Male F344 rats (five per group, 6-week-old) were given 5% Sodium Erythorbate in feed for 22 weeks. The rats eliminated totals of 203.3 +/- 33.2 mg/100 mL erythorbic acid and 9.0 +/- 5.1 mg/100 mL dehydroerythorbic acid during the study. Ascorbic acid and dehydroascorbic acid were not detected.
Effects of 17 environmental chemicals on urinary bladder carcinogenesis were investigated in rats. Male F-344-rats were given orally 0.05 percent N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN). Rats were fed diets containing 5 percent sodium-saccharin, 2 percent sodium-o-phenylphenate (SOPP), 2 percent butylated-hydroxyanisole (BHA), 5 percent sodium-L-ascorbate (SA), 5 percent ascorbic-acid, 5 percent ascorbic-stearate, 5 percent sodium-erythorbate (SE), 0.8 percent ethoxyquin, 0.02 percent N-nitrosopyrrolidine, 0.2 percent methylhydroquinone, 0.2 percent hydroquinone, 0.2 percent resorcinol, 0.8 percent catechol, 0.5 percent pyrogallol, 0.6 percent carbazole, 0.1 percent quinoline, or 1 percent uric-acid. The left ureter was ligated on day 22. Animals were killed after week 24 and autopsied. Urinary bladder, both kidneys, ureter, and liver were stained for light microscopy examination. No cancer was induced in any rat. Papillary or nodular (PN) hyperplasia was induced by BBN in 7 percent of controls. PN hyperplasia incidences and quantitative values were significantly higher in BBN treated rats fed sodium-saccharin, SOPP, BHA, SA, SE, ethoxyquin, and carbazole. Significant differences in incidences and quantitative values of papillomas were observed in BBN treated rats fed sodium-saccharin, SOPP, BHA, SA, and N-nitrosopyrrolidine. Histopathological changes were found in the left kidney, and dilation in the left pelvic space and ureter were common. No changes were found in the right kidney, ureter, or liver. The authors conclude that the ureter ligation system seems to be suitable as a short term method for the screening of bladder carcinogens and promoters.
Studies were made on the carcinogenic activity of butylated hydroxyanisole (BHA) in rats, mice, and hamsters and the effect of the antioxidants BHA, butylated hydroxytoluene (BHT), ethoxyquin (EQ), sodium L-ascorbate (SA), ascorbic acid (AA), sodium erythorbate (SE), propyl gallate (PG), and alpha-tocopherol, on two-stage chemical carcinogenesis in rats initiated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), 1,2-dimethylhydrazine (DMH), diethylnitrosamine (DEN), 7,12-dimethylbenz(a)anthracene (DMBA), N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), N-ethyl-N-hydroxyethylnitrosamine (EHEN), or N-methylnitrosourea (MNU). BHA clearly induced squamous cell carcinomas in both the rat and hamster forestomach. The tumorigenic action of crude BHA on the forestomach is largely due to 3-tert-BHA. In two-stage chemical carcinogenesis, BHA promoted MNNG or MNU-initiated forestomach and BBN- or MNU-initiated urinary bladder carcinogenesis and inhibited DEN- or EHEN-initiated liver and DMBA-initiated mammary carcinogenesis. BHT demonstrated promotion potential for urinary bladder and MNU-initiated thyroid carcinogenesis and inhibited DMBA-initiated ear duct carcinogenesis. EQ promoted EHEN-initiated kidney carcinogenesis and inhibited DMBA-initiated mammary and EHEN-initiated liver carcinogenesis. SA promoted forestomach and urinary bladder carcinogenesis and SE likewise enhanced urinary bladder carcinogenesis. alpha-Tocopherol inhibited ear duct carcinogenesis. No effects of any of the antioxidants on glandular stomach carcinogenesis were found. The results clearly demonstrated that antioxidants have different effects (promoting or inhibitory influences) depending on the organ studied and suggest the importance of a whole body approach to their investigation.
Studies were conducted on the carcinogenic activity of butylated hydroxyanisole (BHA) in rats and hamsters. To obtain information concerning the mechanism of action of BHA on the forestomach, the following areas were examined: the effects of 12 phenolic compounds structurally related to BHA on the hamster forestomach, the effects of combinations of BHA and other antioxidants on the rat forestomach, and the metabolism of BHA in the forestomach. Also examined were the effects of several antioxidants on two-stage carcinogenesis in rats. Squamous-cell carcinomas were induced in the forestomach of rats and hamsters fed BHA. In a limited study, 1 of 13 hamsters developed a squamous-cell carcinoma. The tumorigenic action of crude BHA on the forestomach was largely due to the action of 3-tert-BHA. p-tert-Butylphenol and 2-tert-butyl-4-methylphenol induced pronounced hyperplasia and papillomas in the hamster forestomach. BHA and other antioxidants, particularly propyl gallate and ethoxyquin, showed additive effects in inducing forestomach hyperplasia and cytotoxicity. Neither BHA nor its metabolites were found in the forestomach epithelium, although small amounts of metabolites were detected in the stomach contents. Thus, a direct action on the stomach epithelium may be exerted by BHA itself or by metabolites formed on interaction of BHA with gastric juice. BHA enhanced forestomach carcinogenesis initiated in rats by N-methyl-N'-nitro-N-nitrosoguanidine or N-methylnitrosourea (MNU) and enhanced urinary bladder carcinogenesis initiated by MNU or N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). In contrast, it inhibited carcinogenesis initiated in the liver by either diethylnitrosamine or N-ethyl-N-hydroxyethylnitrosamine (EHEN) and mammary carcinogenesis initiated by 7,12-dimethylbenz[a]anthracene (DMBA). BHT promoted urinary bladder carcinogenesis initiated by BBN or MNU and thyroid carcinogenesis initiated by MNU, but inhibited ear-duct carcinogenesis initiated by DMBA. Ethoxyquin promoted EHEN-initiated kidney carcinogenesis, but inhibited both DMBA-initiated mammary and EHEN-initiated liver carcinogenesis. Sodium ascorbate promoted forestomach and urinary bladder carcinogenesis, and sodium erythorbate also enhanced urinary bladder carcinogenesis. Alpha-tocopherol inhibited ear-duct carcinogenesis. No antioxidants tested had any effect on glandular stomach carcinogenesis. Thus antioxidants have independent modifying (promoting or inhibitory) effects in different organs.
The modifying effects of antioxidants were examined in a carcinogenesis system after N,N-dibutylnitrosamine treatment. Male F344 rats were given 0.05% N,N-dibutylnitrosamine in their drinking water for 4 wk and then treated with basal diet containing 2% butylated hydroxyanisole (BHA), 1% butylated hydroxytoluene (BHT) with 7 ppm vitamin K, 0.8% ethoxyquin, 5% sodium L-ascorbate, 5% sodium erythorbate, or no added chemical for 32 wk. BHA enhanced forestomach carcinogenesis but did not enhance esophageal carcinogenesis. BHT enhanced esophageal carcinogenesis but did not enhance forestomach carcinogenesis. Ethoxyquin significantly enhanced esophageal tumorigenesis. Neither esophageal nor forestomach carcinogenesis was affected by the other antioxidants evaluated. BHA significantly increased DNA synthesis of the forestomach epithelium, whereas BHT tended to increase that of the esophageal epithelium. Thus, BHA and BHT showed different modifying responses in carcinogenesis of the esophagus and forestomach.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
毒性总结
识别和使用：酒石酸氢钠呈白色，自由流动的晶体。它是一种合成抗氧化剂，用于食品和化妆品配方。喷洒和粉尘状的酒石酸氢钠用于控制柑橘树幼树的衰退，并减少臭氧对无籽汤姆逊葡萄的损害。它也用于水力压裂混合物中，以防止金属氧化物（铁控制）的沉淀。人类暴露和毒性：酒石酸氢钠未能在培养的人类胚胎成纤维细胞中引起染色体畸变或姐妹染色单体交换。动物研究：将酒石酸氢钠粉末应用于兔子的完整和磨损皮肤时，并未引起皮肤刺激的迹象。将酒石酸氢钠粉末滴入兔子的结膜囊中，引起了结膜的轻微和暂时性发红，但在24小时内清除。在妊娠期间，通过口服管饲法给予雌性大鼠和小鼠酒石酸氢钠，剂量高达1030毫克/千克/天，并未引起母体或胎儿毒性。在为期13周的致畸研究中，给怀孕大鼠喂食高达5%的酒石酸氢钠，并未发生发育毒性。它在 Ames 测试、使用 S. typhimurium 的宿主介导分析、使用中国仓鼠卵巢成纤维细胞的染色体畸变测试、使用大鼠的显性致死测试以及 B. subtilis rec 测试中均产生了阴性结果。酒石酸氢钠确实在活体大鼠骨髓细胞中引起了染色体畸变。它并未增加 S. cerevisiae D3 在体外的有丝分裂重组频率，也未能诱导雄性小鼠的遗传性易位杂合性。在168天内给大鼠喂食5%的酒石酸氢钠，并未出现如膀胱粘膜增生等形态学改变。在通过饲料给予大鼠最高2.5%的酒石酸氢钠后，并未增强罕见自发性肿瘤的发展或将良性肿瘤转变为癌变。在为期24周的研究中，给大鼠喂食5%的酒石酸氢钠，出现了膀胱上皮细胞的简单增生。在饮用水中添加1.25-2.5%的酒石酸氢钠，在96周的治疗后，并未显著增加小鼠的肿瘤发生率、带肿瘤死亡的时间或肿瘤的分布。它对非腺体和腺体胃、结肠、肝脏、肾脏、乳腺、耳道、甲状腺的第二阶段致癌作用没有修饰效果，但在用 N-丁基-(4-羟基丁基)亚硝胺启动后，增加了膀胱病变的发生率和平均数量。在大鼠服用酒石酸氢钠后，它们以酒石酸和脱氢酒石酸的形式将其排出体外，而未检测到抗坏血酸和脱氢抗坏血酸。生态毒性研究：已经对酒石酸氢钠对淡水鱼虹鳟鱼（Oncorhynchus myldss）的急性毒性进行了研究，并给出了大于100毫克/升的96小时LC50（半静态）。
IDENTIFICATION AND USE: Sodium erythorbate forms white, free-flowing crystals. It is a synthetic antioxidant used in food and cosmetic formulations. Foliar application of sodium erythorbate sprays and dusts are used to control young tree decline in citrus trees and to reduce ozone damage to Thompson seedless grapes. It is also used in hydraulic fracturing mixtures to prevent precipitation of metal oxides (iron control). HUMAN EXPOSURE AND TOXICITY: Sodium erythorbate did not cause chromosomal aberrations or sister chromatid exchanges in cultured human embryo fibroblasts. ANIMAL STUDIES: Sodium erythorbate powder did not cause signs of dermal irritation when applied to the intact and abraded skin of rabbits. Instillation of sodium erythorbate powder to the conjunctival sac of rabbits caused slight and transient reddening of the conjunctiva that cleared within 24 hours. Sodium erythorbate did not cause maternal or fetal toxicity when administered to female rats and mice during gestation by oral intubation at dosages up to 1030 mg/kg/day. Developmental toxicity did not occur after pregnant rats were given up to 5% sodium erythorbate in feed during a 13-week teratogenesis study. It produced negative results in the Ames test, the host-mediated assay using S. typhimurium, chromosomal aberration tests using Chinese hamster ovary fibroblasts, the dominant lethal test using rats, and the B. subtilis rec assay. Sodium erythorbate did cause chromosomal aberrations in rat bone marrow cells in vivo. It did not increase the mitotic recombination frequency of S. cerevisiae D3 in vitro, and did not induce heritable translocation heterozygosity in male mice. Rats given 5% sodium erythorbate in feed for 168 days had no morphological alterations such as hyperplasias of the urinary bladder mucosa. It did not enhance the development of rare spontaneous tumors or transform benign tumors to carcinomas after administration to rats in feed at concentrations up to 2.5%. During a 24-week study, rats given 5% sodium erythorbate in feed had simple hyperplasia of the urinary bladder epithelium. The addition of 1.25-2.5% sodium erythorbate to drinking water did not significantly increase tumor incidence, time to death with tumors, or the distribution of tumors in mice after 96 weeks of treatment. It did not have modifying effects on second-stage carcinogenesis of the nonglandular and glandular stomach, colon, liver, kidneys, mammary gland, ear duct, or thyroid gland, but increased the incidence and average number of lesions of the urinary bladder after initiation with N-butyl-(4-hydroxybutyl)nitrosamine. After administration of sodium erythorbate to rats, they eliminated it in urine as erythorbic acid and dehydroerythorbic acid, whereas ascorbic acid and dehydroascorbic acid were not detected. ECOTOXICITY STUDIES: The acute toxicity of the sodium erythorbate to the freshwater fish rainbow trout (Oncorhynchus myldss) has been investigated and gave a 96-Hour LC50 of greater than 100 mg/L (semi-static).
Male F344 rats (five per group, 6-week-old) were given 5% Sodium Erythorbate in feed for 22 weeks. The rats eliminated totals of 203.3 +/- 33.2 mg/100 mL erythorbic acid and 9.0 +/- 5.1 mg/100 mL dehydroerythorbic acid during the study. Ascorbic acid and dehydroascorbic acid were not detected. Urine pH was 6.98 +/-0.31, which was significantly different from that of rats given basal diet alone (6.31 +/- 0.18; p < 0.05). Urine osmolarity also differed significantly from controls; osmolarity was 1378 +/- 277 mOsmol/kg H20 in rats given Sodium Erythorbate and 1756+/- 200 mOsmol/kg H20 in rats of the control group. Crystals were detected in urine of rats given basal diet and Sodium Erythorbate or basal diet alone.
Studies on scavengers of active oxygen species. 1. Synthesis and biological activity of 2-O-alkylascorbic acids
摘要：
A novel series of 2-O-alkylascorbic acids (5a-u) was synthesized, and their scavenging activities against active oxygen species as well as their suppressive effects on the arrhythmias in rat heart ischemia-reperfusion models were evaluated. Some 2-O-alkylascorbic acids (5e-1) exhibited potent inhibiting activities against lipid peroxidation in rat brain homogenates and in alleviating effects in the ischemia-reperfusion models. Studies on the structure-activity relationship demonstrated that a free 3-enolic hydroxyl group and the longer alkyl chains substituted on the 2-hydroxyl group of ascorbic acid were beneficial for the biological and pharmacological activities. 2-O-Octadecylascorbic acid (5k, CV-3611), one of the most potent and promising compounds, markedly inhibited lipid peroxidation (IC50 = 4.3 X 10(-6) M) and alleviated myocardial lesions induced by ischemia-reperfusion at an oral dose of 1 mg/kg in rats.
The current research focuses on organic and medicinal chemistry, with a specific emphasis on the synthesis of molecules that incorporate diverse heterocycles. As part of this investigation, we have explored the fusion of 2-quinolone with 1,2,3-triazoles. Analytical and spectral data were applied to elucidate the structure of the synthesized compounds. In the preliminary antibacterial studies, analogs 4a, 4f, 6d and 6a were more effective against S. epidermidis corresponding MIC values of 6.32 ± 0.04, 2.38 ± 0.01, 5.18 ± 0.03 and 14.33 ± 0.01 µg/mL, respectively. In addition, compound 4a exhibited outstanding antibacterial activity against strains of Pseudomonas aeruginosa, as evidenced by a remarkable minimum inhibitory concentration (MIC) value of 3.19 ± 0.04 µg/mL. In particular, the synthesized scaffolds 6d, 4f, 4c and 4a showed significant antifungal activity with MIC values of 2.70 ± 0.01, 3.74 ± 0.03, 3.16 ± 0.02 and 4.18 ± 0.03 µg/mL against Candida albicans. The essential binding mode active site interactions in the DNA gyrase complex from Staphylococcus aureus based antibacterial drug candidate with 2XCO protein was also investigated and ligand 4a possesses the highest interacting amino acid residues ArgA:1092, PheA:1266, LysA:1043, AlaA:1172, AlaA:1034, TyrA:1099, HisA:1046, HisA:1046 [O11···NH], GlnA:1267 [O12···NE2], GlyA:1041 [N14···O, 3.22 Å], ThrA:1181 [O1···N]. The resulting scaffolds were assessed for ADMET and physico-chemical characteristics using ADMETlab2.0server, SwissADME web as good drugs with oral bioavailability.
Enantioselective synthesis of loracarbef from sodium erythorbate
作者：Jeffery W. Frazier、Mike A. Staszak、Leland.O. Weigel
DOI：10.1016/s0040-4039(00)91559-4
日期：1992.2
(7) has been converted to (1). Oxidation of sodiumerythorbate to (8) followed by selective monotosylation and treatment with sodium ethoxide provided (10). Swern oxidation of this epoxide into the aldehyde (11), formation with tert-butylglycinate and an reaction with phthalimidoacetyl chloride afforded the (3S,4S)-cis- (13). Appropriate functional group manipulations followed by a condensation, chlorination
An Enantioselective Synthesis of (2<i>S</i>,3<i>R</i>)-3-(<i>N</i>-Benzyloxycarbonyl)amino-1-chloro-4-phenylthiobutan-2-ol, a Central Intermediate of Nelfinavir<sup>1</sup>
(2S,3R)-3-(N-Benzyloxycarbonyl)amino-1-chloro-4-phenylthiobutan-2-ol 1 is a centralintermediate of nelfinavir 2, which, being a potent HIV protease inhibitor, represents one of the most clinically efficacious anti AIDS drugs. Thus, a practical enantioselective synthesis of 1 has been devised which employs sodium erythorbate 9 as a chiral starting material. Consisting of the total 14-step functional
Organoborane compounds are halogenated by reacting an organoborane with iodinemonochloride, brominemono-chloride or a halide salt in the presence of a mild oxidizing agent.
Highly efficient and regioselective production of an erythorbic acid glucoside using cyclodextrin glucanotransferase from Thermoanaerobacter sp. and amyloglucosidase
作者：Akihiro Tai、Yuji Iwaoka、Hideyuki Ito
DOI：10.1016/j.molcatb.2013.03.011
日期：2013.8
In order to continuously supply erythorbic acid (EA) for long-term cell cultures, we synthesized a stable EA derivative, 2-O-alpha-D-glucopyranosyl-D-erythorbic acid (EA-2G), as a useful tool for analyzing the biological function of EA. The specific and efficient production process of EA-2G consisted of two steps: transglycosylation by cyclodextrin glucanotransferase (CGTase) from Thermoanaerobacter sp. and hydrolysis by amyloglucosidase from Aspergillus niger. EA-2G was regioselectively formed by CGTase using EA and gamma-cyclodextrin in pH 4.0 acetate buffer at 40 degrees C for 24h. It seemed that several EA-2-oligoglucosides were also formed in this reaction mixture. Additional hydrolysis at 60 degrees C for 2 h of the reaction mixture by glucoamylase resulted in efficient production of EA-2G. EA-2G was obtained in two steps in 49.1% overall yield from EA. (C) 2013 Elsevier B.V. All rights reserved.
Studies on scavengers of active oxygen species. 1. Synthesis and biological activity of 2-O-alkylascorbic acids
A novel series of 2-O-alkylascorbic acids (5a-u) was synthesized, and their scavenging activities against active oxygen species as well as their suppressive effects on the arrhythmias in rat heart ischemia-reperfusion models were evaluated. Some 2-O-alkylascorbic acids (5e-1) exhibited potent inhibiting activities against lipid peroxidation in rat brain homogenates and in alleviating effects in the ischemia-reperfusion models. Studies on the structure-activity relationship demonstrated that a free 3-enolic hydroxyl group and the longer alkyl chains substituted on the 2-hydroxyl group of ascorbic acid were beneficial for the biological and pharmacological activities. 2-O-Octadecylascorbic acid (5k, CV-3611), one of the most potent and promising compounds, markedly inhibited lipid peroxidation (IC50 = 4.3 X 10(-6) M) and alleviated myocardial lesions induced by ischemia-reperfusion at an oral dose of 1 mg/kg in rats.
