有机化学 ›› 2022, Vol. 42 ›› Issue (4): 1224-1228.DOI: 10.6023/cjoc202109042 上一篇    下一篇

研究简报

新多环大环内酰胺Clifednamide K的发现

罗洁a, 颜雅倩a, 王浩鑫b, 李瑶瑶a,*()   

  1. a 山东大学药学院 天然产物化学生物学教育部重点实验室 济南 250012
    b 山东大学 微生物技术国家重点实验室 山东青岛 266237
  • 收稿日期:2021-09-26 修回日期:2021-12-24 发布日期:2022-01-11
  • 通讯作者: 李瑶瑶
  • 基金资助:
    国家自然科学基金(81773598); 山东大学青年学者计划(2016WLJH31); 长江学者和创新团队发展计划(IRT_17R68)

Discovery of a New Polycyclic Tetramate Macrolactam Clifednamide K

Jie Luoa, Yaqian Yana, Haoxin Wangb, Yaoyao Lia()   

  1. a Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Shandong University, Jinan 250012
    b State Key Laboratory of Microbial Technology, Shandong University, Qingdao, Shandong 266237
  • Received:2021-09-26 Revised:2021-12-24 Published:2022-01-11
  • Contact: Yaoyao Li
  • Supported by:
    National Natural Science Foundation of China(81773598); Young Scholars Program of Shandong University(2016WLJH31); Program for Changjiang Scholars and Innovative Research Team in University(IRT_17R68)

利用组合生物合成策略构建了人工杂合多环特特拉姆酸大环内酰胺(PoTeM)基因簇, 并从异源表达重组菌株SR111-cbmA- OX1-cftC中分离得到2个PoTeM类化合物preikarugamycin (1)和clifednamide K (2). 通过核磁共振和高分辨质谱分析确定化合物1为ikarugamycin生物合成中间体, 化合物2为结构新颖的5/6双环PoTeM. 采用滤纸片法测定了化合物12的抗细菌和抗真菌活性, 结果显示二者在20 μg载药量下均无抗菌活性. 采用噻唑蓝比色法(MTT)测定了化合物12的细胞毒活性, 结果显示化合物1对人肝癌细胞HepG-2和人乳腺癌细胞MCF-7具有较强细胞毒活性, 半抑制浓度(IC50)分别为3.34和2.72 μmol/L, 化合物2对测试细胞株无明显细胞毒活性.

关键词: 天然产物, 生物活性, 多环大环内酰胺, 异源表达

The artificial hybrid polycyclic tetramate macrolactam (PoTeM) gene cluster was constructed through combinatory biosynthesis approach and two PoTeMs, preikarugamycin (1) and clifednamide K (2), were isolated from the recombinant strain SR111-cbmA-OX1-cftC. The chemical structures of 1 and 2 were determined to be the biosynthetic inermediate of ikarugamycin and a new 5/6 dicyclic PoTeM, respectively, by analysis of nuclear magnetic resonance spectroscopy (NMR) data and high resolution mass spectrometry (HRMS). The antibacterial activity of compounds 1 and 2 was tested by filter paper disc diffusion assay. The results showed that they were inactive at 20 μg/disc. The cytotoxicity of compounds 1 and 2 was evaluated by methyl thiazolyl tetrazolium (MTT) colorimetric method. Compound 1 showed potent antiproliferative activity against human liver (HepG-2) and breast cancer cell lines (MCF-7) with half maximal inhibitory concentration (IC50) values of 3.34 and 2.72 μmol/L, respectively, while compound 2 showed no cytotoxicity for the tested cell lines.

Key words: natural product, biological activity, polycyclic tetramate macrolactam, heterologous expression