Bao Xinye, Wei Jian, Tao Cheng, Bashir Muhammad Adnan, Zhang Hai-Jun, Bao Bian, Chen Jian, Zhai Hongbin
School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, China.
Guangzhou Quality Supervision and Testing Institute, Guangzhou, China.
Front Chem. 2023 Apr 28;11:1179948. doi: 10.3389/fchem.2023.1179948. eCollection 2023.
During the past decades, rheumatoid arthritis had become a serious problem, torturing millions of patients because of unclear pathogenesis and no ideal therapies. Natural products remain an important source of medicines to treat various major diseases such as rheumatoid arthritis (RA) given their excellent biocompatibility and structural diversity. Herein, we have developed a versatile synthetic method for constructing various skeletons of akuammiline alkaloid analogs based on our previous research on the total synthesis of the related indole alkaloids. We have also evaluated the effect of these analogs on the proliferation of RA fibroblast-like synoviocytes (FLSs) and analyzed the corresponding structure-activity relationship (SAR). Among these analogs, compounds and have demonstrated a promising inhibitory effect on the proliferation of RA-FLSs, with IC values of 3.22 ± 0.29 μM and 3.21 ± 0.31 μM, respectively. Our findings provide a solid foundation for future pharmacological studies on akuammiline alkaloid derivatives and inspiration for the development of anti-RA small molecule drugs derived from natural products.
在过去几十年中，类风湿性关节炎已成为一个严重问题，由于发病机制不明且缺乏理想的治疗方法，折磨着数百万患者。鉴于天然产物具有出色的生物相容性和结构多样性，它们仍然是治疗类风湿性关节炎（RA）等各种重大疾病的重要药物来源。在此，基于我们先前对相关吲哚生物碱全合成的研究，我们开发了一种通用的合成方法，用于构建阿库铵类生物碱类似物的各种骨架。我们还评估了这些类似物对RA成纤维细胞样滑膜细胞（FLS）增殖的影响，并分析了相应的构效关系（SAR）。在这些类似物中，化合物 和 对RA-FLS的增殖表现出有前景的抑制作用，IC值分别为3.22±0.29 μM和3.21±0.31 μM。我们的研究结果为未来对阿库铵类生物碱衍生物的药理研究提供了坚实基础，并为开发源自天然产物的抗RA小分子药物提供了灵感。
