Molecular Pharmacology, Vol 12, 167-176, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Mode of Action of the Antitumor Compound Bruceantin, an Inhibitor of Protein Synthesis

¹ Departments of Pharmacology and Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, and Department of Chemistry, University of Virginia, Charlottesville, Virginia 22901

The plant derivative bruceantin, an antitumor compound, irreversibly inhibits protein synthesis in HeLa cells, rabbit reticulocytes, and reticulocyte lysates. Bruceantin has a secondary effect on DNA synthesis, but little effect on the synthesis of RNA. After addition of bruceantin to a reticulocyte lysate, there is a delay of 2-3 min before inhibition of protein synthesis is observed. At a concentration of 0.1 mM, bruceantin induces sequential breakdown of polyribosomes to monosomes; concomitantly, nascent peptides are released from the ribosomes as completed chains of globin. These observations suggest that the principal inhibitory effect of the drug is on initiation of protein synthesis. Higher concentrations of bruceantin (1 mM) inhibit elongation of peptide chains; under these conditions, breakdown of polyribosomes is incomplete. Bruceantin does not prevent binding of radioactive poly U, poly C, or Escherichia coli tRNA to reticulocyte ribosomes, nor does it alter the conformation of ribosomal subunits. The structure-activity relationships of bruceantin and its analogues, as determined by their effects on protein synthesis in HeLa cells, rabbit reticulocyte cells, and reticulocyte lysates, correlate well with their activity as antitumor agents in experimental animals. These studies demonstrate that the side chain of bruceantin is important for transport of the drug into intact cells and that partial unsaturation in ring A is required for inhibition of protein synthesis.

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ACKNOWLEDGMENT The authors are grateful to Dr. Arthur P. Grollman for many helpful discussions during the course of this work.

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