Inhibition of tRNA aminoacylation by ethidium dimer and several other bifunctional intercalators with or without antitumor activity

Abstract

The effect of various bifunctional intercalators with or without antitumor activity on the tRNA aminoacylation step was examined. The ethidium dimer appears as the strongest inhibitor of aminoacylation of E. coli methionine, phenylalanine and leucine tRNA and of yeast phenylalanine tRNA. Ethidium dimer binds to tRNA through two classes of sites, I and II ( K I > 10 9 M −1, K II − 10 6M −1) (C.R. Reinhardt, Biophys. J. 25, 44242 (1979)]. Surprisingly, binding of the drug to the high affinity class of sites causes only partial inhibition of tRNA aminoacylation, while full inhibition requires saturation of the second class of sites. This inhibition is reversed by displacement of the drug by an excess of DNA. In the studied systems, the 7H pyridocarbazole dimers 1 and 2 which have antitumor activity [B.P. Roques, D. Pelaprat, J. Le Guen, G. Porcher, C. Gosse and J. B. Le Pecq, Biochem. Pharmac. 28, 1811 (1979); D. Pelaprat, A. Delbarre, J. Le Guen, J. B. Le Pecq and B. P. Roques, J. med. Chem. 23, 1336 (1980)] inhibit aminoacylation at much higher concentrations than that of ethidium dimer. This behavior is discussed in relation to the particular structures of these drugs.