我们提供的证据表明，纳基萜烯辛因的生物学效应在机制上与紫杉醇等已确立的抗有丝分裂剂不同。纳基萜烯辛因可能对那些对现有抗有丝分裂剂有抗性的肿瘤和那些依赖 Hedgehog 途径反应生长的肿瘤有用作为抗癌剂。
