Ex vivo activities of beta-lapachone and alpha-lapachone on macrophages: a quantitative pharmacological analysis based on amperometric monitoring of oxidative bursts by single cells.

ARTIFICIAL SYNAPSES FOR FEMTOMOLAR DETECTION: Amperometry at platinized carbon fibre electrodes has been used to unravel the complexity of beta-lapachone's effects on cellular oxidative stress. Alpha-lapachone, the pharmacologically inactive para-quinone isomer, did not display such characteristics, but over longer incubation periods both quinones induced apoptosis. The observed effects were interpreted in terms of two mechanisms involving opposite reactivities of quinones in living cells. Beta-lapachone (1) has been widely used for its pharmacological activity, particularly against cancer. However, its mechanism of action at the cellular level remains unclear, although a common major hypothesis involves its prooxidant properties. Electrochemical measurements with microelectrodes were taken in order to quantitatively investigate the activity of 1 at different concentrations and several incubation times, on the oxidative bursts released by single macrophages. The exact natures of the electroactive reactive oxygen species (ROS) and reactive nitrogen species (RNS) released by macrophages under the effect of 1 were characterized, and their fluxes were measured quantitatively. This allowed the reconstruction of the primary O2*- and NO production by the cells. In the first hour, at 10 microM, the decrease in the oxidative burst involved mainly RNS, while the amount of H(2)O(2) was found to be higher than in controls. After a longer incubation time-that is, 4 h-at 1 microM, the total amount of ROS and RNS had increased, with significant enhancements of H(2)O(2) and NO. In contrast, alpha-lapachone, the pharmacologically inactive para-quinone isomer, was unable to increase the production of RONS by macrophages significantly. Over much longer incubation periods (about one day), however, each quinone induced cell death by apoptosis. All these effects were interpreted by consideration of two different mechanisms involving opposite reactivities of quinones in living cells.

Mechanism of action of novel naphthofuranquinones on rat liver microsomal peroxidation.

In order to elucidate the effect on mammal systems of new derivatives from 2-hydroxy-3-allyl-naphthoquinone, alpha-iodinated naphthofuranquinone (NPPN-3223), beta-iodinated naphthofuranquinone (NPPN-3222) and beta-methyl naphthofuranquinone (NPPN-3226) synthesized as possible trypanocidal agents, their effect on rat liver microsomal lipid peroxidation was investigated. They (a) inhibited NADPH-dependent, iron-catalyzed microsomal rat liver lipid peroxidation; (b) did not inhibit the tert-butyl hydroperoxide-dependent lipid peroxidation; (c) did not inhibit ascorbate-lipid peroxidation with the exception of NPPN-3226 which did inhibit it; (d) stimulated NADPH oxidation and microsomal oxygen uptake; (e) increased superoxide anion formation by NADPH-supplemented microsomes and (f) stimulated ascorbate oxidation. The three drugs were reduced to their seminaphthofuranquinone radical by the liver NADPH-P450 reductase system, as detected by ESR measurements. These results support the hypothesis that naphthofuranquinones reduction by microsomal NADPH-P450 reductase and semiquinone oxidation by molecular oxygen diverts electrons, preventing microsomal lipid peroxidation. In addition, hydroquinones and/or semiquinones formed by naphthofuranquinones reduction would be capable of lipid peroxidation inhibition and on interacting with the lipid peroxide radicals can lead to an antioxidant effect as we suggested for NPPN-3226 in close agreement to the inhibition of ascorbate-lipid peroxidation. Due to the properties of these molecules and their incoming structure developments, naphthofuranquinones would be considered as potentially promising therapeutic agents, mainly against Chagas disease.

Antiviral activity of naphthoquinones: I. Lapachol derivatives against enteroviruses

Some derivatives obtained by chemical transformation of lapachol (a natural substance extracted from the core of plants belonging to the family Bignoniaceae) vere studied as to their posible antiviral action. Cell cultures were treated with those substances and then inoculated with poliovirus type 1, echovirus 19 and Coxsackievirus B type 4. Only ß-lapachone, succinamidyl-ß-norlapachone and intermediary of Hooker have shown a significant viral inhibition index to echovirus type 19. Those derivatives had in in vitro ion but they did not cause any harm to the viral particles studied (virucidal action)