Cellular uptake and inhibition of DNA synthesis by dihydroxyanthraquinone and two analogues.
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; HAW 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 greater than HAQ greater than 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 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.
D000818:Animals; D000880:Anthraquinones / Q000378:metabolism / Q000494:pharmacology*; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D004256:DNA Polymerase I / Q000378:metabolism; D003864:Depression, Chemical; D004926:Escherichia coli / Q000201:enzymology; D007739:L Cells / Q000378:metabolism*; D051379:Mice; D013950:Thymus Gland / Q000378:metabolism
D000880:Anthraquinones; D004247:DNA; D004256:DNA Polymerase I