文献类型：期刊文献

英文题名：Isolation, bioassay and 3D-QSAR analysis of 8-isopentenyl flavonoids from Epimedium sagittatum maxim. as PDE5A inhibitors

作者：Li, Juntao[1];Wu, Yue[2];Yu, Xinxin[3];Zheng, Xinyu[1];Xian, Jiechen[1];Li, Senjie[1];Shi, Wanyin[2];Tang, Yun[3];Chen, Zhe-Sheng[5];Liu, Guixia[3];Yao, Shen[4];Xu, Jian[2];Zheng, Xiangwei[1]

机构：[1]Shanghai Univ Tradit Chinese Med, Innovat Res Inst Tradit Chinese Med, Engn Res Ctr Modern Preparat Technol Tradit Chines, Minist Educ, 1200 CaiLun Rd,Room 10112, Shanghai, Peoples R China;[2]Jing Brand Co Ltd, Jing Brand Res Inst, Hubei Prov Key Lab Qual & Safety Tradit Chinese Me, 169 Daye Ave, Huangshi, Hubei, Peoples R China;[3]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, 130 Meilong Rd,Box 318, Shanghai 200237, Peoples R China;[4]Sanlin Community Hlth Serv Ctr Shanghai Pudong New, 375 Sanlin Rd, Shanghai 200124, Peoples R China;[5]St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, New York, NY 11439 USA

年份：2022

卷号：17

期号：1

外文期刊名：CHINESE MEDICINE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000906290700001)】；

基金：This study was supported by the Natural Science Foundation of Hubei Province [grant number 2019CFB829]. This research was funded by Jing Brand Research Institute, Jing Brand Co., Ltd. (Daye, China) for financial support.

语种：英文

外文关键词：8-isopentenyl flavonoid; The processed folium of Epimedium sagittatum Maxim; Phosphodiesterase-5 inhibitor; 3D-QSAR; cGMP-PKG-Ca2+ signaling pathway

摘要：Background: As known, inhibition of phosphodiesterase 5 (PDE5) has the therapeutic effect on male erectile dysfunction (ED), and the processed folium of Epimedium sagittatum Maxim. (PFES) characterized by 8-isopentenyl flavonoids is a famous herb for treating ED. However, the main flavonoids inhibitory activities, structure-activity relationship (SAR) and signaling pathway have been not systematically studied so that its pharmacodynamic mechanism is unclear. Methods: We aimed to initially reveal the PFES efficacy mechanism for treating ED. For the first time, 6 main 8-isopentenyl flavonoids (1-6) from PFES were isolated and identified. Then based on HPLC detection, we proposed a novel method to screen inhibitors among them. We further analyze the three-dimensional quantitative structure-activity relationship (3D-QSAR) for those inhibitors. Results: The results were verified by cellular effects of the screened flavonoids. Among 6 compounds, Icariin: (1), 2-O '' rhamnosylicaridide II (2) and Baohuoside I (3) were identified with significant activities (IC50 = 8.275, 3.233, 5.473 mu M). Then 3D-QSAR studies showed that the replacement of C8 with bulky steric groups as isopentenyl, C3 with positive charge groups and C4' with a hydrogen bond acceptor substituent could increase inhibitory effects. In contrast, the substitution of C7 with bulky steric groups or hydrophilic groups tended to decrease the efficacies. And compounds 1, 2, 3 could increase cGMP level and decrease cytoplasmic Ca2+ of rat corpus cavernosum smooth muscle cells (CCSMCs)by activating PKG. Conclusion: 8-isopentenyl flavonoids could be the main pharmacodynamic substances of PFES in the treatment for ED, and some had significant PDE5A1 inhibitory activities so as to activate cGMP/PKG/Ca2+ signaling pathway in CCSMCs, that was related to the substituents at the key sites such as C8, C3, C4 ' and C7 in the characteristic compounds.