Department of Chemistry, University of California, 1102 Natural Sciences II, Irvine, California 92697-2025, USA.
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, France.
Nat Chem. 2017 Nov;9(11):1140-1149. doi: 10.1038/nchem.2800. Epub 2017 Jul 3.
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.
利司扑来因是一类含有琥珀酰亚胺的罕见贝壳杉烷二萜类化合物，具有很强的细胞毒性。我们采用的半合成和基于类似物的合成方法，提供了一系列利司扑来因天然产物及其类似物，扩展了该家族的结构-活性关系（SARs）。半合成方法得到了大量的氯利司扑来因（CL），可用于评估国家癌症研究所的 60 种细胞系，并使我们能够获得与真核 80S 核糖体的合成次生代谢物的 X 射线共晶结构。尽管它与其他基于酰亚胺的天然产物翻译抑制剂共享一个结合位点，但 CL 与配体的烷基氯和鸟嘌呤残基之间存在特别有趣和新颖的面-卤-π相互作用。我们基于类似物的合成提供了更多的利司扑来因化合物，对侵袭性人类癌细胞系进行了测试，并评估了它们的蛋白合成抑制活性。最后，计算建模用于解释某些关键化合物的 SARs，并为基于结构的更好的翻译抑制剂设计奠定了基础。
