Journal
NATURE CHEMISTRY
Volume 9, Issue 11, Pages 1140-1149Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEM.2800
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Funding
- National Institutes of Health (NIH)
- University of California (UC) Cancer Research Coordinating Committee [GM-086483, UCCRCC-55179]
- French National Research Agency [ANR-15-CE11-0021-01]
- European Research Council advanced grant [294312]
- NIH [GM-108889]
- National Cancer Institute of the NIH [P30CA033572]
- Canadian Institutes of Health Research (CIHR) [FDN-148366]
- National Science Foundation [CHE-1464828]
- Brazilian Science Without Borders
- Direct For Mathematical & Physical Scien [1464828] Funding Source: National Science Foundation
- Division Of Chemistry [1464828] Funding Source: National Science Foundation
- European Research Council (ERC) [294312] Funding Source: European Research Council (ERC)
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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-p 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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