Molecular Pharmacology, Vol 11, 310-318, Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics

Influence of Thiols on Inhibition of Ribonucleic Acid Synthesis in Vitro by a 1-Nitro-9-aminoalkylacridine Derivative, C-283

MAREK GNIAZDOWSKI ¹, LESZEK SZMIGIERO ¹, KRYSTYNA LASKA ¹, BARBARA JAROS-KAMISKA ¹, and EWA CIESIELSKA ¹

¹ Department of General Chemistry, Institute of Physiology and Biochemistry, Academy of Medicine, 90-131 ód, Poland

1-Nitro-9,3-N,N-dimethylaminopropylaminoacridine (C-283) is of pharmacological interest as a potent inhibitor of tumor growth and RNA synthesis in vivo. Its effect on RNA synthesis directed by Escherichia coli RNA polymerase is strongly influenced by sulfhydryl compounds. Its maximal inhibitory effect requires simultaneous mixing of a sulfhydryl compound, such as mercaptoethanol, dithiothreitol, or -thioglycerol, with DNA and drug at pH 8.0 prior to addition of the enzyme. Very slight inhibition was observed with the nitroacridine in the absence of a thiol. The influence of sulfhydryl compounds has been ascribed to reaction of the template with the 1-nitro group of the dye. Among the DNA-interacting dyes so far investigated, only 1-nitro analogues of C-283 enhance inhibition in the presence of sulfhydryl compounds. There are indications that the metabolite rather than the nitroacridine itself is responsible for the inhibitory effect in vivo.

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ACKNOWLEDGMENTS We wish to thank Dr. W. Ciesielcki for his help in infrared spectra determinations and their discussion, Miss Magorzata Affeltowicz for excellent technical assistance, and Mrs. Zofia Germarowa, Scientific Research Center of the Medical Academy, for radioactivity measurements.