Molecular Pharmacology, Vol 13, 706-718, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

The Inhibitory Effect of Phenanthridines on the Synthesis of Ribonucleic Acid Catalyzed by Deoxyribonucleic Acid-Dependent Ribonucleic Acid Polymerase

¹ Department of Biochemistry and Biophysics, Stritch School of Medicine, Loyola University of Chicago, Maywood, Illinois 60153

The interaction of RNA polymerase with DNA prior to the initiation of RNA synthesis involves the formation of a specific complex (I) which is in equilibrium with a rapidly starting (RS) complex necessary for the rapid initiation of RNA chains. Phenanthridinium derivatives, including ethidium bromide, are effective inhibitors of RNA synthesis. These inhibitors do not affect either the rate of transformation of the I complex to the RS complex or the rate of transformation of the RS complex to the initiation complex. Phenanthridines, which intercalate into the DNA template and modify its conformation, act instead by limiting the number of enzyme molecules which can recognize and interact productively with the promoter regions of the template to form I complexes. This explanation is also consistent with the observed variation of the effectiveness of various phenanthridinium derivatives as inhibitors of RNA polymerase. Derivatives with a bulky phenyl group at C-6 of the phenanthridinium ring are decidedly better inhibitors of the enzyme than derivatives which carry a small aliphatic group in the same position.

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ACKNOWLEDGMENTS We are indebted to Dr. T. I. Watkins for his kind cooperation and his generous gift of a number of phenanthridinium derivatives.