Structure-activity relationships in the haemolytic activity and nephrotoxicity of derivatives of 1,2- and 1,4-naphthoquinone

Naphthoquinone derivatives are under investigation as potential therapeutic agents. Some such compounds are known, however, to be toxic to both animals and humans. Many naphthoquinone derivatives are haemolytic agents, while others cause necrosis of tubular epithelial cells. In the present study, the short-term toxicity of 16 derivatives of 1,2- and 1,4-naphthoquinone has been examined in rats in order to give information on structure-activity relationships. All the naphthoquinones except one caused haemolytic anaemia, but only hydroxy and amino derivatives were nephrotoxic. Among derivatives of 2-amino-1,4-naphthoquinone, substitution in the 3-position decreased haemolytic activity and abolished nephrotoxicity. Methylation of the hydroxyl group of 2-hydroxy-1,4-naphthoquinone had a similar effect. In contrast, methylation of the amino group of 2-amino-1,4-naphthoquinone increased the severity of both haemolysis and renal damage. Among the 1,2-naphthoquinones tested, the 4-methoxy and 4-amino derivatives were more toxic than the corresponding 1,4-isomers, although 4-methyl-1,2-naphthoquinone was less toxic than 2-methyl-1,4-naphthoquinone. At present, the toxicity of naphthoquinone derivatives cannot accurately be predicted on the basis of their chemical structure. In developing naphthoquinone derivatives for use in humans, toxicological studies in animals should be conducted at an early stage, bearing in mind that clinical studies have shown that humans appear to be particularly vulnerable to the nephrotoxic action of these compounds, and that certain individuals are unusually susceptible to their haemolytic action.     

Mechanisms of toxicity of 2- and 5-hydroxy-1,4-naphthoquinone; absence of a role for redox cycling in the toxicity of 2-hydroxy-1,4-naphthoquinone to isolated hepatocytes

The mechanisms of toxicity to isolated rat hepatocytes of two structurally related naphthoquinones have been studied. Both 5-OH-1,4-naphthoquinone (5-OH-1,4-NQ; juglone) and 2-OH-1,4-naphthoquinone (2-OH-1,4-NQ; lawsone) caused a concentration-dependent cytotoxicity to hepatocytes which was preceded by a depletion of intracellular glutathione. 5-OH-1,4-NQ caused a depletion of intracellular glutathione when incubated either at 4 degrees C or 37 degrees C whereas 2-OH-1,4-NQ caused a depletion of intracellular glutathione when the hepatocytes were incubated at 37 degrees C but not at 4 degrees C. 5-OH-1,4-NQ but not 2-OH-1,4-NQ reacted with glutathione in buffered solution. These results suggested that the depletion of intracellular glutathione by 2-OH-1,4-NQ is enzyme mediated whereas in the case of 5-OH-1,4-NQ the direct chemical reaction with gluathione may be largely responsible for the depletion. A critical role for depletion of protein thiols in menadione-induced cytotoxicity has been proposed. In agreement with earlier work, menadione caused a decrease in protein sulphydryls prior to cell death, however, at cytotoxic concentrations of both 2-OH-1,4-NQ and 5-OH-1,4-NQ this decrease only accompanied rather than preceeded cell death. The mechanism of toxicity of 5-OH-1,4-NQ is similar to that of other naphthoquinones and involves formation of its corresponding naphthosemiquinone, active oxygen species and redox cycling as it stimulated a disproportionate increase in both microsomal NADPH oxidation and oxygen consumption.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanisms of the antiaggregation activity of 1,4-naphthoquinone derivatives

The antiaggregation effects of synthetic derivatives of 1,4-naphtoquinone and ionol were studied as compared with the antioxidant properties of the agents. The proportional relationship was shown to exist between the antiaggregation properties of the compounds and their antiradical activity under conditions of the interaction with biosubstrates. The data obtained suggest that the derivatives of 1,4-naphtoquinone with the intramolecular transfer of the charge are promising antiaggregation agents.     

Reactions of isopropyl-alkylamine with 2,3-dichloro-1,4-naphthoquinone and 2,3-dichloro-1,4-naphthoquinone/acetaldehyde

Isopropyl-alkylamines 2 react with 2,3-dichloro-1,4-naphthoquinone (1) to give red 2-chloro-3-isopropyl-alkylamino-1,4-naphthoquinones 3 and with 2,3-dichloro-1,4-naphthoquinone/acetaldehyde to give blue 2-chloro-3-isopropylalkylamino-vinyl-1,4-naphthoquinones 7. It is evident that the formation of 7 is preferred sterically to the formation of 3. The reaction between 2, 1 and acetaldehyde give also red aminoquinones 3 and blue green 2-chloro-3-(4-isopropylalkylamino-buta-1,3-dienyl)-1,4-naphthoquinone like 11.     

The dimerisation of 2-methyl-1,4-naphthoquinone in acid solution

The Dimerisation of 2-Methyl-1,4-naphthoquinone in Acid Solution 2-Methyl-1,4-naphthoquinone 5 heated with conc. hydrochloric acid dimerises to the red 1-methyl-2,7-dihydroxy-dibenzo-[c;h]-10-oxonia-anthracene-chloride 1 . The conditions and the mechanism of the reaction are shown. In alcoholic solutions 1 and the corresponding alkylethers 2 – 4 or 11 are formed. 1 reacts under alkaline conditions to the colourless xanthene derivative 20 or 19 . Acetylation of 1 gives the colourless xanthene derivative 22 .     

The Craven reaction of the 2-methyl-1,4-naphthoquinone

The Craven-Reaction with 2-Methyl-1,4-napthoquinone By the reaction of 2-methyl-1,4-naphthoquinone with ethyl cyanoacetate and sodium ethylate in ehtanol abs. the blue anion VIc of 2-methyl-3(cyano-carboxyethyl-methyl)-naphtoquinone(1,4) results. Malodinitrile, benzyl cyranide, diethyl malonate, ehtyl acetoacetate, acetylacetone, dimedone and 1,3-indandione give the analogous colour products. The selectivity of the Cravenreaction was investigated and a mechanism is proposed.     

Evidence for redox cycling of lawsone (2-hydroxy-1,4-naphthoquinone) in the presence of the hypoxanthine/xanthine oxidase system

This study reports that lawsone (2-hydroxy-1,4-naphthoquinone) undergoes redox cycling in the presence of the hypoxanthine/xanthine oxidase system. The rate of cytochrome c reduction obtained in the presence of 80 microM lawsone was almost three times the rate of cytochrome c reduction measured in its absence. This increase in the rate of cytochrome c reduction was partially inhibited by superoxide dismutase, suggesting the involvement of O(2)(.-) in this process. It is remarkable to note that, even though lawsone is considered to be a non-redox-cycling quinone in vitro, this quinone was shown to be more toxic in vivo in rats than menadione, causing haemolytic anemia of an oxidative nature and renal damage. The view that this quinone is a non-redox-cycling quinone was based on the inability of one-electron-transferring flavoenzymes such as NADPH-cytochrome c reductase to reduce this naphthoquinone. Our finding that lawsone, like menadione, undergoes redox cycling in the presence of the hypoxanthine/xanthine oxidase system could explain the observed oxidative damage of tissues inflicted by this quinone in rats in vivo. Such an observation therefore reconciles the in vivo toxicity results of this naphthoquinone with those of in vitro experiments.     

One-electron reduction of 2- and 6-methyl-1,4-naphthoquinone bioreductive alkylating agents

The semiquinones, Q.-, of derivatives of 2- and 6-methyl-1,4-naphthoquinones, some incorporating leaving groups with substituents such as CH2Br or CH2OCONHCH3, have been produced by radiolytic reduction of Q by (CH3)2COH radicals. The absorption spectra and decay kinetics of Q.- were all closely similar to that produced from 2-methyl-1,4-naphthoquinone, with no evidence for unimolecular elimination of a leaving group in the semiquinone form, but immediate loss of leaving group upon two-electron reduction of Q to the hydroquinone. The redox equilibria between Q/Q.- and O2/O2.- were characterized, and reduction potentials of the couples Q/Q.- in water at pH 7.6 were calculated. The implications of these observations for the use of these compounds as bioreductive alkylating agents or as radiosensitizers with potential selective activity toward hypoxic cells are discussed.     

Acute and subacute nephrotoxicity of 2-bromophenol in rats

The present report aims at providing broader information on the acute nephrotoxicity of 2-bromophenol (2-BP) (a bromobenzene (BB) metabolite), due to its action on the kidneys, after repeated administration. Investigations were performed on female rats. Following a single dose, the most pronounced changes involved: concentrations and rates of excretion of proteins in urine, the number of epithelial cells excreted in urine, creatinine and urea clearance and reduced glutathione in renal tissue. Immediate effects could be ascribed to both renal tubules and glomeruli, mirrored in the level of urinary proteins and intensified excretion of renal epithelial cells. Less pronounced changes of the indicator values were noted under repeated dosing of 2-BP. The results obtained in a single exposure study confirm earlier reports on the mild nephrotoxicity of 2-BP following exposure to high doses. However, the transition from single to repeated exposure does not result in enhanced nephrotoxicity.     

Stability of hemoglobin and albumin adducts of naphthalene oxide, 1,2-naphthoquinone, and 1,4-naphthoquinone.

Naphthalene is an important industrial chemical, which has recently been shown to cause tumors of the respiratory tract in rodents. It is thought that one or more reactive metabolites of naphthalene, namely, naphthalene-1,2-oxide (NPO), 1,2-naphthoquinone (1,2-NPQ), and 1,4-naphthoquinone (1,4-NPQ) contribute to the tumorigenicity of this chemical. These electrophiles are all capable of covalent binding to macromolecules including DNA and proteins. The stability of cysteinyl adducts of NPO, 1,2-NPQ, and 1,4-NPQ were investigated in both hemoglobin (Hb) and albumin (Alb) of male F344 rats following a single administration of 2 different doses (400 or 800 mg naphthalene per kg body weight). To assess the stability of Alb adducts, we compared the rates of NPO-Alb turnover (half-life of approximately 2 days) and 1,2-NPQ-Alb (half-life of approximately 1 day) to the normal turnover rate of Alb in the rat (half-life = 2.5-3 days). Based on the rapid turnover of these adducts relative to Alb itself, we concluded that they were unstable. However, the stability of Alb adducts was not affected by the dose of naphthalene administered (400 or 800 mg/kg). In contrast, NPO-Hb adducts were relatively stable (rate constant of adduct instability 相似文献   

凤仙花的指纹图谱研究及2种1,4-萘醌成分的含量测定

目的建立凤仙花的HPLC指纹图谱,为凤仙花的质量控制提供可靠方法;对不同产地凤仙花中的指甲花醌(HNQ)和指甲花甲醚(MeONQ)进行含量测定。方法采用Agilent TC-C18(2)色谱柱(250mm×4.6mm,5μm);乙腈(A)-10mL·L~(-1)乙酸(B)为流动相;流速为1.0mL·min~(-1);梯度洗脱;柱温:30℃;检测波长:280nm。结果方法学验证结果显示,指甲花醌和指甲花甲醚质量浓度分别在0.004~0.400(r=0.999 3)和0.008~0.800mg·mL~(-1)(r=0.999 6)范围内线性关系良好;其平均加样回收率分别为98.56%和102.75%;RSD值分别为1.92%和1.96%(n=6)。建立了凤仙花HPLC的指纹图谱共有模式,标定10个共有峰,10批样品指纹图谱相似度在0.837~0.957范围内。将指甲花醌和指甲花甲醚作为主要特征成分进行含量测定,结果显示,不同产地10批凤仙花中指甲花醌和指甲花甲醚的含量范围分别为0.011 3~0.738 6和1.784 9~5.881 3mg·g-1,其中以北京市自种凤仙花的指甲花醌和指甲花甲醚含量最高。结论该测定方法简便、准确、重复性好。不同产地凤仙花的指纹图谱相似度和共有峰相对峰面积差异较大,主要特征成分含量也相差悬殊,说明药材质量优劣与产地有很大关系。     

Inhibition of the arachidonic acid cascade by aza-2-aryl-1,4-naphthoquinone derivatives

Inhibition of the arachidonic acid cascade by aza-2-aryl-1,4-naphthoquinone derivatives To find more potent 5-lipoxygenase(LO)-inhibitors than the up to now studied 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-hydroxy-1,4-naphthoquinone derivatives the analogous aza-1,4-naphthoquinones 14, 15, 16/17 as well as the 3-bromo precursors 7, 8, 9/10 and 11 were synthesized. The naphtho[2,1-b][1,4]thiazin derivative 21 was included in this investigation as a quinone imine. Beside 5-LO inhibition the influence on 12-LO, COX-1 and cPLA2 was determined to investigate the selectivity of the compounds within the arachidonic acid cascade. To test the biochemical properties human granulocytes (5-LO) and human platelets (12-LO/COX-1 and cPLA2) were used. All 3-bromo compounds inhibit completely the arachidonic acid cascade by blocking the cPLA2. The 3-methoxy derivatives of the quinoline quinones 12 and 13 and the 3-hydroxyisoquinoline mixture 16/17 show 5-LO selectivity. 13 inhibits 5-LO selectively, 12 is a dual 5-LO/COX-1-inhibitor and 16/17 are dual 12-LO/COX-1-inhibitors. To verify the hypothesis that the hydroxylated 2-aryl-1,4-benzoquinone structure is the pharmacophore for 5-LO-inhibition within the class of 2-aryl-1,4-naphtho- and -aza-naphthoquinones the 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,4-benzoquinones 24-28 were synthesized. It was shown that the 5-methoxy and 5-hydroxy compounds 24 and 27 are highly selective and potent 5-LO-inhibitors.     

Involvement of reversible binding to alpha 2u-globulin in 1,4-dichlorobenzene-induced nephrotoxicity

Similarly to unleaded gasoline, 1,4-dichlorobenzene (1,4-DCB) administered for 2 years caused a dose-related increase in the incidence of renal tumors in male but not in female rats or in either sex of mice. Unleaded gasoline and 2,2,4-trimethylpentane (TMP), a component of unleaded gasoline, increased protein droplet formation and cell proliferation in male but not in female rat kidneys. These protein droplets contained, alpha 2u-globulin, a male rat-specific low-molecular-weight protein and 2,4,4-trimethyl-2-pentanol, a metabolite of TMP that was reversibly bound to this protein. Studies were undertaken to determine if 1,4-DCB produced similar effects; 1,2-DCB was used for comparison since it did not produce renal carcinogenesis in male rats. Gel filtration chromatography of a 116,000g supernatant prepared from kidneys of 1,4-[14C]DCB-treated rats showed that radiolabel coeluted with alpha 2u-globulin as one sharp peak as opposed to a multipeak pattern observed for 1,2-[14C]DCB; the maximal quantity of radiolabel for 1,4-DCB was twice that for 1,2-DCB. Equilibrium dialysis of kidney cytosol in the presence or absence of sodium dodecyl sulfate demonstrated that the radiolabel was reversibly bound to alpha 2u-globulin; the amount for 1,4-[14C]DCB-treated rats was almost twice as much as that for 1,2-[14C]DCB-treated rats. 1,2-DCB was also shown to be covalently bound to renal alpha 2u-globulin, and covalently bound to liver and plasma high-molecular-weight proteins. 1,4-DCB and, to a minor extent, 2,5-dichlorophenol, the major metabolite of 1,4-DCB, were reversibly bound to renal alpha 2u-globulin from 1,4-DCB-treated rats. 1,4-DCB increased protein droplet formation in male but not in female rat kidneys, whereas equimolar doses of 1,2-DCB showed no effect in either sex. Renal cell proliferation, measured by [3H]thymidine incorporation into renal DNA, was increased after 1,4-DCB but not after 1,2-DCB treatment. Nephrotoxicity and biochemical alterations induced by 1,4-DCB resemble those of unleaded gasoline and suggest that a similar mechanism is involved in the induction of alpha 2u-globulin nephropathy in male rats.