Chlorolissoclimides: new inhibitors of eukaryotic protein synthesis.
Lissoclimides are cytotoxic compounds produced by shell-less molluscs through chemical secretions to deter predators. Chlorinated lissoclimides were identified as the active component of a marine extract from Pleurobranchus forskalii found during a high-throughput screening campaign to characterize new protein synthesis inhibitors. It was demonstrated that these compounds inhibit protein synthesis in vitro, in extracts prepared from mammalian and plant cells, as well as in vivo against mammalian cells. Our results suggest that they block translation elongation by inhibiting translocation, leading to an accumulation of ribosomes on mRNA. These data provide a rationale for the cytotoxic nature of this class of small molecule natural products.
Robert
Francis
F
Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Gao
Hong Qing
HQ
Donia
Marwa
M
Merrick
William C
WC
Hamann
Mark T
MT
Pelletier
Jerry
J
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005057:Eukaryotic Cells / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D008974:Mollusca / Q000737:chemistry; D009687:Nuclear Proteins / Q000032:analysis / Q000378:metabolism; D010441:Peptide Chain Elongation, Translational / Q000187:drug effects*; D020652:Peptide Elongation Factor 2 / Q000032:analysis / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D014176:Protein Biosynthesis / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D011691:Puromycin / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012360:RNA, Transfer, Phe / Q000187:drug effects; D012270:Ribosomes / Q000378:metabolism; D014157:Transcription Factors / Q000032:analysis / Q000378:metabolism
D009687:Nuclear Proteins; D020652:Peptide Elongation Factor 2; D010456:Peptides, Cyclic; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D012360:RNA, Transfer, Phe; D014157:Transcription Factors; D011691:Puromycin; C024777:methionylpuromycin