化学
半合成
丁二酰亚胺
立体化学
天然产物
结构-活动关系
癌细胞系
计算生物学
组合化学
生物化学
癌细胞
癌症
医学
生物
内科学
体外
作者
Zef A. Könst,Anne R. Szklarski,Simone Pellegrino,Sharon E. Michalak,Mélanie Meyer,Camila Zanette,Regina Cencic,Sangkil Nam,Vamsee K. Voora,David Horne,Jerry Pelletier,David L. Mobley,G. Yusupova,Marat Yusupov,Christopher D. Vanderwal
出处
期刊:Nature Chemistry
[Springer Nature]
日期:2017-07-03
卷期号:9 (11): 1140-1149
被引量:38
摘要
The lissoclimides are unusual succinimide-containing labdane diterpenoids that were reported to be potent cytotoxins. Our short semisynthesis and analogue-oriented synthesis approaches provide a series of lissoclimide natural products and analogues that expand the structure-activity relationships (SARs) in this family. The semisynthesis approach yielded significant quantities of chlorolissoclimide (CL) to permit an evaluation against the National Cancer Institute's 60-cell line panel and allowed us to obtain an X-ray co-crystal structure of the synthetic secondary metabolite with the eukaryotic 80S ribosome. Although it shares a binding site with other imide-based natural product translation inhibitors, CL engages in a particularly interesting and novel face-on halogen-π interaction between the ligand's alkyl chloride and a guanine residue. Our analogue-oriented synthesis provides many more lissoclimide compounds, which were tested against aggressive human cancer cell lines and for protein synthesis inhibitory activity. Finally, computational modelling was used to explain the SARs of certain key compounds and set the stage for the structure-guided design of better translation inhibitors.
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