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4,5-Dimethoxykynuramine was synthesized in a three-step sequence originating with veratrole. Indirect evidence indicates that the drug was converted in vivo to the hypotensive agent 6,7-dimethoxy-4-quinolinol by the action of monoamine oxidase.
The analgesic activity of O-(4-methoxylphenylcarbamoyl)-3-diethylaminopropiophenone oxime hydrochloride was investigated in Swiss--Webster mice using an electroshock technique in which the pain threshold was the minimum voltage producing tonic extension of the hindlimbs in response to an electroshock delivered to the feet. The analgesic potency of O-(4-methoxylphenylcarbamoyl)-3-diethylaminopropiophenone oxime hydrochloride was equal to, or greater than, that of morphine. Neither nalorphine nor withdrawal produced visible behavioral effects in rats treated with O-(4-methoxylphenylcarbamoyl)-3-diethylaminopropiophenone oxime hydrochloride for 21 days, suggesting that the physical dependency liability of the compound may be less than that of morphine.
A number of analogues of 3-dimethylamino-2-dimethylaminomethyl-1-(4-methoxyphenyl)-1-propanone dihydrochloride (IIa) and related compounds which showed activity against P388 lymphocytic leukemia were prepared, and of the 16 analogues, three met the criterion for activity in this screen. The toxicity of IIa was examined in rats and either a single dose of 25 mg/kg or nine daily doses of 12.5 mg/kg administered by the intraperitoneal route produced marked irritation and damage to the tissue with which it came into contact. Compound IIa did not show significant activity against eight other tumor systems.
A method for the determination of bupropion and its three major basic metabolites in plasma is described. Following an extraction from alkaline plasma into 1.5% v/v isoamyl alcohol in n-heptane, a portion of the acid-backwashed extract was injected onto a column packed with trimethylsilyl reverse-phase material and eluted with a phosphate buffer-acetonitrile (80:20) mobile phase containing an ion-pairing reagent and triethylamine. The compounds were detected with a dual-wavelength UV detector (214 and 254 nm) to optimize sensitivity and facilitate simultaneous detection. The method provides an absolute recovery of approximately 85% for bupropion and approximately 98% for the metabolites. Day-to-day reproducibility did not exceed 4.0% for all compounds. The detection limits were approximately 5 ng/mL for bupropion and 100 ng/mL for the major metabolites. The limit of 100 ng/mL for metabolite quantitation is imposed by the internal standard concentration selected for steady-state studies. In single-dose pharmacokinetic studies, 10% of the steady-state concentration of internal standard was used; this permitted a 10-ng/mL lower limit of detection. Steady-state plasma levels of bupropion and the metabolites from eight different patients are presented.
The synthesis of a hapten useful in the radioimmunoassay of bupropion is described. Since bupropion has no functional group that can be easily derivatized, a hydroxypropyl group was incorporated into the molecule. Studies in cross-reactivity with possible metabolites required the synthesis of the 4'-hydroxy analogue of bupropion. This synthesis is also described.
Dyclonine hydrochloride, a local anesthetic, is known to degrade in aqueous media. In this paper, the isolation and characterization of two major degradation products, formed by heating of an aqueous solution of dyclonine hydrochloride for 2 weeks at 50 degrees C, are presented. The proton and carbon-13 nuclear magnetic resonance, infrared, and mass spectral data reported conclusively show the two products to be 1-(4-butoxyphenyl)-2-propen-1-one and 1-(4-butoxyphenyl)-3-hydroxy-1-propanone. The proton and carbon-13 nuclear magnetic resonance spectral data of the free dyclonine base are also included.
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Xanthohumol (Xn) has well-established chemopreventive potential in vitro. In order to carry out in vivo bioavailability and tissue distribution studies,( 14)C-labelled Xn was produced by biolabelling. Supplying hop sprouts with 5 mCi [U-(14)C]glucose led to incorporation of (14)C into Xn. Delivering the radioactive precursor at once resulted in Xn with a specific activity of 318 microCi.mmol(-1); if however the amount was supplied in aliquots over 4 days a specific activity of only 53.1 microCi.mmol(-1) Xn was obtained.
B-chronic lymphocytic leukemia (B-CLL) is an indolent lymphoid malignancy with variable prognosis. Adverse prognostic factors comprise treatment resistance, cytogenetics (11q- and 17p-), the presence of unmutated Ig genes, and the more comprehensive activation marker Zap 70. In contrast to diminished sensitivity to chemotherapy, Zap 70+ B-CLL cells retain their responsiveness to manipulation of signal transduction and monoclonals. Xanthohumol (XA) has recently been documented to have an impact on breast cancer cell growth and invasiveness in vitro. Based on these observations, lymphocytes from patients with B-CLL were cultured in the presence of XA in vitro. XA induced a dose-dependent killing of B-CLL cells at an LD(50) ((24 h)) of 24.4 +/- 6.6 microM, independent of known adverse prognostic factors including functional loss of p53. Cell death was associated with poly (ADP)-ribose polymerase cleavage and annexin V positivity, suggestive of an apoptotic mechanism. Surprisingly, p 70(S 6 K) phosphorylation was stimulated upon XA treatment. In conclusion, XA has an antitumor activity on B-CLL cells in vitro. The molecular mechanisms behind this pro-apoptotic effect deserve further investigation.
Xanthohumol (XN), a prenylated chalcone, has been proposed to have beneficial effects on human health, including antimicrobial activity. To clarify whether the exposure to XN has an impact on the composition of the intestinal microbiota, 100 mg XN/kg body weight was given daily to rats for 4 wk. Diversity of the fecal microbial community was analyzed using PCR-DGGE. Although intact XN was detected in the feces of the rats at a concentration of up to 2.3 mg/g fecal dry weight, major shifts in the PCR-DGGE patterns in response to this flavonoid were not observed. The similarity index decreased slightly from 70 to 62% for the XN-treated rats and from 71 to 63% for the untreated animals. Thus, changes in the rat fecal microbiota observed in the course of the XN application are most likely due to intraindividual variability. However, the water content of the feces increased significantly during the XN treatment period.
Xanthohumol (XN), a component of hops, is lost in significant quantities in the conventional brewing process. In commercial beers less than 0.2 mg XN/L are found. In order to increase the yield of XN in the brewing process, the parameters of XN recovery were studied. During wort boiling, XN is largely isomerised to isoxanthohumol. Further losses are owing to the precipitation and absorption of XN to yeast cells and haze particles and by filtration. The use of XN-enriched hop products combined with a late hop dosage during wort boiling proved to be effective in increasing the XN content in beer. The yield was further raised by a low-pitching rate and the abnegation of beer stabilisation. The use of dark malts had a positive effect on the XN recovery. Investigations of roasted malt extracts revealed several high-molecular substances that are able to form complexes with XN. These complexes proved to be stable in the brewing process. Depending on the addition of roasted malt or special XN-enriched roasted malt extracts, dark beers with more than 10 mg XN/L were achieved. Results obtained led to a brewing technology that produced on an industrial scale pale wheat beer with more than 1 mg XN/L.
Sodium-iodide-symporter (NIS), an integral plasma membrane glycoprotein, mediates the sodium-dependent active uptake of iodide (I(-)) into the thyroid gland, which is a fundamental step in thyroid hormone synthesis. In this work, we analyzed the influence of xanthohumol (XN), a prenylated chalcone from hops (Humulus lupulus L.), on the I(-) uptake in a cell culture model of normal, nontransformed rat thyrocytes (FRTL-5). Acute treatment with nanomolar concentrations of XN does not influence I(-) uptake, but after 2 and 3-days of XN stimulation an increase in I(-) uptake was observed; I(-) uptake was maximally increased by 50% compared to control after 3-days of XN stimulation at 1 nM. A clear time-dependent stimulation was observed which showed no marked concentration relationship, however. To investigate whether expression of NIS mRNA is also increased, we grew FRTL-5 cells for 3-days in a medium containing increasing concentrations of XN (0.1 nM-1 muM). Northern blot analysis showed no difference in NIS mRNA transcript levels between control cells and those treated with different concentrations of XN. This study revealed that nanomolar concentrations of XN, a unique compound with anticancer properties, exert stimulating effects on radioiodide uptake. In contrast to many other plant-derived phenolic secondary metabolites such as (iso-)flavonoids, which inhibit I(-) uptake, XN might be an interesting candidate for more efficient radioiodide therapy of thyroid and perhaps other cancer expressing NIS such as breast cancer.
Xanthohumol (XN) is the principal prenylated flavonoid of the hop plant and has recently gained considerable interest due to its potential cancer-chemopreventive effects. However, the metabolism of XN has not yet been investigated in detail. Therefore, we studied the in vitro phase II metabolism of XN using nine human recombinant UDP-glucuronosyltransferases (UGT) and five sulfotransferases (SULT). The identification of the metabolites formed was elucidated using HPLC with diode array detection as well as HPLC/API-ES MS. XN was efficiently glucuronidated by UGT 1 A 8, 1 A 9, and 1 A 10; further important UGTs were UGT 1 A 1, 1 A 7, and 2 B 7. With respect to the sulfation reaction, SULT 1 A 1*2, 1 A 2, and 1 E 1 were the most active SULT forms. UGT 1 A 3, 1 A 4, and 1 A 6 as well as SULT 1 A 3 and 2 A 1 were of minor importance for the conjugation of XN. Three mono-glucuronides as well as three mono-sulfates were identified. Considering the tissue distribution of the tested UGT and SULT enzyme forms, these findings suggest a prominent role for the glucuronidation and sulfation of XN in the liver as well as in the gastrointestinal tract.
Xanthohumol (XN) is one of the major prenylflavonoids found in hop cones (Humulus lupulus L.). In this study, we investigated the cell growth inhibitory potential of XN on cultured human colon cancer cells. Cell proliferation was measured by sulforhodamine B staining. Poly(ADP-ribose)polymerase (PARP) cleavage, activation of caspases-3, -7, -8, and -9, and Bcl-2 family protein expression were detected by Western blot analyses. XN significantly reduced proliferation of the HCT 116-derived colon cancer cell line 40--16. Half-maximal inhibitory concentrations decreased from 4.1 microM after 24 h treatment to 3.6 and 2.6 microM after 48 and 72 h incubation, respectively. Treatment with 15 microM XN for 48 h and with 5 microM for 72 h led to the detection of the cleaved 89 kDa fragment of 116 kDa PARP as an indication of apoptosis induction. Concomitantly, we observed activation and cleavage of the effector caspases-3 and -7, induced by activation of the initiator caspases -8 and -9. Expression of anti-apoptotic Bcl-2 was down regulated when the cells were treated with XN for 48--72 h. We conclude that induction of apoptosis by downregulation of Bcl-2 and activation of the caspase cascade may contribute to the chemopreventive or therapeutic potential of XN.
Xanthohumol (XN) is a prenylated chalcone, which has been shown to possess a broad range of potential cancer preventive and additional biological activities. In the present study, we have determined the subchronic 4-wk toxicity of XN and monitored its influence on fertility and development of offspring in two fertility studies. Four-week-old female Sprague Dawley (SD) rats were treated with 0.5% XN in the diet or with 1,000 mg XN/kg body weight (b.w.) per day by gavage for 28 days. No remarkable treatment-related changes in general appearance and b.w. occurred during the study. After autopsy, liver, kidney, lung, heart, stomach, and spleen were examined macroscopically and histopathologically. Relative liver weights of animals in both treatment groups were significantly reduced by 30--40% in comparison with the control group, indicating weak hepatotoxicity. Also, mammary glands of treated rats appeared less developed compared to the controls. Consequently, we investigated the influence of XN on rat reproduction. In two fertility studies, XN (100 mg/kg b.w. per day), given either for 4 wk prior to or during mating, gestation, and nursing, did not cause any adverse effects on female reproduction and the development of offspring. Noteworthy, treatment of male rats prior to mating significantly (p=0.027) increased the sex ratio of male to female offspring. Overall, lifelong treatment at a daily dose of 100 mg/kg b.w. in a two-generation study did not affect the development of SD rats.
This review summarizes the capacity of xanthohumol (XN) in comparison with additional hop constituents and metabolites to act as an antiinfective agent against microorganisms including bacteria, viruses, fungi and malarial protozoa. XN was shown to inhibit the Gram-positive bacteria Staphylococcus aureus and Streptococcus mutans. Antiviral activity was demonstrated against bovine viral diarrhea virus, cytomegalovirus, herpes simplex virus type 1 and 2 and human immunodeficiency virus 1. Inhibition of two Trichophyton spp. was indicative of antifungal activity. Finally, XN potently inhibited the replication of Plasmodium falciparum, the causative agent of malaria. This effect was linked to the inhibition of glutathione-mediated degradation and detoxification of haemin, a by-product of the parasitic digestion of haemoglobin. Overall, these activities further contribute to the broad spectrum of biological effects observed with XN.
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Complex metabolic mixtures of 2-aminopropiophenones, obtained both after in vitro and human in vivo metabolism of these compounds, have been investigated using both mass spectrometry and gas chromatography/mass spectrometry. The mass spectrometric fragmentation schemes of the compounds have been proposed and verified. The schemes are based on the characteristic fragments obtained by alpha-cleavage of these compounds using direct inlet mass spectrometry or gas chromatography/mass spectrometry. These findings were confirmed with chemical ionization mass spectrometry, when quasi-molecular (MH+) ions were obtained as the highest relative abundance ions for all the compounds investigated, and were used in metabolic investigations of 2-aminopropiophenones.