Synthesis facilitates an understanding of the structural basis for translation inhibition by the lissoclimides

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 (S...

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Vydáno v:	Nature chemistry Ročník 9; číslo 11; s. 1140 - 1149
Hlavní autoři:	Könst, Zef A., Szklarski, Anne R., Pellegrino, Simone, Michalak, Sharon E., Meyer, Mélanie, Zanette, Camila, Cencic, Regina, Nam, Sangkil, Voora, Vamsee K., Horne, David A., Pelletier, Jerry, Mobley, David L., Yusupova, Gulnara, Yusupov, Marat, Vanderwal, Christopher D.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 01.11.2017 Springer Nature Nature Publishing Group
Témata:	631/535/1266 639/638/309/2420 639/638/549/977 Analogs Analytical Chemistry Animals Antineoplastic Agents, Phytogenic - chemical synthesis Antineoplastic Agents, Phytogenic - chemistry Antineoplastic Agents, Phytogenic - pharmacology Binding sites Biochemistry Biological Products - chemical synthesis Biological Products - chemistry Biological Products - pharmacology Biotechnology Cancer Cell Line, Tumor Cell Proliferation - drug effects Chemistry Chemistry, Multidisciplinary Chemistry/Food Science Computer applications Crystal structure Crystallography, X-Ray Cytotoxins Diterpenes Diterpenes - chemical synthesis Diterpenes - chemistry Diterpenes - pharmacology Drug Screening Assays, Antitumor Eukaryotic Initiation Factors - antagonists & inhibitors Eukaryotic Initiation Factors - metabolism Guanine Humans Inhibitors Inorganic Chemistry Life Sciences Metabolites Mice Models, Molecular Molecular Conformation Natural products Organic Chemistry Peptides, Cyclic Physical Chemistry Physical Sciences Protein biosynthesis Protein Biosynthesis - drug effects Protein synthesis Science & Technology Semisynthesis Structure-activity relationships Succinimide Succinimides - chemical synthesis Succinimides - chemistry Succinimides - pharmacology Translation Tumor cell lines CORE DICHLOROLISSOCLIMIDE PROTEIN LACTIMIDOMYCIN CYTOTOXIC DITERPENE ALKALOIDS RIBOSOME
ISSN:	1755-4330, 1755-4349, 1755-4349
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Popis
Shrnutí:	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. Several natural and unnatural lissoclimide cytotoxins have been prepared via semi-synthesis and total synthesis. An X-ray co-crystal structure of chlorolissoclimide with the ribosome and evaluation of cytotoxicity and translation inhibition of new compounds in the series improves our understanding of the molecular basis for cytotoxicity.
Bibliografie:	NIH RePORTER European Research Council (ERC) National Science Foundation ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC6021127 These authors contributed equally.
ISSN:	1755-4330 1755-4349 1755-4349
DOI:	10.1038/nchem.2800