Naphthoquinones inhibition

Effects of Allelochemlcals on ATPases. Several flavonoid compounds inhibit ATPase activity that is associated with mineral absorption. Phloretin and quercetin (100 pM) inhibited the plasma membrane ATPase Isolated from oat roots (33). The naphthoquinone juglone was inhibitory also. However, neither ferulic acid nor salicylic acid inhibited the ATPase. Additional research has shown that even at 10 mM salicylic acid inhibits ATPase activity only 10-15% (49). This lack of activity by salicylic acid was substantiated with the plasma membrane ATPase Isolated from Neurospora crassa (50) however, the flavonols fisetln, morin, myricetin, quercetin, and rutin were inhibitory to the Neurospora ATPase. Flavonoids inhibited the transport ATPases of several animal systems also (51-53). Thus, it appears that flavonoids but not phenolic acids might affect mineral transport by inhibiting ATPase enzymes. 

The family Droseraceae consists of four genera and about 100 species of perennial herbs, of which Drosera burmannii Vahl, Drosera rotundifolia L, Drosera indica L., and Drosera peltata Sm. are used in Asia for the treatment of cough. Naphthoquinones and flavonoids, which occur in this family, have not been fully studied for pharmacology, and it appears that flavonoids inhibit human neutrophil elastase, hence the potential for the treatment of inflammation. 

In the case of ubiquinones we have already considered the ability of quinones to react with superoxide and other free radicals. Naphthoquinones, vitamin K and its derivatives, especially menadione, are the well known producers of superoxide through redox cycling with dioxygen. However, in 1985, Canfield et al. [254] have shown that vitamin K quinone reduced the oxidation of linoleic acid while vitamin K hydroquinone stimulated lipid peroxidation. Surprisingly, later on, conflicting results were reported by Vervoort et al. [255] who found that only hydroquinones of vitamin K and its analogs inhibited microsomal lipid peroxidation. 

Matthews, N., Neale, M.L., Jackson, S.K., and Stark, J.M., 1987, Tumor cell kilhng by tumor necrosis factor inhibition by anearobiotic condition, free-radical scavengers and inhibitors of arachidonate metabolism. Immunology 62 153-155 Miller, M.G., Rodgers, A., and Cohen, G.M., 1986, Mechanisms oftoxicity of naphthoquinones to isolated hepatocytes. Biochem. Pharmacol. 35 1177-1184 Minko, T., Kopeckova, P., and Kopecek, J., 1999, Comparison ofthe anticancer effect of free and HPMA copolymer-bound adtiamycin in human ovarian carcinoma cells. Pharmaceut. Res. 16 986-996... 

Amino-substituted naphthoquinones and heterocyclic variants have been disclosed in the patent literature as 5-LO inhibitors. Compounds represented by (80) (X = C, N) from Lilly inhibited SRS-A release from sensitized guinea-pig lung tissue [218]. Similar compounds such as (81) (R = carboxylic ester, acyl, or aryl) and related naphthalene derivatives, from American Cyanamid, gave good inhibition in guinea-pig ISN (at 10 //g/ml) and in passive cutaneous anaphylaxis in mice (25-60 /zM i.p.) [219,220]. 

I. 1.4.1] catalyzes the reaction of 2-methyl-3-phytyl-l,4-naphthoquinone with oxidized dithiothreitol and water to produce 2,3-epoxy-2,3-dihydro-2-methyl-3-phytyl-l,4-naphthoquinone and 1,4-dithiothreitol. In the reverse reaction, vitamin K 2,3-epoxide is reduced to vitamin K and possibly to vitamin K hydroquinone by 1,4-dithioer-ythritol (which is oxidized to the disulfide). Some other dithiols and butane-4-thiol can also act as substrates. This enzyme is strongly inhibited by warfarin. 

Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystic activity. Since 2000 atovaquone is available as a fixed dose preparation (Malarone) with proguanil for the oral treatment of falciperum malaria. Its activity probably is based on a selective inhibiton of mitochondrial electron transport with consequent inhibition of pyrimidin synthesis. Malarone should not be used to treat severe malaria, when an injectable drug is needed. 

Atovaquone is a naphthoquinone whose mechanism of action involves inhibition of the mitochondrial electron transport system in the protozoa. Malaria parasites depend on de novo pyrimidine biosynthesis through dihy-droorotate dehydrogenase coupled to electron transport. Plasmodia are unable to salvage and recycle pyrimidines as do mammalian cells. 

A. Liposomal amphotericin B was approved by the US. Food and Drug Administration to treat visceral leishmaniasis. Pentavalent antimony compounds, pentamidine, amphotericin B, and aminosi-dine (paromomycin) have all been demonstrated efficacious here. The liposomal amphotericin appears to be better taken up by the reticuloendothelial system, where the parasite resides, and partitions less in the kidney, where amphotericin B traditionally manifests its toxicity. In addition to being better tolerated by patients, it has proved to be very effective in India, where resistance to antimony drugs is widespread. This patient appears to have acquired his infection there, where many infected patients develop darkening of the skin, hence the name kala-azar, or black sickness. Albendazole, an anthelmintic, has no role here. Atovaquone, a naphthoquinone, is used to treat malaria, babesiosis, and pneumocystosis. Pyrimethamine-sulfadoxine is used to treat malaria and toxoplasmosis. Proguanil inhibits the dihydrofolate reductase of malaria parasites and is used in combination with atovaquone. 

However, attempts by Kiefer and Carlson59 to prohibit undesired bi-molecular reactions by irradiating 2,3,3-trimethyl-l-penten-4-one adsorbed onto silica gel were unsuccessful (due probably to steric inhibition of adsorption) the product composition was the same as that previously obtained in solution. Werbin and Strom80 attempted to restrain the freedom of movement of the radicals formed from the photolysis of vitamin K3 (2-methyl-1,4-naphthoquinone) by adsorption onto silica gel, but obtained the same mixture of dimers as that obtained from the irradiation in acetone solution, viz., syn and anticyclobutanes, an oxetane dimer, and a binaphthoquinone dimer. Photolysis of the solid substrate, however, produced only the syn isomer of cyclobutane, in this case no migration of radicals is possible, hence only one product. 

Methyl, 2-hydroxymethyl-, and 2-formylanthraquinones in the heart wood of teak (Tectona grandis, Verbenaceae) are effective in inhibiting termite activity (105). Several naphthoquinone derivatives including lapachol are thought to impart marine borer resistance to woods, e.q. that of Tabebuia quayacan (Bignoniaceae) (108). 

More recently, a new class of insecticides derived from naphthoquinones found in the South American alpine plant Calceolaria andina has entered development. Compounds are being developed jointly through the British Technology Group (BTG) (following the discovery at Rothamsted Experimental Station) and by Bayer. The mode of action of these compounds is believed to be an inhibition of respiration at site... 

Using the same strategy, Benrezzouk et al. also reported a naphthoquinone diterpene, aethiopinone, from the roots of Salvia aethiopis L. (Labiatae), possessed 5-LOX inhibition activity with IC50 value of O.llpM without affecting COX and PLA2 pathways [140]. 

Cys202 [208]. Human immunodeficiency virus (HIV) is the primary cause of acquired immunodeficiency syndrome (AIDS). In an effort to find new drugs preventing the growth of HIV, Masao et al developed an in vitro assay method of RNase H activity associated with reverse transcriptase (RT) from HIV-1. Some 1,4-naphthoquinones moderately inhibited RNase H activity [209]. Several natural occurring naphtoquinones have showed antiretroviral activity [210-211],... 

Finally, one 2-hydroxy-3-alkyl-l,4-naphthoquinone has been shown to be bactericidal and to produce a shut-down of all major biosynthetic processes. This is the result of an inhibition of the transport of nutrients/precursors through the membrane into the bacterial cell. Detailed experiments on the permeation of uracil demonstrated that ingress and egress were inhibited by the substituted naphthoquinone61). 

The rifamycins were first isolated by Sensi et al.3) from Nocardia mediterranei as a complex mixture (Rifamycins A—E). Addition of diethylbarbiturate to the fermentation medium led to the sole production of rifamycin B6 which was obtained in crystalline form. Its structure has been determined by chemical7,and X-ray analysis9. The rifamycins might easily have excaped detection altogether, since rifamycin B has no antibacterial activity. However, it is spontaneously oxidized to rifamycin 0 and hydrolyzed to rifamycin S, a naphthoquinone derivative reduction yields the naphthohydroquinone derivative rifamycin SV (Fig. 4). These compounds inhibit the growth of Gram-positive bacteria at concentration as low as 0.0025 jug/ml. 

Pritsos CA, Pisani DE, and Pardini RS (1985) Inhibition of liver glycolysis in rats by dietary dichlone (2,3-dichloro-1,4-naphthoquinone). Bulletin of Environmental Contamination and Toxicology 35 23-28. 

Roland, B. Vandendriessche, J. Lombaerts, R. Denturck, B. Jakus, C. Thermal crosslinking by unexposed naphthoquinone diazides as diffusion inhibition mechanism in the DESIRE process. Proc. SPIE 1988, 920, 120-127. 

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