β‐Lapachone, an Inhibitor of Oncornavirus Reverse Transcriptase and Eukaryotic DNA Polymerase‐α

Abstract

P-Lapachone is a naturally occurring 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 DNAdependent DNA polymerase-u activity; 50 % inhibition is reached in 60-min incubation time by about 8 pM P-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 P-lapachone appears to be the enzyme protein, as is also borne out by the specificity of its action. Eukaryotic DNA-dependent DNA polymerase-B, 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-a may be in someway related in possessing similarly exposed '-SH structures' in their active sites. P-Lapachone thus affords a novel means of studying such interrelationships and of further characterizing enzymes.

Correlations between the activities of DNA polymerase alpha and the glucocorticoid receptor.

“…1) agrees with the published effects of this rifamycin derivative on the nuclear binding ofavian oviduct progesterone-receptor complexes (25). We also have demonstrated that /3-lapachone, a specific inhibitor of DNA polymerase a and reverse transcriptase (22), inhibits the specific binding of [6,7-3H]T-A when preineubated with unbound glucocorticoid receptors (Fig. 2).…”

Three inhibitors of type 1 human immunodeficiency virus long terminal repeat-directed gene expression and virus replication.

“…However, a 40,000-fold higher concentration of camptothecin was required to inhibit viral topoisomerase than to decrease p24 antigen production after acute HTLV-IIIB infection (22,23). Also, our results suggest a target for j-lapachone other than oncovirus reverse transcriptase (24).…”

A new approach for the synthesis of 3-substituted cytotoxic nor-β-lapachones

“…The multiple and varied antimicrobial activity of lapachol and structurally related compounds highlights the importance of this class of compounds (Figure 1). An important derivative of lapachol (1) is the β-lapachone (4), an ortho-naphthoquinone naturally obtained from a native South America tree Tabebuia avellanedae with a wide range of pharmacological activities, including anti-bacterial, antifungal, anti-trypanosomal, anti-retroviral and anti-inflammatory activities [19][20][21][22][23][24][25][26] Another compound, nor-lapachol (5), is a synthetic derivative that can be obtained from 1 by a degradation reaction with H 2 O 2 , known as the Hooker reaction, 27 or by the condensation of 2-hydroxy-1,4-naphthoquinone with isobutyraldehyde. 28 Compound 5 can be cyclized in a strong acid, producing nor-β-lapachone (6).…”