RESUMEN
In order to find a 3,4-dihydro-2H-naphtho[1,2-b]pyran-5,6-dione more potent than the naturally occurring 2,2-dimethyl derivative [beta-lapachone (10a)], we synthesized a series of analogous compounds with modifications at position 2 of the pyran ring or at positions 8 and 9 of the benzene ring. Of the compounds tested in vitro for inhibition of RNA-dependent DNA polymerase and in mice infected with Rauscher leukemia, all retained good enzyme activity. Inhibition of the reverse transcriptase activity of the 2,2-substituted derivatives 10b-e was as strong as 10a. However, only the 2-methyl-2-phenyl derivative 10e proved to be about as potent as the 2,2-dimethyl reference compound 10a in prolonging the mean survival time of mice with Rauscher leukemia virus induced leukemia.
Asunto(s)
Antibióticos Antineoplásicos/síntesis química , Naftoquinonas/síntesis química , Animales , Leucemia Experimental/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Naftoquinonas/uso terapéutico , Virus Rauscher , Inhibidores de la Transcriptasa InversaAsunto(s)
ADN Polimerasa Dirigida por ADN/metabolismo , Sarcoma de Mastocitos/enzimología , Animales , ADN Polimerasa Dirigida por ADN/aislamiento & purificación , Calor , Cinética , Ratones , Neoplasias Experimentales/enzimología , Inhibidores de la Síntesis del Ácido Nucleico , Conformación Proteica , Especificidad por Sustrato , Reactivos de Sulfhidrilo/farmacología , Moldes GenéticosRESUMEN
beta-Lapachone is a naturally occuring compound that can be isolated from a number of tropical trees. It is shown to be a potent inhibitor of reverse transcriptase activity from both avian myeloblastosis virus and Rauscher murine leukaemia virus. In addition, it affects eukaryotic DNA-dependent DNA polymerase-alpha activity: 50% inhibition is reached in 60-min incubation time by about 8 micron beta-lapachone. Enzyme activity is inhibited irrespective of the purity of the enzyme used or of the amount or type of template/primer or substrate present. The inhibitory effect of the drug is only observed in the presence of dithiothreitol. The primary site of action of beta-lapachone appears to be the enzyme protein, as is also borne out by the specificity of its action. Eukaryotic DNA-dependent DNA polymerase-beta, prokaryotic DNA-dependent DNA polymerase I, several other nucleic acid polymerases and some completely unrelated enzymes are not affected. Reverse transcriptase and DNA-dependent DNA polymerase-alpha may be in someway related in possessing similarly exposed '--SH structures' in their active sites. beta-lapachone thus affords a novel means of studying such interrelationships and of further characterizing enzymes.