The mechanism by which safrole exerts the weak carcinogenicity that has been demonstrated in rats and mice is considered. Metabolic conversion of the allyl group gives rise to intermediates capable of covalent binding with DNA and protein, and recent findings are compatible with conversion of the methylenedioxy group to a carbene, which forms ligand complexes with the heme moiety of cytochrome P450 and P448.
Following oral or ip administration... to rats and guinea pigs, 3'-N,N-dimethylamino-1'-(3, 4-methylenedioxyphenyl)-1'-propanone was identified as major urinary metabolite in guinea pigs and as minor metabolite in rats. ...Oral or ip administration... to rats... 3'-pyrrolidinyl-1' -(3,4-methylenedioxyphenyl)-1'-propanone, a further minor metabolite, and 3'-piperidyl-1'-(3,4-methylenedioxyphenyl)-1'-propanone were found in urine of rats.
来源:Hazardous Substances Data Bank (HSDB)
代谢
产量4-丙烯基儿茶酚可能在老鼠和家蝇中；3,4-亚甲基二氧苯甲醛可能在蝇中。/来自表格/
Yields 4-allylcatechol probably in mouse and housefly; 3, 4-methylenedioxybenzaldehyde probably in fly. /from table/
Metabolites resulting from incubation of safrole with adrenal homogenates were 1'-hydroxysafrole, 4-allyl-1,2-dihydroxybenzene, 3'-hydroxysafrole, 2',3'-epoxysafrole and 2',3'-dihydro-2',3'-dihydroxysafrole.
IDENTIFICATION AND USE: Safrole is a colorless or pale yellow oil. Safrole is a major chemical constituent of aromatic oil present in sassafras root bark. According to FDA, safrole and safrole-containing products cannot be recognized as being safe for human use. Oil of sassafras containing safrole was formerly used as flavoring agent in soft drinks. Safrole is the main precursor for producing the amphetamine-type stimulant drug, N-methyl-3,4-methylenedioxyamphetamine (MDMA), also known as ecstasy. HUMAN STUDIES: A maximization test (Kligman) was carried out on 25 volunteers. The material was tested at a concentration of 8% in petrolatum and produced no sensitization reactions. Safrole-DNA adducts were detected in in tissue specimens from esophageal cancer patients with a history of habitual areca chewing. Similarly, the presence of safrole-DNA adduct was demonstrated in two out of 28 hepatic tissues from hepatocellular carcinoma patients, and only these two patients had a history of betel quid chewing lasting more than 10 years. Safrole was a potent inhibitor of human CYP1A2, CYP2A6, and CYP2E1. With relatively less potency, CYP2D6 and CYP3A4 were also inhibited. ANIMAL STUDIES: Safrole applied at full strength to intact or abraded rabbit skin for 24 hr under occlusion was moderately irritating. Applied undiluted to the backs of hairless mice, it was not irritating. In a feeding study in dogs, groups of 2 males and 2 females fed 5 or 20 mg safrole/kg/day for 6 years showed liver enlargement, fatty change, minimal focal necrosis, mild post-necrotic cirrhosis, bile duct and Kupffer cell proliferation, hepatic cell atrophy and leucocytic infiltration. Similar liver changes were seen with higher doses of 40 and 80 mg/kg/day given over much shorter periods of 91-116 and 26-39 days, respectively. Dietary administration of safrole caused hepatocellular carcinoma in male mice and benign or malignant liver tumors (hepatocellular carcinoma or adenoma or cholangiocarcinoma) in rats of both sexes. Hepatocellular carcinoma was also observed in mice of both sexes administered safrole by stomach tube from 7 to 28 days of age, followed by dietary exposure for up to 82 weeks, and in infant male mice administered safrole by sc injection. The incidence of liver tumors (adenoma and carcinoma) was increased in male mice exposed during infancy via milk and in adult female mice administered safrole in the diet. Safrole did not increase sister chromatid exchange frequency in cultured Chinese hamster cells. Safrole was mutagenic in Salmonella typhimurium strain TA 100 at concentration of 10 and 25 ug/mL. Safrole showed positive results in the absence of metabolic activation when its mutagenicity was determined with DNA repair-deficient Escherichia coli rec- strains. Hepatic safrole-DNA adduct were detected in mice that were treated with safrole. In pregnant mice, safrole was bound to the DNA of maternal and fetal liver, lung, kidney, heart, brain, intestine, skin, maternal uterus and placenta. Fetal adduct levels were lower than maternal, exhibiting the greatest difference (42-fold) in liver, but little difference in lung, brain, and intestines.
The Human Health Assessment Group in EPA's Office of Health and Environmental Assessment has evaluated safrole for carcinogenicity. According to their analysis, the weight-of-evidence for safrole is group B2, which is based on sufficient evidence in animals. No data are available in humans. As a group B2 chemical, safrole is considered probably carcinogenic to humans.
No data are available in humans. Sufficient evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 2B: The agent is possibly carcinogenic to humans.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
黄樟素：合理预期为人类致癌物。
Safrole: reasonably anticipated to be a human carcinogen.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌物分类
国际癌症研究机构致癌物：黄樟素
IARC Carcinogenic Agent:Safrole
来源:International Agency for Research on Cancer (IARC)
Pregnant ICR mice were treated orally with 600 umol/kg safrole (SA) dissolved in 4 mL/kg trioctanoin, on day 18 of gestation. The mice were killed 24 hr after treatment and the fetuses were removed and prepared for tissue isolation. A sensitive (32)P-postlabeling method was used to study the binding of safrole to the DNA of various maternal and fetal tissues. The results showed that safrole bound to the DNA of maternal and fetal liver, lung, kidney, heart, brain, intestine, skin, maternal uterus and placenta, and the quantitative and qualitative differences in binding were organ-specific. The covalent binding index (umol adducted nucleotides per molecule of DNA nucleotides/umol carcinogen administered per g body weight) 24 hr after safrole treatment, ranged from 0.1 to 247 and 0.1 to 5.8 for maternal and fetal DNA, respectively. In both maternal and fetal tissues, safrole exhibited preferential binding to liver DNA, with brain DNA the least affected. Autoradiography fingerprints derived from maternal and fetal organs revealed DNA adduct spots that were identified as several metabolites of safrole. Fetal adduct levels were lower than maternal, exhibiting the greatest difference (42-fold) in liver, but little difference in lung, brain, and intestines.
/Factors affecting transplacental DNA damage were examined. Timed pregnant mice or monkeys were given a single dose of carcinogen on different gestation days, sacrificed 1-50 days later, and analyzed for DNA adducts by (32)P post labeling assay. The following results were obtained. The chemical types of carcinogen determine the fetal and fetal/maternal adduct levels and whether there is a gestation stage dependency in DNA binding. ... Safrole preferentially bound to fetal liver (as for adults) with strong gestation stage specificity. ... All carcinogens tested bound ubiquitously to all fetal and possible embryonic DNA with levels exhibiting little relationship to placental levels. Fetal adduct levels varied from 0.05-2 fold of maternal levels depending on the carcinogen tested. Thus, fetal competence in metabolism of a specific carcinogen is a determining factor for transplacental DNA damage. Placental adduct levels are a qualitative, but not a quantitative, indicator of fetal exposure.
In mice given (14)C-labeled /in methylene dioxy position/ safrole or dihydrosafrole orally, 96 and 101% of radioactivity were recovered; 64 and 61% were found in carbon dioxide, 18 and 23% in urine, 6 and 5% in feces and intestine, 2 and 2.5% in liver and 6 and 9% in carcasses... .
Safrole was absorbed from the gastrointestinal tract by passive diffusion, with the absorption kinetics apparently dependent on its lipid solubility as determined in an in situ perfusion method in the rat. In this same procedure, safrole, at a level of 2 mg/mL of perfusion medium, reduced the absorption of glucose and methionine but not butyric acid.
Small doses of [C14]-safrole were absorbed rapidly and excreted almost completely via the urine in 24 hours in both man (doses 0.165 mg or 1.655 mg) and the rat (dose 0.63 mg/kg). A large dose (750 mg/kg) in the rat resulted in a decrease in the rate of elimination, only 25% being excreted in 24 hours, and plasma and tissue levels of safrole and its metabolites were elevated for 48 hours.
An internally activated tin hydride with enhanced reducing ability
摘要：
Tin hydride 1 is activated for nucleophilic hydride transfer and also for radical chain reduction, depending on solvent. The nucleophilic hydride pathway is favored in methanol, and 1 can be used as a selective reducing agent for ketones. Simple ketones are not reduced in aprotic solvents, but beta-hydroxy ketones are activated internally by the hydroxyl group and can be reduced in THF with good control of stereochemistry, as in the conversion from 7 to 9 (30:1 9:8). A catalytic version of the nucleophilic hydride reductions in methanol has been developed using PhSiH3 as the stoichiometric hydride source. Radical chain dehalogenations can also be achieved with 1 at room temperature and without added radical initiators. Simple xanthates are not reduced efficiently in the absence of an initiator, but the reaction proceeds in the presence of AIBN.
DOI：
10.1021/jo00063a024
作为试剂：
描述：
对氯甲苯 在
palladium on activated charcoal 、 黄樟素 、 soda lime 作用下，
生成 2-(4-甲基苯基)吡啶
参考文献：
名称：
Murakoshi, Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan, 1957, vol. 77, p. 490,492
Hydrazines and Azides via the Metal-Catalyzed Hydrohydrazination and Hydroazidation of Olefins
作者：Jérôme Waser、Boris Gaspar、Hisanori Nambu、Erick M. Carreira
DOI：10.1021/ja062355+
日期：2006.9.1
which the H and the N atoms come from two different reagents, a silane and an oxidizing nitrogen source (azodicarboxylate or sulfonyl azide). The hydrohydrazination reaction using di-tert-butyl azodicarboxylate is characterized by its ease of use, large functional group tolerance, and broad scope, including mono-, di-, tri-, and tetrasubstituted olefins. Key to the development of the hydroazidation
报道了 Co 和 Mn 催化的烯烃加氢肼和加氢叠氮化反应的发现、研究和实施。这些反应等效于 CC 双键与受保护的肼或偶氮酸的直接加氢胺化，但基于不同的概念，其中 H 和 N 原子来自两种不同的试剂，硅烷和氧化性氮源（偶氮二羧酸或磺酰叠氮化物） ）。使用偶氮二羧酸二叔丁酯的加氢肼反应具有使用方便、官能团耐受性大、适用范围广的特点，包括单、二、三和四取代烯烃。氢叠氮化反应发展的关键是使用磺酰叠氮化物作为氮源和叔丁基过氧化氢的活化作用。发现该反应对于单、二和三取代烯烃的官能化是有效的，并且只有少数官能团是不能容忍的。获得的烷基叠氮化物是通用中间体，可以在不分离叠氮化物的情况下转化为游离胺或三唑。初步的机理研究表明，烯烃的氢化钴是限速的，然后是胺化反应。不能排除并可能涉及自由基中间体。然后进行胺化反应。不能排除并可能涉及自由基中间体。然后进行胺化反应。不能排除并可能涉及自由基中间体。
Reaction of natural-occurring phenolic derivatives with bis(trimethylsilyl) sulfate
作者：G. Nuissier、P. Bourgeois、M. Grignon-Dubois
DOI：10.1007/s10600-008-9100-5
日期：2008.7
applications inthe dying industry and in sulfa drugs as antibiotics [3].Aromatic substrates can be sulfonated with concentratedsulfuric acid, sulfur trioxide-dioxane complex, trifluoroaceticacid-sulfuric acid, or sulfurtrioxide in dichloromethane [4].Bourgeois and Duffaut [5] have shown thatbis(trimethylsilyl)sulfate allows the sulfonation of anisoleunder mild conditions. It is thermally stable and soluble
Ni(0)-CMC-Na Nickel Colloids in Sodium Carboxymethyl-Cellulose: Catalytic Evaluation in Hydrogenation Reactions
作者：Mohamed Anouar Harrad、Pedro Valerga、M. Carmen Puerta、Issam Houssini、Mustapha Ait Ali、Larbi El Firdoussi、Abdallah Karim
DOI：10.3390/molecules16010367
日期：——
A recyclable catalyst, Ni(0)-CMC-Na, composed of nickel colloids dispersed in a water soluble bioorganic polymer, sodium carboxymethylcellulose (CMC-Na), was synthesized by a simple procedure from readily available reagents. The catalyst thus obtained is stable and highly active in alkene hydrogenations.
[EN] ASH1L INHIBITORS AND METHODS OF TREATMENT THEREWITH<br/>[FR] INHIBITEURS DE ASH1L ET MÉTHODES DE TRAITEMENT AU MOYEN DE CEUX-CI
申请人：UNIV MICHIGAN REGENTS
公开号：WO2017197240A1
公开（公告）日：2017-11-16
Provided herein are small molecule inhibitors of ASH1L activity and small molecules that facilitate ASH1L degradation and methods of use thereof for the treatment of disease, including acute leukemia, solid cancers and other diseases dependent on activity of ASH1L.
Synthesis of Podophyllotoxin and its Derivatives via NiCl2/NaBH4 Reduction of Isoxazoline Ring
作者：Meduri Suresh Babu、Kuria Madhavu Lokanatha Rai
DOI：10.14233/ajchem.2013.15073
日期：——
A novel synthesis of podophyllotoxin was carried out in four steps. The key step was reduction of isoxazoline ring followed by diazotization and the resultant alkene was treated with Mn(OAc)3/CH3COOK to form podophyllotoxin.
