Chemoinformatic and bioassay-guided fractionation of a gorgonian coral Junceella juncea resulted in the isolation of 45 briarane-type diterpenoids, of which 16 new analogues were characterized. Their structures were identified by extensive analyses of the spectroscopic data. Most isolated briaranes showed significant inhibition against the receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation in bone marrow-derived macrophages cells (BMMs). Praelolide, one of the active analogues, significantly activates nuclear factor erythroid-2-related factor 2 (Nrf2) nucleus translocation, induces the expression of Nrf2-targeted genes, suppresses reactive oxygen species (ROS) production, abrogates the activation of downstream mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NFκB) signaling, and subsequently attenuates osteoclast differentiation. Mechanically, praelolide interacts with Kelch-like ECH-associated protein 1 (Keap1) protein by non-covalent interaction to interrupt the interaction between Keap1 and Nrf2 and thereby to activate the Nrf2 signaling pathway. In addition, praelolide rescues the bone loss in prednisone-induced zebrafish. The present study provided praelolide as a new natural scaffold to remedy osteoclastogenic bone disease.

柳珊瑚Junceella juncea的化学信息学和生物测定引导分馏结果分离出 45 种 briarane 型二萜类化合物，其中 16 种新的类似物得到了表征。它们的结构是通过对光谱数据的广泛分析确定的。大多数分离的 briaranes 对核因子 κB 受体激活剂配体 (RANKL) 诱导的骨髓来源巨噬细胞 (BMM) 中的破骨细胞分化有显着抑制作用。Praelolide 是活性类似物之一，可显着激活核因子红细胞 2 相关因子 2 (Nrf2) 核易位，诱导 Nrf2 靶向基因的表达，抑制活性氧 (ROS) 的产生，消除下游有丝分裂原的激活活化蛋白激酶 (MAPK)/核因子-κB (NFκB) 信号，随后减弱破骨细胞分化。机械地，praelolide 通过非共价相互作用与 Kelch 样 ECH 相关蛋白 1 (Keap1) 蛋白相互作用，中断 Keap1 和 Nrf2 之间的相互作用，从而激活 Nrf2 信号通路。此外，praelolide 可挽救泼尼松诱导的斑马鱼的骨质流失。本研究提供了 praelolide 作为一种新的天然支架来治疗破骨细胞性骨病。