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PubMed2000

Coumarins and antiplatelet constituents from the root bark of Zanthoxylum schinifolium.

Further study on the chloroform-soluble portion of the root bark of Zanthoxylum schinifolium led to the isolation of eight new coumarins: methylschinilenol (1), hydroxyepoxycollinin I (2), 8-methoxyanisocoumarin H (3), hydroxyschininallylol (4), hydroxyepoxycollinin II (5), schinitrienin (6), schininallylone (7), and isoschinilenol (8), along with twenty-six known compounds including fourteen coumarins, and nine alkaloids. The structural elucidation was determined by spectroscopic data. Among the isolates, terpenyl-coumarins and furoquinolines were the active constituents with antiplatelet aggregation in vitro and collinin (10) showed significant anti-HBC DNA replication activity.

Coumarins↗
PubMed2003

Cytotoxic coumarins from Mammea harmandii.

Two new naturally occurring coumarins, isomesuol (1) and mammearin A (2), together with nine known Mammea coumarins 3-11 were isolated from the EtOAc extract of the leaves and twigs of Mammea harmandii. Coumarins 1, 3 and 4 showed cytotoxicity against a panel of mammalian cancer cell lines. Their structures were determined by spectroscopic methods. The assignments of 13C-NMR signals of isomesuol (1), which was isolated for the first time as a natural product, have been revised.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Two new coumarin derivatives from the roots of Heracleum rapula.

Two new coumarins, 13- O-[ beta- D-apiofuranosyl(1-->6)- beta- D-glucopyranosyl]-(12 R)-heraclenol ( 1) and (12 R,12" R)-diheraclenol ( 2) were isolated from the acetone extract of the fresh roots of Heracleum rapula. Their structures were determined by means of spectroscopic analysis and, in the case of compound 1, the structure elucidation was supported by acid hydrolysis. Compound 1 is a coumarin glycoside while 2 is a coumarin dimer. The inhibitory effects of 1, its aglycone ( 3), and 2 on rabbit platelet aggregation induced by PAF, AA and ADP were tested. Weak activities were observed for each compound with the percentages of inhibition in the range of 0.7 - 24.8 %.

Animals↗
PubMed2005

Determination of five coumarins in Cnidii Fructus by micellar electrokinetic capillary chromatography.

A micellar electrokinetic capillary chromatography (MEKC) method for the separation and quantification of the coumarins in Cnidii Fructus was developed for the first time. Within 25 minutes, 5 major coumarins were separated using 18 mM borate, 12 mM phosphate and 50 mM SDS (pH 9.2) containing 20 % methanol. The relative standard deviations of migration times and peak areas were less than 5 %. The total contents of the five coumarins in plants from different habitats ranged from 13.6 to 44.6 mg/g, and recoveries ranged from 96.0 to 102.8 %. The effects of buffer concentration, SDS, pH value and organic modifier on the separation were investigated.

Chromatography, Micellar Electrokinetic Capillary↗
PubMed2006

Photoinduced electron transfer from N,N-dimethylaniline to 7-amino coumarins in protein-surfactant complex: slowing down of electron transfer dynamics compared to micelles.

Photoinduced electron transfer from N,N-dimethylaniline to different Coumarin dyes has been investigated in dodecyl trimethyl ammonium bromide (DTAB) micelles and in Bovine serum albumin (BSA)-DTAB protein-surfactant complex using steady-state and picosecond time-resolved fluorescence spectroscopy. We observed a slower fluorescence quenching rate in the DTAB micelles and in the protein-surfactant complex as compared to that in pure acetonitrile solution. Moreover, the observed fluorescence quenching in BSA-DTAB complex was found to be slower than that in DTAB micelles. In the correlation of free-energy change with the fluorescence quenching constant we observed a deviation in the fluorescence quenching electron transfer rate for Coumarin 151 (C-151) from the normal Marcus curve. This observation is ascribed to the stronger interaction of C-151 with the surfactant molecules present in the micelles. This is evident from the slower translation diffusion (D(L)) of Coumarin 151 compared to other probe molecules.

Aniline Compounds↗
PubMed2004

Biochemical and biological characterization of a novel anti-aromatase coumarin derivative.

Estrogen stimulates the proliferation of estrogen receptor (ER)-positive breast cancer cells. Aromatase is the enzyme responsible for the conversion of androgens into estrogens, and synthetic aromatase inhibitors such as letrozole, anastrozole, and exemestane have proven to be effective endocrine regimens for ER-positive breast cancer. In a recent study, we have found that 4-benzyl-3-(4'-chlorophenyl)-7-methoxycoumarin is a potent competitive inhibitor of aromatase with respect to the androgen substrate. Its K(i) value was determined to be 84 nm, significantly more potent than several known aromatase inhibitors. The specific interaction of this compound with aromatase was further demonstrated by the reduction of its binding by several mutations at the active site region of aromatase and evaluated by computer modeling analysis. The structure-activity studies have revealed that three functional groups (i.e. 3-(4'-chlorophenyl), 4-benzyl, and 7-methoxyl) of this coumarin are important in its inhibition of aromatase. In addition, through a matrigel thread three-dimensional cell culture, this compound was shown to behave like known aromatase inhibitors that suppress the proliferation of aromatase and estrogen receptor positive MCF-7aro breast cancer cells. This coumarin has been shown not to be cytotoxic at up to 40 mum. It was found not to be an inhibitor of steroid 5alpha-reductase that also utilizes androgen as the substrate and not to be a ligand of ERalpha, ERbeta, estrogen-related receptors, or androgen receptor. These results demonstrate that coumarins (a common type of phytochemical) or their derivatives can be potent inhibitors of aromatase and may be useful in suppressing aromataseand ER-positive breast tumors.

Androgens↗
PubMed2005

Kinetic analysis of oxidation of coumarins by human cytochrome P450 2A6.

Human cytochrome P450 (P450) 2A6 catalyzes 7-hydroxylation of coumarin, and the reaction rate is enhanced by cytochrome b5 (b5). 7-Alkoxycoumarins were O-dealkylated and also hydroxylated at the 3-position. Binding of coumarin and 7-hydroxycoumarin to ferric and ferrous P450 2A6 are fast reactions (k(on) approximately 10(6) m(-1) s(-1)), and the k(off) rates range from 5.7 to 36 s(-1) (at 23 degrees C). Reduction of ferric P450 2A6 is rapid (7.5 s(-1)) but only in the presence of coumarin. The reaction of the ferrous P450 2A6 substrate complex with O2 is rapid (k > or = 10(6) m(-1) s(-1)), and the putative Fe2+.O2 complex decayed at a rate of approximately 0.3 s(-1) at 23 degrees C. Some 7-hydroxycoumarin was formed during the oxidation of the ferrous enzyme under these conditions, and the yield was enhanced by b5. Kinetic analyses showed that approximately 1/3 of the reduced b5 was rapidly oxidized in the presence of the Fe2+.O2 complex, implying some electron transfer. High intrinsic and competitive and non-competitive intermolecular kinetic deuterium isotope effects (values 6-10) were measured for O-dealkylation of 7-alkoxycoumarins, indicating the effect of C-H bond strength on rates of product formation. These results support a scheme with many rapid reaction steps, including electron transfers, substrate binding and release at multiple stages, and rapid product release even though the substrate is tightly bound in a small active site. The inherent difficulty of chemistry of substrate oxidation and the lack of proclivity toward a linear pathway leading to product formation explain the inefficiency of the enzyme relative to highly efficient bacterial P450s.

7-Alkoxycoumarin O-Dealkylase↗
PubMed2006

Modulation of chaperone function and cochaperone interaction by novobiocin in the C-terminal domain of Hsp90: evidence that coumarin antibiotics disrupt Hsp90 dimerization.

The C-terminal domain of Hsp90 displays independent chaperone activity, mediates dimerization, and contains the MEEVD motif essential for interaction with tetratricopeptide repeat-containing immunophilin cochaperones assembled in mature steroid receptor complexes. An alpha-helical region, upstream of the MEEVD peptide, helps form the dimerization interface and includes a hydrophobic microdomain that contributes to the Hsp90 interaction with the immunophilin cochaperones and corresponds to the binding site for novobiocin, a coumarin-related Hsp90 inhibitor. Mutation of selected residues within the hydrophobic microdomain significantly impacted the chaperone function of a recombinant C-terminal Hsp90 fragment and novobiocin inhibited wild-type chaperone activity. Prior incubation of the Hsp90 fragment with novobiocin led to a direct blockade of immunophilin cochaperone binding. However, the drug had little influence on the pre-formed Hsp90-immunophilin complex, suggesting that bound cochaperones mask the novobiocin-binding site. We observed a differential effect of the drug on Hsp90-immunophilin interaction, suggesting that the immunophilins make distinct contacts within the C-terminal domain to specifically modulate Hsp90 function. Novobiocin also precluded the interaction of full-length Hsp90 with the p50(cdc37) cochaperone, which targets the N-terminal nucleotide-binding domain, and is prevalent in Hsp90 complexes with protein kinase substrates. Novobiocin therefore acts locally and allosterically to induce conformational changes within multiple regions of the Hsp90 protein. We provide evidence that coumermycin A1, a coumarin structurally related to novobiocin, interferes with dimerization of the Hsp90 C-terminal domain. Coumarin-based inhibitors then may antagonize Hsp90 function by inducing a conformation favoring separation of the C-terminal domains and release of substrate.

Alanine↗
PubMed1997

Facilitation of retinal function recovery by coumarin derivatives.

Ischemic retinopathy is a difficult disease to treat, although numerous drugs have been tried in the clinics. Coumarin was one of those tried as an anti-coagulant with a marginal efficacy. In this study, 15 coumarin derivatives were studied on the b-wave recovery in electroretinogram which is an indicator of the functional recovery of retina after ischemic insult. It was found that when positions 6, 7 and 8 were occupied by various functional groups, the b-wave recovery could be markedly enhanced. On the other hand, single occupation of position 3 with any functional group would cause damaging effects to the anti-ischemic activity. It is concluded that some coumarin derivatives with two or all of these positions at 6, 7 and 8 occupied by certain functional groups could result in useful drugs for the treatment of ischemic retinopathy.

Animals↗
PubMed1999

Interaction of oligonucleotides conjugated to substituted chromones and coumarins with HIV-1 reverse transcriptase.

Ten different pyranone-related substituents (chromones or coumarins) were covalently linked to the 5' end of various oligonucleotides (ODN). The interaction of these compounds with human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) was analyzed. A different behavior was found to depend on the structure of the oligonucleotide derivatives. Some compounds activated the enzyme at relatively low concentrations (0.1-0.5 microM), followed by an inhibition of the activity at higher concentrations (5-20 microM), whereas others behave just as inhibitors. Because the presence of some coumarin or chromone derivatives conjugated to ODNs enhanced the interaction with the reverse transcriptase, we analyzed the capacity of such ODN derivatives to be used as primers. The introduction of substituent I, a chromone derivative, the 2-[(3-(aminopropyl)amino]-8-isopropyl-5-methyl-4-oxo-4H-1-benzopyran-3-c arbaldehyde], and II, a coumarin derivative, the 1-(3-aminopropoxy)-2-ethyl-3H-naphto[2,1-b]pyran-3-one, into the 5' end of a noncomplementary ODN allowed these compounds to be used as primers. In the case of complementary primers, the presence of conjugated derivatives enhanced the affinity with Km values that were two to three orders of magnitude lower than that of a complementary primer of the same length. After addition of a ddT-unit to the 3'-terminal end of the ODN, some of these primers became very effective inhibitors of RT with Ki values in the nanomolar range.

Chromones↗
PubMed1979

Prothrombin time after heparin removal. Application to monitoring simultaneous anticoagulation with heparin and coumarins.

Coumarin-anticoagulated plasmas from 31 subjects comprising two study groups were passed through epichlorohydrin triethanolamine cellulose (ECTEOLA) chromatography columns. Group I plasmas, which were run with nothing added, had mean prothrombin times of 21.6 +/- 5.4 sec prior to and 22.4 +/- 5.6 sec following exposure to these columns (r = 0.9449; t = 1.8307, P less than 0.100). The mean prothrombin time for Group II, 18.2 +/- 4.9 sec, lengthened with 5 u/ml heparin to 35.5 +/- 16.2 sec, and returned to 19.2 +/- 5.0 (r = 0.9763) after chromatography. Therefore, it appears that coumarin anticoagulation had no significant influence upon the capacity of ECTEOLA effectively to remove heparin in therapeutic doses. This means that virtually all prothrombin time reagent systems can be employed to monitor concurrent heparin and coumarin anticoagulation. In addition, quality control of the combined technic is simpler, and the technic more sensitive to low levels of fibrinogen and factor V.

Cellulose↗
PubMed1990

Studies on the anti-tumor-promoting activity of naturally occurring substances. IV. Pd-II [(+)anomalin, (+)praeruptorin B], a seselin-type coumarin, inhibits the promotion of skin tumor formation by 12-O-tetradecanoylphorbol-13-acetate in 7,12-dimethylbenz[a]anthracene-initiated mice.

Since Pd-II [(+)anomalin, (+)praeruptorin B], a seselin-type coumarin, was found to inhibit tumor promoter induced phenomenon in vitro, the effect of Pd-II on the in vivo tumor-promoting action of 12-O-tetradecanoylphorbol-13-acetate (TPA) in 7,12-dimethylbenz[a]anthracene-initiated mouse skin was investigated. Pd-II, applied 40 min before the TPA treatment, at a dose of 10 mumol/painting, completely suppressed tumor formation up to 20 weeks of tumor promotion, without any toxicity. Besides Pd-II, various anti-tumor-promoter coumarins were found in the traditional Chinese medicine Qian-Hu, from which Pd-II was obtained. These coumarins may be useful for the development of an effective method to prevent cancer.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1991

Novel coumarins as potential anticarcinogenic agents.

The potential anticarcinogenic properties of several novel coumarin derivatives whose structures are based on polycyclic aromatic hydrocarbons (PAHs) were examined in the multistage model of mouse skin tumorigenesis. The test compounds were evaluated for their affinity to bind competitively with rat cytosolic Ah-receptor in rat hepatic cytosol, their effects on mouse epidermal aryl hydrocarbon hydroxylase (AHH) after topical application, and for their effects on the levels of hydrocarbon-DNA adducts formed in vivo. All compounds showed good correlations between cytosolic Ah-receptor binding and their ability to induce epidermal AHH activity. Among the derivatives evaluated the coumarin (8-methyl-9H-10-oxabenzo[a]pyren-9-one) exhibited the highest affinity for the Ah-receptor and was also the most potent inducer of epidermal AHH activity. This compound also effectively inhibited the covalent binding of 7,12-dimethylbenz[a]anthracene (DMBA) to epidermal DNA when given either 5 min or 24 h prior to application of [3H]DMBA. This novel coumarin derivative significantly inhibited skin tumor initiation by DMBA in SENCAR mice when given at a dose of 200 nmol, 5 min (69% inhibition) or 24 h (76% inhibition) prior to initiation. The results of these studies suggest that this class of compounds shows considerable promise for future development as potential inhibitors of PAH-mediated tumor initiation on mouse skin. Potential mechanism(s) for the anti-initiating action of these compounds are discussed.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2001

Sunflower (Helianthus annuus L.) response to broomrape (Orobanche cernua Loefl.) parasitism: induced synthesis and excretion of 7-hydroxylated simple coumarins.

The interaction of the parasitic plant Orobanche cernua with resistant and susceptible cultivars of Helianthus annuus L. was investigated. Using different bioassays to evaluate the early stages of the parasite life cycle (germination, attachment, penetration, and establishment), differences were observed between O. cernua-resistant and O. cernua-susceptible sunflower varieties. Germination of O. cernua seeds in the presence of resistant sunflower roots was approximately half that of germination in the presence of susceptible roots, and germinated seeds displayed enhanced browning symptoms. Parasite radicles or host-tissue around the contact point turned brown after O. cernua attachment to sunflower roots, especially in the resistant varieties. These observations suggested the possible accumulation of toxic compounds as a defence strategy in the resistant sunflower varieties. Sunflower 7-hydroxylated simple coumarins may play a defensive role against O. cernua parasitism by preventing successful germination, penetration and/or connection to the host vascular system. This hypothesis is supported by the following data: (i) coumarins inhibited the in vitro germination of O. cernua seeds induced by the strigol analogue GR(24) and caused a browning reaction in germinated seeds and (ii) resistant sunflowers accumulated higher levels of coumarins in roots and excreted greater amounts than susceptible varieties in response to O. cernua infection.

Coumarins↗
PubMed1995

Randomised study using IFN-alpha versus IFN-alpha plus coumarin and cimetidine for treatment of advanced renal cell cancer.

BACKGROUND: Treatment results in patients with metastatic renal cell cancer (RCC) are still extremely unsatisfactory. Rates of response to IFN-alpha monotherapy and/or IL-2 mono/combination therapy vary between 10% and 20%. Coumarin (Cum) together with cimetidine (Cim) has yielded objective responses in 20%-33% of patients with RCC, according to two recent phase II studies. PATIENTS AND METHODS: In the present study 148 patients with metastatic RCC were randomised to receive either IFN-alpha (5 MU 5 x weekly s.c.) + coumarin (100 mg/d p.o.) + cimetidine (3 x 400 mg/d p.o.), or IFN-alpha-monotherapy (5 MU 5 x weekly s.c.). RESULTS: Of the 148 patients in the study 137 were evaluable for response. No differences in remission rates (RR IFN-alpha + Cum + Cim 17.1% and IFN-alpha 20.8%) or survival times (median survival 9 months and 8 months, respectively) were found between these two treatment arms. CONCLUSIONS: This study confirms that INFN-alpha has antitumoral activity in RCC. Adding coumarin + cimetidine to IFN-alpha in the dose and regimen prescribed in this study did not increase response rates or survival.

Adult↗
PubMed1993

The interaction between coumarin drugs and DNA gyrase.

The coumarin group of antibiotics have as their target the bacterial enzyme DNA gyrase. The drugs bind to the B subunit of gyrase and inhibit DNA supercoiling by blocking the ATPase activity. Recent data show that the binding site for the drugs lies within the N-terminal part of the B protein, and individual amino acids involved in coumarin interaction are being identified. The mode of inhibition of the gyrase ATPase reaction by coumarins is unlikely to be simple competitive inhibition, and the drugs may act by stabilizing a conformation of the enzyme with low affinity for ATP.

Adenosine Triphosphatases↗
PubMed2006

Treatment of coumarin-associated coagulopathy: a systematic review and proposed treatment algorithms.

BACKGROUND: An excessive anticoagulant effect because of coumarins is frequently encountered. OBJECTIVE: To review available literature on the management of warfarin-associated coagulopathy and to propose evidence-based treatment algorithms. METHODS: Data sources were Medline and Embase. Papers published between 1966 and December 2005 describing randomized trials or prospective cohort studies evaluating treatments for coumarin-associated coagulopathy were abstracted. RESULTS: Low dose oral vitamin K rapidly and reliably returns the international normalized ratio (INR) to the usual therapeutic range in non-bleeding patients. Simple withholding of acenocumarol results in rapid correction of its anticoagulant effect. The impact of oral vitamin K on phenprocumon-associated coagulopathy cannot be determined from available literature. Intravenous vitamin K and coagulation factors should be given to patients with major or life-threatening hemorrhage. The optimal dose and type of coagulation factor is not known. CONCLUSIONS: Vitamin K therapy is an effective treatment for INR prolongation in patients with coumarin-associated coagulopathy; coagulation factor replacement is required, in addition, in patients with major bleeding or with indication for immediate correction of their INR. Clinical trials powered to detect differences in rates of bleeding and thrombosis are now required to determine if vitamin K reduces the risk of bleeding without causing thrombosis in non-bleeding patients with prolonged INR.

Algorithms↗
PubMed1989

Quinolones and coumarins eliminate chloroplasts from Euglena gracilis.

Quinolones and coumarins were potent eliminators of chloroplasts from Euglena gracilis. There was a remarkable similarity between antichloroplastic and antibacterial activities of DNA gyrase inhibitors. Quinolones produced 100% chloroplast-free cells in concentrations which do not affect cell viability. Optimal conditions were exponential growth, continuous illumination, and neutral or slightly alkaline pH. Coumarins were more toxic than quinolones. Among the quinolones, ofloxacin was the most potent in eliminating chloroplasts. Among the coumarins, coumermycin A1 was the most potent. New quinolones and coumermycin A1 were able to induce the complete inability of originally green cells to form green colonies after 24 h of drug exposure, while clorobiocin and novobiocin required several days of exposure. Darkness, heat shock (42 degrees C, 10 min), or simultaneous treatment with chloramphenicol or rifampin decreased the potency of DNA gyrase inhibitors for producing chloroplast-free cells. Remarkably, in cells in which division was blocked by three different methods (resting medium, hyperthermic conditions [37 degrees C], or addition of cycloheximide), new quinolones and coumermycin A1 nevertheless eliminated chloroplasts. The antichloroplastic activity of DNA gyrase inhibitors is additional data suggesting an evolutionary relationship between chloroplasts and eubacteria.

4-Quinolones↗