This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Nishio, A. Articles by Uyeki, E. M. Search for Related Content PubMed PubMed Citation Articles by Nishio, A. Articles by Uyeki, E. M.

Cellular Uptake and Inhibition of DNA Synthesis by Dihydroxyanthraquinone and Two Analogues¹

Department of Pharmacology, The University of Kansas Medical Center, Kansas City, Kansas 66103

Three analogues of aminoalkylamino-substituted anthraquinone derivatives, namely, 1,4-dihydroxy-5,8-bis{{{2-[(2-hydroxyethyl)amino]ethyl}amino}}-9,10-anthracenedione (DHAQ), 1-hydroxy-5,8-bis{{{2-[(2-hydroxyethyl)amino]ethyl}amino}}-9,10-anthracenedione (HAQ), and 1,4-bis{{{2-[(2-hydroxyethyl)amino]ethyl}amino}}-9,10-anthracenedione (AQ), were chosen with respect to the number of hydroxyl groups on the aromatic ring. DHAQ showed about 100 times more potent antiproliferative activity on cultured mouse L-cells than did AQ; HAQ showed intermediate activity. This antiproliferative activity was correlated with their inhibitory effect on DNA synthesis in culture. When their inhibitory effect on DNA synthesis was conducted in a permeabilized L-cell assay, all compounds were inhibitory; the order of potency was DHAQ > HAQ > AQ. The same order of potency was also observed in calf thymus DNA and Escherichia coli DNA polymerase I system. Their inhibitory effect in the latter system was correlated with the drug:DNA molar ratio, and not with the drug:enzyme ratio. Comparative uptake of the drugs by intact L-cells showed the highest uptake of DHAQ followed by those of HAQ and AQ. The large differences in their uptake by intact cells became minimal when cells were rendered permeable to exogenous materials or when nuclei were used. Hence, these studies revealed that the hydroxyl group on the aromatic ring of the compounds influenced their biological activity not only by potentiating drug-target interaction but also by drug uptake into cells.

¹ Supported by Grant ES 02046 from National Institute of Environmental Health Sciences.

² To whom requests for reprints should be addressed.

³ Present address: Second Department of Medicine, Kyoto Prefectural University of Medicine, Kajii-cho, Kawaramachi-Hirokoji, Kamikyo-ku, Kyoto 602, Japan.

Received 7/19/82. Accepted 1/14/83.