Tan Hui, Ashour Ahmed, Katakura Yoshinori, Shimizu Kuniyoshi
Department of Agro-environmental Sciences, Faculty of Agriculture, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan.
Department of Agro-environmental Sciences, Faculty of Agriculture, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan; Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt.
Phytomedicine. 2015 Apr 15;22(4):498-503. doi: 10.1016/j.phymed.2015.03.002. Epub 2015 Mar 20.
Our previous results elucidated that the leaves of Eriobotrya japonica possessed the potential to suppress ovariectomy-induced bone mineral density deterioration, and ursolic acid, the major bioactive component in these leaves, suppressed the osteoclast differentiation. The aim of this study was to discover more candidates for development of novel antiosteoclastogenesis agents from the leaves of E. japonica. Phytochemical analysis following a cell-based osteoclastic tartrate-resistant acid phosphatase (TRAP) activity assay revealed 11 more compounds with a potent antiosteoclastogenesis effect. The potency of ursane-type triterpenoids from the leaves of E. japonica prompted us to investigate the structure-activity relationships underlying their antiosteoclastogenesis. The results revealed that both the hydroxyl group at C-3 and the carboxylic group at C-17 played indispensable roles in the antiosteoclastogenesis activity of ursane-type triterpenoids. The configuration at C-3 (a beta-form of the hydroxyl group) was found to be important for this activity. While introducing a hydroxyl group at C-19 increased the inhibitory activity of ursane-type triterpenoids carrying an alpha-form hydroxyl group at C-3. The bioactivity analyses of ursolic acid and oleanolic acid demonstrated that the antiosteoclastogenesis effect of ursolic acid may be related to different positions of the C-29 and C-30 methyl groups on the E-ring, since oleanolic acid showed limited activity. The addition of a hydroxyl group at C-2 would dramatically improve the inhibition of oleanane-type triterpenoids. Collectively, these findings could provide important clues for the improvement of multi-targeted antiosteoclastogenesis agents from the leaves of E. japonica.
我们之前的研究结果表明，枇杷叶具有抑制去卵巢诱导的骨密度下降的潜力，且熊果酸作为这些叶片中的主要生物活性成分，可抑制破骨细胞分化。本研究旨在从枇杷叶中发现更多新型抗破骨细胞生成药物的开发候选物。基于细胞的抗酒石酸酸性磷酸酶（TRAP）活性测定后的植物化学分析显示，还有11种化合物具有显著的抗破骨细胞生成作用。枇杷叶中乌苏烷型三萜类化合物的效力促使我们研究其抗破骨细胞生成作用的构效关系。结果表明，C-3位的羟基和C-17位的羧基在乌苏烷型三萜类化合物的抗破骨细胞生成活性中均起着不可或缺的作用。发现C-3位的构型（羟基的β型）对该活性很重要。而在C-19位引入羟基会增加C-3位带有α型羟基的乌苏烷型三萜类化合物的抑制活性。熊果酸和齐墩果酸的生物活性分析表明，熊果酸的抗破骨细胞生成作用可能与E环上C-29和C-30甲基的不同位置有关，因为齐墩果酸的活性有限。在C-2位添加羟基会显著提高齐墩果烷型三萜类化合物的抑制作用。总的来说，这些发现可为从枇杷叶中开发多靶点抗破骨细胞生成药物提供重要线索。
