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.     

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   

Reactions between dialkylamine drugs, 2,3-dichloro-1,4-naphthoquinone and acetaldehyde

Dialkylamine drugs desipramine, propanolol, pindolol, alprenolol and metoprolol 4a-e react with 2,3-dichloro-1,4-naphthoquinone (2) and acetaldehyde to give red coloured 2-dialkylamino-3-chloro-1,4-naphthoquinones 5a, b, d, e, blue coloured 2-dialkylamino-vinyl-3-chloro-1,4-naphtho-quinones 1a-e and bluish green coloured 2-dialkylamino-butadienyl-3-chloro-1,4-naphthoquinones 6b-e. The colour products are isolated by column chromatography.     

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.     

Antiplatelet and antithrombotic activities of CP201, a newly synthesized 1,4-naphthoquinone derivative

The antiplatelet and antithrombotic activities of a newly synthesized CP201, 2-(3,5-di-tert-butyl-4-hydroxyl)-3-chloro-1,4-naphthoquinone on human platelet aggregation in vitro and murine pulmonary thrombosis in vivo were examined. In addition, the antiplatelet activity of CP201 involved in calcium-signaling cascade was also investigated. CP201 showed concentration-dependent inhibitory effects on platelet aggregation induced by collagen and thrombin, with IC50 values of 4.1+/-0.3 and 4.6+/-0.4 microM, respectively. Orally administered CP201 protected mice against the collagen plus epinephrine-induced thromboembolic death in a dose-dependent manner. On the other hand, CP201 did not alter such coagulation parameters as activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) in human plasma in vitro. These results suggest that the antithrombotic activity of CP201 may be due to antiplatelet rather than anticoagulation activity. CP201 potently inhibited platelet aggregation challenged by calcium ionophore A23187 and thapsigargin, which is a selective inhibitor of the Ca(2+)-ATPase pump, in a concentration-dependent manner, indicating that CP201 may have an inhibitory effect on calcium-signaling cascade. This was supported by measuring [Ca2+]i in platelets loaded with fura-3AM, where CP201 inhibited the rise in cytosolic Ca2+ mediated by thrombin. Taken together, these results suggest that CP201 may be a promising antithrombotic agent, and the antithrombotic effect of CP201 may be due to antiplatelet activity, which was mediated, at least partly, by the inhibition of cytosolic calcium mobilization.     

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.     

Haemolytic activity and nephrotoxicity of 2-hydroxy-1,4-naphthoquinone in rats

The short-term toxicity of 2-hydroxy-1,4-naphthoquinone (lawsone) and 2-methyl-1,4-naphthoquinone (menadione) has been compared in rats. 2-Methyl-1,4-naphthoquinone has been shown previously to cause haemolytic anaemia in animals, and this was confirmed in the present experiment. 2-Hydroxyl-1,4-naphthoquinone was found also to cause haemolysis, in a dose-dependent manner, as reflected by decreased blood packed cell volumes and haemoglobin levels and by histopathological changes in spleen, liver and kidney. With both naphthoquinones, the haemolysis was of the oxidative type, characterized by the presence of Heinz bodies within erythrocytes. Haemolysis was the only toxic change identified in rats dosed with 2-methyl-1,4-naphthoquinone. In contrast, 2-hydroxyl-1,4-naphthoquinone was not only a haemolytic agent but also a nephrotoxin, causing renal enlargement, elevated plasma levels of urea and creatinine and histologically-identified tubular necrosis, largely confined to the distal segment of the proximal convoluted tubules. The relationship between the in vivo toxic effects of these naphthoquinones and previously-reported data on their in vitro cytotoxic action is discussed.     

Antitrypanosomal activities and cytotoxicity of some novel imidosubstituted 1,4-naphthoquinone derivatives

The antitrypanosomal activities, cytotoxicity, and selectivity indices of eleven imido-substituted 1,4-naphthoquinone derivatives and nifurtimox have been studied. Compared to nifurtimox (IC₅₀ = 10.67 μM), all the imido-naphthoquinone analogs (IMDNQ1-IMDNQ11) are more potent on Trypanosoma cruzi with IC50 values ranging from 0.7 μM to 6.1 μM (p < 0.05). Studies of the cytotoxic activities of these compounds on a Balb/C 3T3 mouse fibroblast cell line revealed that four of these compounds, IMDNQ1, IMDNQ2, IMDNQ3, and IMDNQ10 displayed selectivity indices of 60.25, 53.97, 31.83, and 275.3, respectively, rendering them significantly (p < 0.05) more selective in inhibiting the parasite growth than nifurtimox (selectivity index = 10.86).     

Synthesis of novel 1,4-naphthoquinone derivatives: antibacterial and antifungal agents

A novel series of substituted 1,4-naphthoquinone derivatives was synthesized and evaluated for antibacterial and antifungal activity. The structures of the novel products were characterized by spectroscopic methods. Among the tested compounds, 3a and 9 are the most effective compounds against M. luteum as potent antibacterial and C. tenuis and A. niger as potent antifungal. These two compounds are promising as biologically active compounds.     

Effects of 1,4-naphthoquinone derivatives on red blood cell metabolism

The effect on red blood cell metabolism of a series of substituted 1,4-naphthoquinones has been investigated. 2-Methoxy-1,4-naphthoquinone was found to be a potent oxidative compound, generating hydrogen peroxide in erythrocytes and causing both methemoglobin formation and glutathione depletion in the absence of glucose. Flux of glucose through both glycolysis and the hexose monophosphate shunt was stimulated. 2-Hydroxy- and 2,3-dihydroxy-1,4-naphthoquinone were less oxidative. Both compounds caused oxidation of glutathione and formation of hydrogen peroxide with corresponding stimulation of the hexose monophosphate shunt, but did not cause methemoglobin formation. 2-Hydroxy-3-alkyl-1,4-naphthoquinones were not oxidative but did increase the flux of glucose through glycolysis, possibly reflecting membranal damage. The in vitro oxidative effects of these substances do not correlate with their hemolytic activity in rats, indicating that factors other than oxidative damage are important in mediating the in vivo toxicity of these substances.     

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 .     

Potent inhibition of serum-stimulated responses in vascular smooth muscle cell proliferation by 2-chloro-3-(4-hexylphenyl)-amino-1,4-naphthoquinone, a newly synthesized 1,4-naphthoquinone derivative

Atherosclerosis, a disease of the large arteries, is the primary cause of heart disease and stroke. The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial walls is an important pathogenetic factor of vascular disorders like atherosclerosis and restenosis after angioplasty. In the present study, the possible anti-proliferative effect of a synthetic 1,4-naphthoquinone derivative, 2-chloro-3-(4-hexylphenyl)-amino-1,4-naphthoquinone (NQ304) was investigated on rat aortic VSMCs. NQ304 was shown to potently inhibit 5% fetal bovine serum (FBS)-induced the growth of VSMCs. Pre-treatment of VSMCs with NQ304 (1-10 microM) for 24 h resulted in significant cell number decreases, i.e., inhibition percentages were 44.75+/-10.77, 73.85+/-6.38 and 89.77+/-6.52% at NQ304 concentrations of 1, 5 and 10 microM, respectively. NQ304 was also found to significantly inhibit 5% FBS-induced DNA synthesis in a concentration-dependent manner. Furthermore, NQ304 elevated p21(cip1) and p27(kip1) mRNA levels and caused G0/G1 phase arrest in cell cycle progression. However, no evidence of NQ304-induced apoptotic or necrotic cell death was obtained, as determined by flow cytometry analysis and DNA fragmentation assays. To investigate the mechanism underlying the anti-proliferative effect of NQ304, we examined the effects of NQ304 on c-fos mRNA expression, activator protein-1 (AP-1) binding activity and extracellular signal-regulated kinase1/2 (ERK1/2) and Akt activation. Pre-treatment of VSMCs with NQ304 (1-10 microM) was found to significantly inhibit the 5% FBS-induced phosphorylations of ERK1/2 and Akt, the activation of AP-1 and the expression of c-fos. These data suggest that the anti-proliferative and cell cycle arresting effects of NQ304 on serum-induced VSMCs may be mediated by AP-1 activation downregulation via the suppression of phosphatidylinositol 3-kinase (PI3K)/Akt and ERK1/2 signaling pathways, and it may contribute to the prevention of atherosclerosis through inhibition of VSMC proliferation.     

Pharmacological and biological evaluation of a series of substituted 1,4-naphthoquinone bioreductive drugs

The indolequinone compound EO9 has good pharmacodynamic properties in terms of bioreductive activation and selectivity for either NAD(P)H:quinone oxidoreductase-1 (NQO1)-rich aerobic or NQO1-deficient hypoxic cells. However, its pharmacokinetic properties are poor and this fact is believed to be a major reason for EO9's lack of clinical efficacy. The purpose of this study was to develop quinone-based bioreductive drugs that retained EO9's good properties, in terms of bioreductive activation, but have improved pharmacokinetic properties. Out of 11 naphthoquinone compounds evaluated, 2-aziridinyl-5-hydroxy-1,4-naphthoquinone (compound 2), 2,3-bis(aziridinyl)-5-hydroxy-1,4-naphthoquinone (compound 3), and 2-aziridinyl-6-hydroxymethyl-1,4-naphthoquinone (compound 11) were selected for further evaluation based on good substrate specificity for NQO1 and selectivity towards NQO1-rich cells in vitro. Compound 3 was of particular interest as it also demonstrated selectivity for NQO1-rich cells under hypoxic conditions. Compound 3 was not metabolised by murine whole blood in vitro (in contrast to compounds 2, 11 and EO9) and pharmacokinetic studies in non-tumour-bearing mice in vivo (at the maximum soluble dose of 60 mg kg(-1) administered intraperitoneally) demonstrated significant improvements in plasma half-life (16.2 min) and AUC values (22.5 microM h) compared to EO9 (T(1/2) = 1.8 min, AUC = 0.184 microM h). Compound 3 also demonstrated significant anti-tumour activity against H460 and HCT-116 human tumour xenografts in vivo, whereas EO9 was inactive against these tumours. In conclusion, compound 3 is a promising lead compound that may target both aerobic and hypoxic fractions of NQO1-rich tumours and further studies to elucidate its mechanism of action and improve solubility are warranted.