Department of Chemistry, Yale University, New Haven, CT 06520, USA.
Chemical Biology Institute, Yale University, West Haven, CT 06516, USA.
Mar Drugs. 2018 Aug 27;16(9):297. doi: 10.3390/md16090297.
The Wnt/β-catenin signaling pathway is known to play critical roles in a wide range of cellular processes: cell proliferation, differentiation, migration and embryonic development. Importantly, dysregulation of this pathway is tightly associated with pathogenesis in most human cancers. Therefore, the Wnt/β-catenin pathway has emerged as a promising target in anticancer drug screening programs. In the present study, we have isolated three previously unreported metabolites from an undescribed sponge, a species of (Order Poecilosclerida, Family ), closely related to the northeastern Pacific species , collected from deep waters off the Aleutian Islands of Alaska. Through an assortment of NMR, MS, ECD, computational chemical shifts calculation, and DP4, chemical structures of these metabolites have been characterized as spirocyclic ring-containing sesterterpenoid () and cholestane-type steroidal analogues ( and ). These compounds exhibited the inhibition of β-catenin response transcription (CRT) through the promotion of β-catenin degradation, which was in part implicated in the antiproliferative activity against two CRT-positive colon cancer cell lines.
Wnt/β-catenin 信号通路在广泛的细胞过程中发挥着关键作用：细胞增殖、分化、迁移和胚胎发育。重要的是，该通路的失调与大多数人类癌症的发病机制密切相关。因此，Wnt/β-catenin 通路已成为抗癌药物筛选计划中一个很有前途的靶点。在本研究中，我们从一种未被描述的海绵中分离出三种以前未报道的代谢物，这种海绵属于（Order Poecilosclerida，Family ），与来自阿拉斯加阿留申群岛深海的东北太平洋物种密切相关。通过一系列 NMR、MS、ECD、计算化学位移计算和 DP4，这些代谢物的化学结构被表征为具有螺环的甾体类似物（和）。这些化合物通过促进 β-catenin 降解来抑制 β-catenin 反应转录（CRT），这部分涉及到对两种 CRT 阳性结肠癌细胞系的抗增殖活性。
