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PubMed2005

Antiulcerogenic activity of a crude hydroalcoholic extract and coumarin isolated from Mikania laevigata Schultz Bip.

The leaves of Mikania (Asteraceae) species are used in folk medicine as antispasmodic, antiulcerogenic and antirheumatic agents. Phytochemical screening of the crude hydroalcoholic 70% extract (CHE) of Mikania laevigata Shultz Bip. revealed coumarins, terpenes and organic acids. Antiulcerogenic activity of CHE was evaluated, employing different experimental models in rats, to discern the pharmacological mechanism of action. Both the antisecretory and the cytoprotection hypothesis were evaluated. The crude hydroalcoholic extract (1000 mg/kg body wt., vo) decreased the ulcerative lesion index produced by indomethacin, ethanol, stress and reserpine in rats by 85%, 93%, 82% and 50%, respectively. In the pyloric ligation model, a decrease of hydrogenionic concentration (53%) was observed, suggesting that the pharmacological mechanism has a relationship to antisecretory activity. The antisecretory mechanisms of CHE and the coumarin isolated from M. laevigata were confirmed by acid hypersecretion induced by histamine, pentagastrin and bethanechol. Duodenal administration of CHE (1000 mg/kg body wt.) and coumarin (100 mg/kg body wt.) inhibited only the gastric acid secretion produced by bethanecol. These results suggest that both CHE and coumarin may influence the secretion control mediated by the parasympathetic system.

Animals↗
PubMed2006

Accumulation of coumarins in Arabidopsis thaliana.

The biosynthesis of coumarins in plants is not well understood, although these metabolic pathways are often found in the plant kingdom. We report here the occurrence of coumarins in Arabidopsis thaliana ecotype Columbia. Considerably high levels of scopoletin and its beta-d-glucopyranoside, scopolin, were found in the wild-type roots. The scopolin level in the roots was approximately 1200nmol/gFW, which was approximately 180-fold of that in the aerial parts. Calli accumulated scopolin at a level of 70nmol/gFW. Scopoletin and scopolin formation were induced in shoots after treatment with either 2,4-dichlorophenoxyacetic acid (at 100microM) or a bud-cell suspension of Fusarium oxysporum. In order to gain insight into the biosynthetic pathway of coumarins in A. thaliana, we analyzed coumarins in the mutants obtained from the SALK Institute collection that carried a T-DNA insertion within the gene encoding the cytochrome P450, CYP98A3, which catalyzes 3'-hydroxylation of p-coumarate units in the phenylpropanoid pathway. The content of scopoletin and scopolin in the mutant roots greatly decreased to approximately 3% of that in the wild-type roots. This observation suggests that scopoletin and scopolin biosynthesis in A. thaliana are strongly dependent on the 3'-hydroxylation of p-coumarate units catalyzed by CYP98A3. We also found that the level of skimmin, a beta-d-glucopyranoside of umbelliferone, was slightly increased in the mutant roots.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1990

Influence of coumarin treatment on patency and limb salvage after peripheral arterial reconstructive surgery.

The effect of coumarin on patency, limb salvage, and survival after primary femoro-popliteal and femoro-distal reconstructions was studied in 116 randomized patients (61 in the study group and 55 in the control group). All patients were treated postoperatively with heparin. Patients allocated to the study group received dicumarol (a coumarin derivative) orally postoperatively. The overall patency after 1 year was 75 +/- 6%, compared with 74 +/- 6%, after 2 years 65 +/- 9 compared with 57 +/- 8%, and after 3 years 46 +/- 11% compared with 42 +/- 9% (mean +/- SE) in the study and control groups, respectively. There were no statistically significant differences in limb salvage or survival rates between the two groups. In contrast, coumarin treatment was associated with serious bleeding complications in 4% to 5% of the study patients. As expected, limb salvage was lower in patients with critical ischemia (p less than 0.03), and this was also true for survival (p less than 0.04), which was also influenced by the level of the reconstruction; survival was lower in patients with femoro-distal reconstructions (p less than 0.001). Our results demonstrate that coumarin treatment does not improve outcome in routine femoro-popliteal and femoro-distal reconstructive surgery.

Adult↗
PubMed2001

Monoterpene coumarins from Ferula ferulago.

Two monoterpene coumarins, designated ferulagol A and B, as well as three known monoterpene coumarins and three sesquiterpene lactones were isolated from the chloroform extract of the roots of Ferula ferulago. The structures of ferulagol A and B were determined to be 7-[(E)-3'-hydroxy-3',7'-dimethyl-4',6'-octadienyloxy]coumarin and 7-[(3'Z,5'E)-7'-hydroxy-3',7'-dimethyl-3',5'-octadienyloxy]coumarin, respectively.

Coumarins↗
PubMed2003

Synthesis of vanillin ethers from 4-(bromomethyl) coumarins as anti-inflammatory agents.

4-(Bromomethyl) coumarins 1 have been reacted with vanillins, 2 and 2A to obtain the corresponding ethers 3 and 5. Ethers 3 have been reacted with ethyl cyanoacetate to obtain the unsaturated esters 4. Ethers 5 have been converted to the corresponding 4-(2'-benzo[b] furanyl) coumarins 6 by an intramolecular aldol condensation. Eight compounds have been screened for their anti-inflammatory activity. Out of these the 5,6-benzo-4-2'-benzo[b]furanyl) coumarin (6c) and the aryloxymethyl coumarin (4) with p-formyl group were found to be most active.

Animals↗
PubMed1996

Simultaneous determination of coumarin, 7-hydroxycoumarin and 7-hydroxycoumarin glucuronide in human serum and plasma by high-performance liquid chromatography.

A HPLC method was developed for the determination of the metabolites of coumarin and 7-hydroxycoumarin in plasma and serum. Separation was based on gradient elution of 7-hydroxycoumarin glucuronide, 7-hydroxycoumarin, coumarin and finally 4-hydroxycoumarin (which is used as an internal standard). Standards, prepared in plasma or serum, and samples were treated with trichloroacetic acid, mixed and centrifuged. The supernatant was removed and analyzed by reversed-phase high-performance liquid chromatography on a C18 column. The limit of detection was 50 ng/ml for 7-hydroxycoumarin and 200 ng/ml for coumarin and 7-hydroxycoumarin glucuronide. The linear range was 0.5-100 micrograms/ml for each of the analytes. The percentage relative standard deviation about the mean measured concentrations were all below 10%. There was no statistical difference between the standard curves prepared in plasma or serum. The method developed was applied to the determination of each of the three compounds in serum, after the administration of 7-hydroxycoumarin, and in plasma after the administration of coumarin. The concentrations of total 7-hydroxycoumarin in the serum samples were also determined by another HPLC method and the results were compared. There was no statistical difference between the results determined.

Chromatography, High Pressure Liquid↗
PubMed2001

Role of dipole moment of solvents in formation and stabilization of the TICT states in Coumarin 445 under nitrogen laser excitation.

In this paper we report the observation of dual Amplified Spontaneous Emission (ASE) from solutions of 7-ethylamino-4-methyl coumarin dye (Coumarin 445) in certain solvents such as n-butyl acetate, dioxane etc. when pumped by high power nitrogen laser. The two ASE bands appear to be from two different excited species (ICT and TICT conformation) one of which is the precursor of the other. The spectral characteristics of dye Coumarin 445 depend upon the solvent environment. The TICT coumarin photoisomers, which form exciplexes with the solvent molecules, have enough gain to produce amplified spontaneous emission even when there is apparently no detectable fluorescence. The behaviour of this dye in the excited state is studied by measuring the small signal gain and variation of the gain slope with temperature in different solvents. It is observed that polarity of the solvent plays a more dominant role in formation and stabilization of TICT states.

Coumarins↗
PubMed2001

Interaction of coumarin derivatives with human serum albumin: investigation by fluorescence spectroscopic technique and modeling studies.

Interactions of several 7-aminocoumarins with human serum albumin (HSA) were studied by using fluorescence spectroscopic technique and modeling studies. There is a large change in fluorescence spectral parameters like intensity, emission maxima and anisotropy for all aminocoumarins. There were two binding sites for cou-1, 311 and a single binding site for other coumarins. The binding constant(s) are large for all coumarins reflective of a strong binding. These spectral studies show that structural variants at the third, fourth and seventh position affects binding. The probable location of these coumarins in domain II has been predicted based on modeling. The effect of structural modification on the efficiency of binding was obtained for various other coumarins, using modeling.

Binding Sites↗
PubMed2004

Fluorescence quenching of coumarins by halide ions.

Fluorescence quenching of 4-methyl-7-methoxy coumarin (1) and 4-methyl-5-ethoxy-7-methoxy coumarin (2) in aqueous solutions have been studied at different concentrations of halide ions (Cl-, Br-, I-), at room temperature approximately 20 degrees C. It is observed that the fluorescence intensity of both the coumarin compounds (1 and 2) decrease with increase in the concentration of Br- and I- ions but remains almost constant in case of Cl- ion. It is observed that the quenching due to halide ions proceeds via both a diffusional and static quenching processes. The rate constants for diffusional as well as static component of quenching process have been calculated using modified Stern-Volmer relation. It is further observed, that I- ion has very high quenching ability than Br- ion and Cl) ion almost behaves as a non-quencher. It is explained in terms of the sphere of action model by showing that the value of radius of sphere of action of the halide quencher is greater than the sum of the radii of the respective coumarin and quencher. Further, pattern of the quenching ability of the halide quenchers is found to be as I- > Br- > Cl- and interestingly this is in the same order as of their ionization energy. Finally, the present quenching process has been attributed to the electron transfer resulting between colliding species.

Bromides↗
PubMed1990

The CYP2A3 gene product catalyzes coumarin 7-hydroxylation in human liver microsomes.

Three cDNAs, designated IIA3, IIA3v, and IIA4, coding for P450s in the CYP2A gene subfamily were isolated from a lambda gt11 library prepared from human hepatic mRNA. Only three nucleotide differences and a single amino acid difference, Leu160----His, were found between IIA3 and IIA3v, indicating that they are probably allelic variants. IIA4 displayed 94% amino acid similarity with IIA3 and IIA3v. The three cDNAs were inserted into vaccinia virus, and recombinant viruses were used to infect human hepatoma Hep G2 cells. Only IIA3 was able to produce an enzyme that had a reduced CO-bound spectrum with a lambda max at 450 nm. This expressed enzyme was able to carry out coumarin 7-hydroxylation (turnover number of 15 min-1) and ethoxycoumarin O-deethylation. cDNA-expressed IIA3v and IIA4 failed to incorporate heme and were enzymatically inactive. Analysis of IIA proteins in human liver microsomes, using antibody against rat IIA2, revealed two proteins of 49 and 50 kDa, the former of which appeared to correlate with human microsomal coumarin 7-hydroxylase activity. A more striking correlation was found between IIA mRNA and enzyme activity. The rat antibody was able to completely abolish coumarin 7-hydroxylase activity in 12 liver samples. In addition, kinetics of coumarin metabolism in two livers were monophasic over the substrate concentration tested. Km values obtained from human liver (2.3 microM) were similar to those obtained from lysates of hepatoma cells expressing IIA3 (3.6-7.1 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1996

The interaction of coumarin antibiotics with fragments of DNA gyrase B protein.

DNA gyrase is the target of the coumarin group of antibacterial agents. The drugs are known to inhibit the ATPase activity of gyrase and bind to the 24-kDa N-terminal subdomain of gyrase B protein. Supercoiling assays with intact DNA gyrase and ATPase assays with a 43-kDa N-terminal fragment of the B protein suggest that the drugs bind tightly, with Kd values <10(-7) M. In addition, the ATPase data suggest that 1 coumermycin molecule interacts with 2 molecules of the 43-kDa protein while the other coumarins form a 1:1 complex. This result is confirmed by cross-linking experiments. Rapid gel-filtration experiments show that the binding of ADPNP(5'-adneylyl beta,gamm-imidodiphosphate) and coumarins to the 43-kDa protein is mutally exclusive, consistent with a competitive mode of action for the drugs. Rapid gel-filtration binding experiments using both the 24-and 43-kDa proteins also show that the drugs bind with association rate constants of >10(5) M-1.s-1, and dissociation rate constants of approximately 3x10(-3)s-1 and approximately 4x10(-3)s-1 for the 43-and 24-kDa proteins, respectively. Titration calorimetry shows that the Kd values for coumarins binding to both proteins are approximately 10-8M and that binding is enthalpy driven.

Adenylyl Imidodiphosphate↗
PubMed1994

In vitro photoinduced cytotoxicity and DNA binding properties of psoralen and coumarin conjugates of netropsin analogues: DNA sequence-directed alkylation and cross-link formation.

he synthesis, DNA binding and in vitro photoinduced cytotoxic properties of a number of minor groove and sequence-directed psoralen and coumarin conjugates of pyrrole- and imidazole-containing distamycin analogues 2-5 are described. Results from an ethidium displacement assay on calf thymus and T4 DNA suggest that like distamycin these agents bind strongly to the minor groove of DNA. The data show that these conjugates exhibit a lower AT preference than distamycin and the decrease is significantly greater for the imidazole-containing compounds. All of the compounds along with 8-methoxypsoralen, 1, were relatively noncytotoxic in the dark with only the imidazole-psoralen compound 3 giving an IC50 value below 100 microM. Following UV activation, all compounds showed an increased potency with photoinduced dose modifications in the human chronic myeloid leukemia K562 cells of > 333, 12, > 1.3, and > 2.5 for compounds 2-5, respectively, under the UV irradiation conditions employed. The psoralen-pyrrole analogue 2 was over 300 times more active following UV activation than agent 1, 250 times more potent than the corresponding coumarin conjugate 4, and 15-fold more potent than its imidazole analogue 3. Data from CD dilution (with DMF) studies show that upon irradiation with light at 366 nm, compounds 2-5 bind irreversibly to DNA. Furthermore, upon irradiation compound 2 produced interstrand cross-linked DNA in quantitative yield, with isolated DNA, at > 300- and > 3000-fold lower drug concentrations than the imidazole analogue 3 and 8-methoxypsoralen, respectively. As expected coumarin conjugates 4 and 5 did not produce any cross-linked DNA under any conditions. Since the psoralen conjugates are more phototoxic than their coumarin analogues, these results suggest that DNA interstrand cross-link formation may be an important mechanism by which they exert their biological activity in cells. In addition, the enhanced photocytotoxic potency of conjugate 2 over 3 may be related to its larger binding constant, more efficient DNA cross-linking ability, and possibly to its preference for AT-rich sequences.

Alkylation↗
PubMed2005

Sequential Pd(II)-Pd(0) catalysis for the rapid synthesis of coumarins.

Electrophilic palladium-catalyzed cycloisomerization of brominated aryl propiolates produces brominated coumarins. The brominated coumarins can be diversified by reduction of the Pd(II) catalyst to Pd(0) followed by Suzuki, Sonogashira, Heck, or Hartwig-Buchwald coupling. Thus, a single loading of precatalyst can be used to conduct sequential reactions, allowing the synthesis of functionalized coumarins. Extension of this methodology toward the synthesis of coumarin libraries is discussed.

Bromine↗
PubMedDate not supplied

Plant antimutagenic agents, 3. Coumarins.

Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.

Benzo(a)pyrene↗
PubMed1992

Coumarins from Phebalium tuberculosum ssp. megaphyllum and Phebalium filifolium.

A total of 14 coumarins have been isolated from the aerial parts of Phebalium tuberculosum ssp. megaphyllum and 9 from Phebalium filifolium (Rutaceae). Three of the coumarins obtained from P. tuberculosum ssp. megaphyllum are novel and have been characterized, on the basis of spectroscopic analysis, as (E)-7-(6-hydroperoxy-3,7-dimethylocta-2,7- dienyloxy)coumarin [3], (E)-8-(6-hydroperoxy-3,7-dimethylocta-2,7-dienyloxy)psoralen [16] and (E,E)-8-(7-hydroxy-3,7-dimethylocta-2,5-dienyloxy)psoralen [15] In addition, both species yielded the simple acetophenone xanthoxylin, and P. tuberculosum ssp. megaphyllum gave (E)-betulin-3-p-coumarate [20] and (Z)-betulin-3-p-coumarate [21], both of which appear to be novel. The chemotaxonomic implications of coumarin distribution in the two species are discussed.

Chromatography, Liquid↗
PubMed1996

Mechanism-based inactivation of hepatic ethoxyresorufin O-dealkylation activity by naturally occurring coumarins.

Several naturally occurring coumarins contained in the human diet have been found to be effective inhibitors and inactivators of murine hepatic ethoxyresorufin O-dealkylase (EROD) and pentoxyresorufin O-dealkylase in vitro [Cai, Y., Bennett, D., Nair, R.V., Ceska, O., Ashwood-Smith, M., and DiGiovanni, J. (1993) Chem. Res. Toxicol. 6, 872-879]. In the present study, these same coumarins decreased the content of cytochrome P450 (P450) in either 3-methylcholanthrene (MC)- or phenobarbital-induced murine hepatic microsomes but did not have a major effect on heme content. Detailed in vitro studies with [14C]coriandrin, which selectively inhibits and inactivates P450 1A1-mediated EROD activity, demonstrated that it covalently bound, in a preferential manner, to hepatic microsomal protein from MC-pretreated mice. A linear relationship was observed between covalent binding and loss of EROD activity. The inclusion of electrophile trapping agents in the incubations significantly inhibited the covalent binding of [14C]coriandrin to microsomal protein. In addition, the covalent binding of [14C]coriandrin was decreased 46% by 7,8-benzoflavone (7,8-BF), 58% by a monoclonal antibody with specificity toward MC-induced form(s) of P450, and 60% by ethoxyresorufin, implicating the bioactivation of coriandrin by P450 1A1. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of [14C]coriandrin-bound microsomal protein from MC-pretreated mice showed that [14C]coriandrin bound covalently to a protein with an approximate molecular mass of 49 kDa. Again, addition of 7,8-BF or polyclonal antibody against P450 1A1 reduced the covalent binding of [14C]coriandrin to this specific protein band. Interestingly, coriandrin was also found to be a potent inhibitor and inactivator of purified human P450 1A1. These results demonstrate that certain coumarins to which humans are exposed in the diet are bioactivated by P450 1A1 to reactive intermediates that subsequently form covalent adducts with the apoprotein, effectively destroying enzyme activity. Thus, certain naturally occurring coumarins may have a significant effect on human health.

Animals↗
PubMed2004

Adherence to a guideline for coumarins in pregnancy.

OBJECTIVE: To asses the adherence in daily clinical practice to a guideline for anticoagulation during pregnancy. METHODS: The Dutch anticoagulation clinics developed a pregnancy guideline for anticoagulant therapy in order to avoid foetal exposure to coumarins between the 6th and 9th week of gestation. Anticoagulation was studied in 282 prospectively-registered pregnant women, who were treated by 26 different anticoagulation clinics. RESULTS: The guideline was adhered to in 93% of treated women. Conforming to the guideline, the majority of patients commenced anticoagulation with heparin in the first trimester (n = 81) or started treatment from the second trimester onwards (n = 168). At the time of conception, 31 anticoagulated women were on coumarin treatment. In 13 of these patients (42%), coumarins were withdrawn before the 6th gestational week. In two pregnant women coumarin therapy started unintentionally during the first trimester of gestation. CONCLUSION: The present study shows that the guideline under study is useful in daily clinical practice. A careful instruction of women of child-bearing age who need medication remains important.

Adult↗
PubMed2001

New coumarins from Pterocaulon polystachyum.

Aerial parts of Pterocaulon polystachyum from Chaco province, Argentina, afforded the known coumarins ayapin, isoscopoletin, prenyletin, prenyletin methyl ether, virgatenol, obtusinin, 5-methoxy-6,7-methylenedioxycoumarin, 5-(3,3-dimethylallyloxy)-6,7-methylenedioxycoumarin, 5-(2',3'-dihydroxy-3-methylbutanoxy)-6,7-methylenedioxycoumarin, haplopinol methyl ether, 6-(1,1-dimethyl-2-propenyl)-7-hydroxycoumarin and demethylnieshoutin; the last two are new as natural products while the five new coumarins from the collection were isovirgatenol, 3'-deoxyobtusinin, 6-methoxy-7-(2'-hydroxyethoxy)-coumarin, 5-(2'-hydroxyethoxy)-6,7-methylenedioxycoumarin and a substance tentatively identified as 5-hydroxy-6,7-methylenedioxy-8-(3,3-dimethylallyl)-coumarin.

Argentina↗