3,4-Dihydroxybenzylamine: an improved dopamine analog cytotoxic for melanoma cells in part through oxidation products inhibitory to dna polymerase.
The dopamine analog 3,4-dihydroxybenzylamine (3,4-DHBA), a novel antitumor agent, was shown to inhibit directly DNA polymerase in cells of the deeply pigmented murine melanoma, S-91A, permeabilized to nucleotides by lysolecithin. In contrast, levodopa and dopamine did not inhibit DNA polymerase in permeabilized cells in the absence of exogenous tyrosinase. Analysis using isolated DNA polymerase showed that the inhibitory activity of the ortho dihydroxy compounds was totally dependent upon enzymatic activation. The enzymatic activation of the ortho derivative 3,4-DHBA by tyrosinase results in two reactive species: a semiquinone intermediate and a less reactive quinone. Inhibition of DNA polymerase by activated 3,4-DHBA was shown by dialysis and kinetic studies to involve an irreversible reaction which occurs at two inhibitor interaction sites as determined by a Hill plot analysis. Double-stranded DNA protected the enzyme from inhibition by 3,4-DHBA, suggesting that the inhibitory sites are at or near the template-initiator binding site.
D000818:Animals; D001711:Biotransformation; D002417:Cattle; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors; D004261:DNA Replication / Q000187:drug effects; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D014442:Monophenol Monooxygenase / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy; D019384:Nucleic Acid Synthesis Inhibitors; D013950:Thymus Gland / Q000201:enzymology
D019384:Nucleic Acid Synthesis Inhibitors; C022133:3,4-dihydroxybenzylamine; D004317:Doxorubicin; D014442:Monophenol Monooxygenase; D004257:DNA Polymerase II; D004298:Dopamine