Coumarin appears as colorless crystals, flakes or colorless to white powder with a pleasant fragrant vanilla odor and a bitter aromatic burning taste. (NTP, 1992)
颜色/状态：
Orthorhombic, rectangular plates
气味：
Pleasant, fragrant odor resembling that of vanilla beans.
...Recombinant human and rat CYP1A forms and recombinant human CYP2E1 readily catalyzed CE /coumarin-3,4-epoxide/ production. Coinhibition with CYP1A1/2 and CYP2E1 antibodies blocked CE formation by 38, 84, and 67 to 92% (n=3 individual samples) in mouse, rat, and human hepatic microsomes, respectively. Although CYP1A and 2E forms seem to be the most active catalysts of CE formation in liver, studies conducted with the mechanism-based inhibitor 5-phenyl-pentyne demonstrated that CYP2F2 is responsible for up to 67% of CE formation in whole mouse lung microsomes. In contrast to the CE pathway, coumarin 3-hydroxylation is a minor product of coumarin in liver microsomes from mice, rats, and humans and is catalyzed predominately by CYP3A and CYP1A forms, confirming that CE and 3-hydroxycoumarin are formed via distinct metabolic pathways.
...To examine species differences in CYP2A function, liver microsomes from nine mammalian species (rat, mouse, hamster, rabbit, guinea pig, cat, dog, cynomolgus monkey and human were tested for their ability to catalyze the 7 alpha- and 15 alpha-hydroxylation of testosterone and the 7-hydroxylation of coumarin. Antibody against rat CYP2Al recognized one or more proteins in liver microsomes from all mammalian species examined. However, liver microsomes from cat, dog, cynomolgus monkey, and human catalyzed negligible rates of testosterone 7 alpha- and/or 15 alpha-hydroxylation, whereas rat and cat liver microsomes catalyzed negligible rates of coumarin 7-hydroxylation. Formation of 7-hydroxycoumarin accounted for a different proportion of the coumarin metabolites formed by liver microsomes from each of the various species examined. 7-Hydroxycoumarin was the major metabolite (>70%) in human and monkey, but only a minor metabolite (<1%) in rat. The 7-hydroxylation of coumarin by human liver microsomes was catalyzed by a single, high-affinity enzyme (Km 0.2-0.6 uM, which was markedly inhibited (>95%) by antibody against rat CYP2Al. The rate of coumarin 7-hydroxylation varied approximately 17-fold among liver microsomes from 22 human subjects. This variation was highly correlated (r2=0.956) with interindividual differences in the levels of CYP2A6... . These results indicate that CYP2A6 is largely or entirely responsible for catalyzing the 7-hydroxylation of coumarin in human liver, microsomes. Treatment of monkeys with phenobarbital or dexamethasone increased coumarin 7-hydroxylase activity, whereas treatment with beta-naphthoflavone caused a slight decr. In contrast to rats and mice, the expression of CYP2A enzymes in cynomolgus monkeys and humans was not sexually differentiated. Despite their structural similarity to coumarin, the anticoagulants dicumarol and warfarin do not appear to be substrates for CYP2A6. ...
来源:Hazardous Substances Data Bank (HSDB)
代谢
老鼠可以在香豆素的3位进行羟基化。兔也能做到。
/The rat can/ hydroxylate coumarin in the 3-position. As can... the rabbit... .
The hepatic enzyme system, coumarin-7-hydroxylase, responsible for a high proportion of the hydroxylation of coumarin in cats, guinea pigs, hamsters, rabbits, and especially in man, is absent from the livers of ferrets, mice and rats. Rat liver contains an inhibitor of this enzyme.
来源:Hazardous Substances Data Bank (HSDB)
代谢
香豆素已知的人类代谢物包括7-羟基香豆素、香豆素3,4-环氧化物和3-羟基香豆素。
Coumarin has known human metabolites that include 7-Hydroxycoumarin, Coumarin 3,4-epoxide, and 3-Hydroxycoumarin.
IDENTIFICATION: Coumarin occurs in fruits, roots, bark, stalks, leaves and branches of a wide variety of plants including Tonka bean, cassie, levender, lovage, yellow sweet clover, deer tongue and woodruff. It is used as a flavoring agent in food; a fixative and enhancer for the odor of essential oils in perfumes; in toilet soaps, toothpastes and in hair preparations; in tobacco products to enhance and fix the natural taste, flavor and aroma; and in industrial products to mask disagreeable odors. HUMAN EXPOSURE: Four male and four female volunteers were given 200 mg each of coumarin in a capsule. Most of dose was excreted in the first 24 hr, primarily as 7-hydroxycoumarin and another metabolic product O-hydroxyphenylacetic acid. Blood concentration time profiles calculated after oral or iv administration of coumarin to four male and two female adults indicated an open two compartment model. The major site of metabolism is the liver and the glucuronidation of the metabolites may occur at several sites, including the liver and intestinal wall along with other tissues. ANIMAL STUDIES: Coumarin administered to female Albino rats caused hyperglycemia which lasted about 24 hr. An oral dose of coumarin dissolved in Arachis oil administered daily for seven dats to virgin female Wistar rats resulted in a decrease in serum progesterone levels. Groups of six male rats were given coumarin in Arachis oil daily for seven days by oral intubation. There was no increase in relative liver weight at lower doses; however, there was a dose related increase at the highest dose tested. Histological changes at the highest dose consisted of fatty change abd vacuolar degeneration in the centrilobular hepatocytes. A centrilobular loss of G6P and aniline hydroxylase resulted at the two highest doses. Lysosomal and ultrastructural changes also occurred at the two highest doses; the latter consisted of hypertrophy and dilation of the rough endoplasmic reticulium in centrilobular hepatocytes, increases in the size of lysosomes and the number of autophagic vacoules. Dose related depression in cytochrome p-450 and aminopyridine demethylase also occurred at the two highest dose levels. Coumarin was fed for 32 weeks in the diet to DBA/2 mice and to CH3/HeJ mice. Minimal increases in serum glutamate oxalate transferase, gamma-glutamyl transferase and sorbitol dehydrogenase activities were noted, but no gross or microscopic liver lestions were reported. Coumarin was found to inhibit Uvr repair of ultraviolet induced lesions in Escherichia coli. Groups of pregnant mice were fed in the diet on days 6-17 of pregnancy. No increase in malformations at any dose was noted although delayed ossification and increased still births at the high dose group was found. Groups of three male and three female Orsborne-Mendel rats were fed coumarin in the diet for four weeks. Marked growth retardation, testicular atrophy and slight to moderate liver damage was noted. Liver damage consisted of dead and dying cells, a decrease in oxyphillia and cytoplasm in the centrilobular cells and proliferation of bile ducts. One male and one female dog were given coumarin by capsures 6 days/wk for up to 16 days. The male was sacrificed in extremis after nime days and the female was found dead on day 16. The livers were yellow colored and had a nutmeg appearance. Microscopically there was marked disorganization of the lobular pattern, moderate increase in the size of liver cells, vacoulation, a large amount of diffusely distributed fat, focal necrosis, fibrosis and a very slight to moderate bile duct proliferation. The spleen was pale colored and the bone marrow was thin and fatty and the gall bladder moderately distended. Groups of 4 to 8 male baboons of several species were fed coumarin in the diet for two years. No changes in body weight were noted. Relative liver weights were increased in the high dose animals. No treatment related effects on liver histology were observed in six to ten month biopsy specimens. No biliary hyperplasia or fibrosis was seen at any dose. Marked dilation of the endoplasmic reticulum was seen upon sultrastructural examination of the liver in three high dose animals.[
Evaluation: No epidemiological data relevant to the carcinogenicity of coumarin were available. There is limited evidence in experimental animals for the carcinogenicity of coumarin. Overall evaluation: Coumarin is not classifiable as to its carcinogenicity to humans (Group 3).
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：香豆素
IARC Carcinogenic Agent:Coumarin
来源:International Agency for Research on Cancer (IARC)
毒理性
致癌物分类
国际癌症研究机构（IARC）致癌物分类：第3组：对其对人类的致癌性无法分类
IARC Carcinogenic Classes:Group 3: Not classifiable as to its carcinogenicity to humans
来源:International Agency for Research on Cancer (IARC)
IARC Monographs:Volume Sup 7: Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42, 1987; 440 pages; ISBN 92-832-1411-0 (out of print)
来源:International Agency for Research on Cancer (IARC)
A species difference has been reported for the excretion of an oral dose of (14)C-coumarin. Within 4 days rats excreted 47% of the label in the urine and 39% in the feces, whereas rabbits excreted 92% in the urine and negligible amount in the feces.
Female rabbits dosed orally with 50 mg/kg of 3-14C-coumarin excreted over 80% of the label in the urine in 24 hours. No label was found in the expired air and only a small amount in the feces.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
口服(14)C-香豆素后大鼠粪便中大量排出(14)C的原因...可能代表未被吸收的物质。
The reason for the considerable fecal excretion of (14)C /after oral administration of (14)C-coumarin/ in rat... may represent unabsorbed material.
Twenty-four hr after an IP dose to rats of... (14)C-coumarin, 38% had been excreted in the urine, 13% in the feces, 30% was excreted in the air as (14)C-carbon dioxide and 9% of the remainder was mainly present in the cecum.
The invention relates to novel 3-amino pyrrolidine derivatives, as well as methods for modulating calcium channel activity and for treating conditions associated with calcium channel function. In particular, the compounds generally contain at least one benzhydril moiety, and are useful in treating conditions which benefit from blocking calcium ion channels.
The present invention relates to oligoesters and their use or the creation of additives. Oligoester containing additives and/or oligoesters themselves may be used for formulating pharmaceutical preparations, cosmetics or personal care products such as shampoos and conditioners. These oligoesters are particularly useful for the creation of multi-purpose additives that can impart conditioning, long substantivity and/or UV protection. Individual oligoesters and oligoester mixtures are described.
DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
申请人：BAYER PHARMA AKTIENGESELLSCHAFT
公开号：US20160221965A1
公开（公告）日：2016-08-04
The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.
NEW STRIGOLACTONE ANALOGUES AND THE USE THEREOF FOR THE TREATMENT OF PLANTS
申请人：INSTITUT NATIONAL DE LA RECHERCHE AGRONOMIQUE
公开号：US20150141255A1
公开（公告）日：2015-05-21
A compound of general formula (I):
in which X represents O, S, NH or an N-alkyl radical, R
1
and R
2
, identical or different, each represent H or a C
1
-C
10
hydrocarbon radical, R
1
and R
2
not both representing H, R
3
represents a C
1
-C
10
hydrocarbon radical, and R represents a phenyl radical monosubstituted or disubstituted by a substituent Y and, if applicable, a substituent Z, chosen from Cl, Br, I and CF
3
, or R represents a C═R
4
(R
5
) radical in which R
4
represents an hydrocarbon radical and R
5
represents a linear or branched, saturated or unsaturated, hydrocarbon radical, optionally substituted, a COR
6
group or a CO
2
R
6
group, where R
6
represents a hydrogen atom or a linear or branched, saturated or unsaturated, hydrocarbon radical. This compound can be used for the treatment of higher plants for controlling their growth and architecture.
Anticancer compounds according to formula I are described herein.
wherein R
1
, R
2
, R
3
and R
4
are selected from H, CH
3
, OH, SH, OCH
3
, NHR′, halogen, CF
3
, N-linked pyrrolidine, and SO
2
NHR′, or any combination thereof; R
5
is an alkyl, alkenyl, or alkaryl group including from 4 to 11 carbons, X is selected from CH
2
, CHOH, C═O, S═O, O═S═O, and an oxetane ring, Y is selected from CH
2
, O, and NH, and R′ is a H, aryl, or a lower alkyl group, or pharmaceutically acceptable salts thereof. The compounds have been shown to facilitate site-specific dephosphorylation of Akt at Ser-473, thereby inactivating Akt and decreasing dysregulation of Akt signaling that can occur in cancer cells.
