Urine samples from melanoma patients treated with mequinol were analyzed and various mequinol metabolites were identified, including 3,4-dihydroxyanisole, the two o-methyl derivatives 3-hydroxy-4-methoxyanisole and 4-hydroxy-3-methoxyanisole, and even hydroquinone which may have originated at least partly from mequinol. All these identified metabolites were excreted predominantly as sulphates and glucuronides - only a small portion of the substances were present in urine in an unconjugated form. Ultimately, the 3,4-dihydroxyanisole is considered the most important metabolite of mequinol.
A tyrosinase-directed therapeutic approach for treating malignant melanoma uses depigmenting phenolic prodrugs such as 4-hydroxyanisole (4-HA) for oxidation by melanoma tyrosinase to form cytotoxic o-quinones. However, in a recent clinical trial, both renal and hepatic toxicity were reported as side effects of 4-HA therapy. In the following, 4-HA (200 mg/kg i.p.) administered to mice caused a 7-fold increase in plasma transaminase toxicity, an indication of liver toxicity. Furthermore, 4-HA induced-cytotoxicity toward isolated hepatocytes was preceded by glutathione (GSH) depletion, which was prevented by cytochrome p450 inhibitors that also partly prevented cytotoxicity. The 4-HA metabolite formed by NADPH/microsomes and GSH was identified as a hydroquinone mono-glutathione conjugate. GSH-depleted hepatocytes were much more prone to cytotoxicity induced by 4-HA or its reactive metabolite hydroquinone (HQ). Dicumarol (an NAD(P)H/quinone oxidoreductase inhibitor) also potentiated 4-HA- or HQ-induced toxicity whereas sorbitol, an NADH-generating nutrient, prevented the cytotoxicity. Ethylenediamine (an o-quinone trap) did not prevent 4-HA-induced cytotoxicity, which suggests that the cytotoxicity was not caused by o-quinone as a result of 4-HA ring hydroxylation. Deferoxamine and the antioxidant pyrogallol/4-hydroxy-2,2,6,6-tetramethylpiperidene-1-oxyl (TEMPOL) did not prevent 4-HA-induced cytotoxicity, therefore excluding oxidative stress as a cytotoxic mechanism for 4-HA. A negligible amount of formaldehyde was formed when 4-HA was incubated with rat microsomal/NADPH. These results suggest that the 4-HA cytotoxic mechanism involves alkylation of cellular proteins by 4-HA epoxide or p-quinone rather than involving oxidative stress.
Many of the well-known depigmenting agents such as hydroquinone and 4-hydroxyanisole are, in fact, melanocytotoxic chemicals which are oxidized in melanocytes to produce highly toxic compounds such as quinones. These cytotoxic compounds are responsible for the destruction of pigment cells, which results in skin depigmentation. However, cells are capable of protecting themselves against cytotoxic agents by intracellular glutathione (GSH). This protection takes place under the enzymatic action of the detoxification enzyme glutathione S-transferase (GST), which is responsible for the conjugation of toxic species to GSH. The depigmenting effect of hydroquinone is shown to be potentiated by buthionine sulfoximine (BSO) and cystamine as the result of the reduction of intracellular levels of GSH by these two agents. Additionally, BSO and cystamine are shown to inhibit the activity of GST. The combination of all-trans-retinoic acid (tretinoin, TRA) with hydroquinone or 4-hydroxyanisole is also known to produce synergetic skin depigmentation. TRA serves as a potent inhibitor of mammalian GSTs and is known to make cells more susceptible to the cytotoxic effect of chemicals by inhibiting the activity of this enzyme. This agent is also shown to reduce the level of intracellular GSH in certain cells. We have proposed that the mechanism of action of TRA to synergistically enhance the melanocytotoxic effect of chemicals involves the inhibition of GST and the impairment of glutathione-dependent cytoprotection against melanocytotoxic agents.
IDENTIFICATION AND USE: 4-Methoxyphenol (4-MP) is available as a colorless to white, waxy solid or white to tan, flaky, crystalline substance with the odor of caramel and phenol. It is used as an inhibitor for acrylic monomers and acrylonitirles, as a stabilizer for chlorinated hydrocarbons and ethyl cellulose, as an ultraviolet inhibitor, as a chemical intermediate in the manufacture of antioxidants, pharmaceuticals, plasticizers, and dyestuffs. It is also used as a medication for dyschromias, especially hyperpigmentation often in combination with Tretinoin (Solage). HUMAN EXPOSURE AND TOXICITY: In 11 of the 16 patients (69%; 95% confidence interval [CI], 41%-89%) total depigmentation was achieved using the 4-MP cream. Onset of depigmentation was between 4 and 12 months. Mild burning or itching was reported with the cream in 4 cases (25%). Of the 11 patients who responded to the 4-MP cream, 4 had recurrence of pigmentation (relapse rate of 36%; 95% CI, 11%-69%) after a treatment-free period of 2 to 36 months. Excessive application of 4-MP, can result in marked redness, peeling, discomfort, or hypopigmentation. Oral ingestion of the drug may lead to the same adverse effects as those associated with excessive oral intake of vitamin A (hypervitaminosis A). In a vinylidene chloride plant 2 out of 8 process workers handling hydroquinone monomethyl ether developed depigmentation (occupational leukoderma) of skin of forearms and in 1 of them depigmentation of skin of forehead. Report of the follow-up of 2 cases of leukodermia (vitiligo) following exposure to 4-MP described 8 years previously and survey of 169 men exposed to 4-MP or paratertiary-amyl-phenol or both revealed that repigmentation of a significant degree was found in one man and of a limited degree in the other. Screening by means of the Wood's light technique (an ultra-violet light which is absorbed by normally pigmented skin and reflected by non-pigmented skin) of the 169 men surveyed in the same plant revealed no cases of leukoderma attributed to exposure to 4-MP in 148 men tested or in the 129 men exposed to paratertiary-amyl-phenol. In regards to possible genotoxicity, results from cytogenetic analysis show that the salt of 4-MP (p-methoxyphenol phosphate) induced the decrease of numerical and structural chromosome aberration after the first passage of the treated cells. In terms of the results obtained by cytogenetic analysis the reduction of genetic instability seems to remain constant from the first to the sixth passage in the cell cultures treated with p-methoxyphenol phosphate associated to benzo(a)pyrene. ANIMAL STUDIES: Rabbit studies with 4-MP have shown that it can cause considerable necrosis if exposure is not limited to 1 day. Prolonged contact can cause a severe burn. There is also indication that the material is absorbed in toxic amounts when in solution, especially through abraded skin. Acute parenteral poisoning in rabbits included paralysis and anoxia at lower doses and CNS depression at high doses. 4-MP caused depigmentation of the skin when applied topically to guinea pigs (within 5 to 10 days of treatment) and miniature pigs. In a dermal teratology study in rabbits, there were no statistically significant differences in fetal malformation data; however marked hydrocephaly with visible doming of the head was observed in one mid-dose litter (12 and 0.06 mg/kg or 132 and 0.66 mg/sq m of 4-MP and tretinoin, respectively. 4-MP does not appear to be carcinogenic when applied topically. In studies with 5% or 10% 4-MP (0.02 mL) twice a week between the shoulder blades of mice (for 93 weeks) or interior ears of rabbits, there was no significant decrease in survival rates, or tumor incidence compared to controls. Tumors were evident when 4-MP was administered in the diet of F344 rats (30 male and 30 females) administered diets of 2% 4-MP for 104 weeks. Histopathological findings in the 4-MP case included atypical hyperplasias (male, 67%, female, 37%), papillomas (50%, 23%) and squamous-cell carcinomas (77%, 20%) in the forestomach. 4-MC induced forestomach papillomas (70%, 93%) and squamous-cell carcinomas (53%, 37%), also glandular stomach submucosal hyperplasias (90%, 93%), adenomas (100%, 100%) and adenocarcinomas (57%, 47%), with ulceration or erosion. No genotoxic effects were observed when 4-MP was tested in Salmonella typhimurium TA98, TA100, TA1535, and TA1537 or in rats exposed dermally for 6 months.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
暴露途径
该物质可以通过摄入被身体吸收。
The substance can be absorbed into the body by ingestion.
来源:ILO-WHO International Chemical Safety Cards (ICSCs)
The systemic exposure to mequinol was assessed in eight healthy subjects following two weeks of twice-daily topical treatment of a tretinoin and mequinol combination product. About dose of the product corresponding to about 37.3 ug/cm^2 of mequinol was applied to the subjects' backs. The mean Cmax for mequinol was 9.92 ng/mL (range between 4.22 and 23.62 ng/mL) and the Tmax was 2 hours (range between 1 to 2 hours). The safety of mequinol in this combination formulation is supported by the low systemic exposures of the agent in the subjects.
来源:DrugBank
吸收、分配和排泄
消除途径
Mequinol主要以其代谢物形式通过肾脏排出。
Mequinol is predominantly renally eliminated as its metabolites.
The volume of distribution is one that suggests mequinol is distributed throughout the total body water, and intracellular concentrations are not expected to vary greatly from gross measurements.
来源:DrugBank
吸收、分配和排泄
清除
关于米奎酸的清除数据并不容易获得。含有米奎酸的产品通常指示为局部使用。
Readily accessible data regarding the clearance of mequinol is not available. The use of mequinol containing products is typically indicated for topical use.
Solage is a combination product composed of 2% mequinol (4-hydroxyanisole) and 0.01% tretinoin (all-trans-retinoic acid) in an ethanolic solution ... The purpose of this study was to evaluate the extent of percutaneous absorption of [(3)H]tretinoin and to estimate the systemic exposure to mequinol from this combination product when topically applied to the backs of healthy subjects. Eight subjects received bid /twice per day/ topical applications of nonradiolabelled 2% mequinol/0.01% tretinoin solution on a 400 sq cm area of the back for 14 days. The subjects then received a single topical application of 2% mequinol/0.01% ((3)H)tretinoin solution. After 12 hr, the radiolabelled dose was removed and bid /twice per day/ treatment with nonradiolabelled 2% mequinol/0.01% tretinoin solution was continued for 7 days. Plasma, urine and faecal samples were analysed for total radioactivity and plasma was analysed for both mequinol and tretinoin by GC/MS procedure. Mean percutaneous absorption of [(3)H]tretinoin based on the cumulative recoveries of radioactivity in the urine and faeces was about 4.5% (median 2.18%). Tretinoin concentrations in plasma did not increase above endogenous levels. This was consistent with the concentrations of radioactivity in plasma, which showed an average Cmax of 91 pg-eq/mL (median 26 ng/mL). Average Cmax and AUC(0-12 hr) values for mequinol were 10 ng/mL and 33 ng h/mL, respectively. Based on the results of this study, systemic toxicity from topical application of tretinoin in this formulation is unlikely, because percutaneous absorption of tretinoin is minimal and because endogenous levels of tretinoin are not increased following bid /twice per day/ dosing with this combination formulation. The safety of mequinol in this combination formulation is supported by the low systemic exposures of the subjects in this study compared with the systemic exposures at the highest doses in the dermal toxicity studies in mice (16.6-fold) and rats (34.6-fold).
1.周国泰，化学危险品安全技术全书，化学工业出版社，1997 2.国家环保局有毒化学品管理办公室、北京化工研究院合编，化学品毒性法规环境数据手册，中国环境科学出版社.1992 3.Canadian Centre for Occupational Health and Safety,CHEMINFO Database.1998 4.Canadian Centre for Occupational Health and Safety, RTECS Database, 1989
A series of new hypervalentiodinereagents based on the 1,3‐dihydro‐3,3‐dimethyl‐1,2‐benziodoxole and 1,2‐benziodoxol‐3‐(1H)‐one scaffolds, which contain a functionalized tetrafluoroethyl group, have been prepared, characterized, and used in synthetic applications. Their corresponding electrophilic fluoroalkylation reactions with various sulfur, oxygen, phosphorus, and carbon‐centered nucleophiles
[EN] HYPERVALENT IODINE CF2CF2X REAGENTS AND THEIR USE<br/>[FR] RÉACTIFS CF2CF2X À BASE D'IODE HYPERVALENT ET LEUR UTILISATION
申请人：ETH ZUERICH
公开号：WO2016019475A1
公开（公告）日：2016-02-11
A hypervalent iodine of formula (I) or formula (II) wherein R is a nucleophile and a method for their production is described. Such compounds can be used for fluoroethylation of compounds carrying a reactive group. A preferred compound carrying a reactive group is cystein in any environment such as peptide targets.
Nitrosonium ion catalysis: aerobic, metal-free cross-dehydrogenative carbon–heteroatom bond formation
作者：Luis Bering、Laura D’Ottavio、Giedre Sirvinskaite、Andrey P. Antonchick
DOI：10.1039/c8cc08328b
日期：——
coupling of heteroarenes with thiophenols and phenothiazines has been developed under mild and environmentally benign reaction conditions. For the first time, NOx+ was applied for catalytic C–S and C–N bond formation. A comprehensive scope for the C–H/S–H and C–H/N–H cross-dehydrogenative coupling was demonstrated with >60 examples. The sustainable cross-coupling conditions utilize ambient oxygen as the
杂芳烃与硫酚和吩噻嗪的催化交叉脱氢偶联已在温和且环境友好的反应条件下得到发展。首次将NO x +用于催化C–S和C–N键的形成。用60多个例子证明了C–H / S–H和C–H / N–H交叉脱氢偶联的综合范围。可持续的交叉偶联条件利用环境氧作为末端氧化剂，而水是唯一的副产物。
Synthesis and characterizations of novel thiazolyl-thiadiazole derivatives as telomerase activators
Pyridine-3/4-thiocarboxamide derivatives were used as starting materials for the synthesis of the target compounds. The pyridine-3/4-thiocarboxamide derivatives were reacted with ethyl 2-chloroacetoacetate in ethanol to give the thiazole derivatives (1, 2). The two ethyl thiazole-carboxylate derivatives (1, 2) thus obtained were treated with sodium hydroxide solution and ethanol and converted to carboxylic acids (3, 4). The carboxylic acid derivatives (3, 4) were reacted with thiosemicarbazide in phosphoroxy trichloride and aminothiadiazole rings (5, 6) were formed. Thus, two thiazolyl-thiadiazole amine derivatives (5, 6) were obtained. These two derivatives (5, 6) were converted into two chloroacetamidothiadiazole derivatives (7, 8) by reaction with chloroacetylchloride over the amino group in the presence of triethylamine in acetone. After all these steps, the starting materials (7, 8) needed to reach the target compounds were obtained. With the two derivatives (7, 8) obtained in this last step, phenol and thiophenol derivatives were reacted in acetone in the presence of potassium carbonate. The target compounds, thiazolyl-thiadiazole derivatives (TDA$_\mathbf1-16}})$, are completely unique and their structure has been elucidated by elemental analysis, IR, NMR, and MS spectral data. After all these synthesis steps, telomerase activity studies were performed on the target compounds obtained. For this purpose, a PCR ELISA-based TRAP method was used on the heart of zebrafish. According to the enzyme assay results, derivative TDA$_\mathbf8}}$ has shown an increase of telomerase enzyme activity.
