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An amphiphilic barbituric acid derivative was found to form stable monolayers showing a clear phase transition at the air/water interface. It is interesting to find that the deposited Langmuir-Blodgett (LB) films of the compound showed circular dichroism (CD) although the molecule itself was achiral. AFM measurements on the transferred one-layer LB film revealed that spiral nanoarchitectures were formed. It was further found that the supramolecular chirality of the LB films was related to symmetry breaking at the interface. Hydrogen bonding and the pi-pi stacking between the neighboring molecules resulted in chiral fibers which formed the spiral structures. To the best of our knowledge, this is the first report on the chirality of the molecular assemblies and spiral nanostructures formed through the air/water interface by achiral molecules.
Barbituric acid is widely used in the manufacturing of plastics, textiles, polymers, and pharmaceuticals. Three assay methods are presented, which can utilize either aqueous or solid samples. The detection of as little as 10 microg of barbituric acid can be accomplished, either as an aqueous or solid sample, when using micro reaction tubes. The red-violet endpoint is easily discerned and results upon the formation of a violuric acid derivative. A Spot Test protocol is described which allows for a positive/negative indication of barbituric acid presence. The Spot Test is sensitive to as little as 18.75 microg/ml of barbituric acid. The construction of a Standard Curve for assaying multiple samples and over longer time periods is demonstrated, and is shown to be linear from 18.75 microg/ml to 2.25 mg/ml of barbituric acid. Spectrophotometer readings are made from an absorption peak appearing at 530 nm. The molar absorptivity of the violuric acid derivative is calculated to be 31.4 per mol/l per cm. The micro reaction tube assay will quantitate as little as 10 microg of barbituric acid through interpolation with controls containing a known amount of analyte. Inorganic salts such as NaCl, NaN(3), LiBr, and CaCO(3) do not interfere with endpoint determination. Many organic compounds (also pharmaceuticals) do not inhibit the reaction.
Precise partition coefficients in 1-octanol-water at 25 degrees C were determined for three 2-thiobarbituric acids and 14 barbituric acids with a wider range of substituents. The experimental log P values (log Pexp) of barbituric acids were correlated with the carbon number and the branching effect of the C5 substituent(s) by linear regression analysis. The carbon number term makes a major contribution to the partition coefficients. The contribution of the polar effect of the C5 substituents was insignificant in contrast to a previous report. Hydrophobic constants (pi) were determined for allyl, phenyl, and chloro-substituents, and these empirical pi values gave much closer predicted calculated log P (log Pcalc) values when applied to the reported log Pexp values.
Complex monolayers of barbituric acid and melamine were formed by spreading a chloroform solution of amphiphilic barbituric acid on the subphase of melamine solution. It was confirmed that the complex monolayer was formed through in situ complementary hydrogen bonding at the air-water interface. It was interesting to find that the complex LB films showed supramolecular chirality although both of the molecules were achiral, as verified by the circular dichroism spectral measurements. It was suggested that the pi-pi stacking of the neighboring barbituric acid and melamine group in a helical sense resulted in the chirality of the molecular assemblies. Due to the directionality of the hydrogen bonding, the BA-M film could form regular aligned nanofibers on the AFM images. Increasing the subphase temperature will lead to the decrease of CD intensity and the change of the morphologies. We suggested that the strength of the hydrogen bonding resulted in the difference.
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After taking 5-vinyl-5-(1-methylbutyl)-barbituric acid (vinylbital, Speda) another not yet known metabolite (Sp 1) was isolated from urine and was identified as 5-vinyl-5-(1-methyl-3-carboxy-propyl)-bartiburic acid. Compound Sp 2a is 1-methylhydantoin. Presumably this compound is an artifact from creatinine. We have not yet been able to identify a third mercury(I)-nitrate-positive substance Sp 2b. The supposition that this compound were a metabolite of 5-vinyl-5-(1-ethyl-propyl)-barbituric acid could not be upheld. The three mercury(I)-nitrate-positive substances appearing in the urine after taking 5-vinyl-5-(1-ethyl-propyl)-barbituric acid, behaved in chromatographic analysis completely differently from the unknown compound Sp 2b. The substances were isolated. Two of them are the metabolites 5-vinyl-5-(1-ethyl-2-carboxy-ethyl)-barbituric acid and 5-(1-ethyl-propyl)-barbituric acid. We are not sure whether the third compound identified as 5-hydroxy-5-(1-ethyl-propyl)-barbituric acid, is formed in vivo, as the substance could have developed by oxidation or by the influence of peroxide contained in ether, as well. A product hydroxylized in the side chain, like in vinylbital, was not found in the metabolite urine of 5-vinyl-5-(1-ethyl-propyl)-barbituric acid.
The effects of barbituric acid and phenobarbital upon carbohydrate metabolism in mice were compared. An intraperitoneal dose of 100 mg/kg of barbituric acid increased blood glucose concentrations during an intravenous glucose tolerance test, but did not alter the rate of glucose disappearance from the blood. Barbituric acid also antagonized the hypoglycemic effect of intravenously administered tolbutamide. The same dose of phenobarbital had no effect. An in vitro concentration of 100 mug/ml of barbituric acid decreased the responsiveness of isolated mouse pancreatic islets to glucose stimulation (3.0 mg/ml D-glucose). Again phenobarbital, 100 mug/ml, was without effect. The structural similarities between barbituric acid, tolbutamide and alloxan suggest that the effects observed in these experiments might reflect a competition for binding to reactive sites on or within the pancreatic B-cell.
A bolaform Schiff base, N,N'-bis(salicylidene)-1,10-decanediamine (BSC10), has been synthesized and its interfacial hydrogen bond formation or molecular recognition with barbituric acid was investigated in comparison with that of a single chain Schiff base, 2-hydroxybenzaldehyde-octadecylamine (HBOA). It has been found that while HBOA formed a monolayer at the air/water interface, the bolaform Schiff base formed a multilayer film with ordered layer structure on water surface. When the Schiff bases were spread on the subphase containing barbituric acid, both of the Schiff bases could form hydrogen bonds with barbituric acid in situ in the spreading films. As a result, an increase of the molecular areas in the isotherms was observed. The in situ H-bonded films could be transferred onto solid substrates, and the transferred multilayer films were characterized by various methods such as UV-vis and FT-IR spectrosopies. Spectral changes were observed for the films deposited from the barbituric acid subphase, which supported the hydrogen bond formation between the Schiff bases and barbituric acid. By measuring the MS-TOF of the deposited films dissolved in CHCl3 solution, it was concluded that a 2:1 complex of HBOA with barbituric acid and a 1:2 complex of BSC10 with barbituric acid were formed. On the other hand, when the multilayer films of both Schiff bases were immersed in an aqueous solution of barbituric acid, a similar molecular recognition through the hydrogen bond occurred. A clear conformational change of the alkyl spacer in the bolaform Schiff base was observed during the complex formation with the barbituric acid.
Barbiturates derived by minor structural changes to the butenyl sidechain of the convulsant 5-ethyl-5-(3'-methyl-but-2'-enyl)-barbituric acid are almost devoid of convulsant activity, but all have anaesthetic and anticonvulsant effects. Anticonvulsant activity is also observed in the convulsant barbiturate. Increased lipophilic character does not increase anaesthetic potency, only speed of onset, and anticonvulsant activity is reduced in the more lipophilic compounds. The stereochemistry at the 3'-position of the sidechain is vitally important to convulsant activity, and also influences anticonvulsant potency.
5-(Benzyloxybenzyl)barbituric acid acyclonucleoside (BBBA) was recently synthesized as a potent and specific inhibitor of uridine phosphorylase (EC 2.4.2.3), the enzyme responsible for the catabolism of 5-fluoro-2'-deoxyuridine (FdUrd) in many types of tumors that are deficient or have little thymidine phosphorylase (EC 2.4.2.4) activity. The effect of BBBA on modulating the antitumor efficacy of FdUrd was evaluated in vitro, against the human colon carcinomas DLD-1 and HCT-15 grown in culture, and in vivo, against DLD-1 grown as xenografts in anti-thymocyte serum immunosuppressed mice. The concentrations of FdUrd that produced 50% growth inhibition after a 3-h exposure were 88 and 340 nM for HCT-15 and DLD-1, respectively. BBBA alone, at all concentrations tested, had no significant effect on the growth of DLD-1 and HCT-15 in culture. However, BBBA at 5, 10, 20, and 40 nM potentiated (P < 0.05) the cytotoxicity of FdUrd (340 nM; 3 h) against DLD-1 in culture by 20, 33, 55, and 63%, respectively. Similarly, BBBA at 10 and 20 nM potentiated the cytotoxicity of FdUrd (88 nM; 3 h) against HCT-15 in culture by 37 and 45%, respectively. In soft agar, BBBA (10 nM) also enhanced the cytocidal effect of FdUrd (10 and 32 nM) against DLD-1 by 41 and 55%, respectively, and against HCT-15 by 6 and 31%, respectively. Increasing BBBA dose to 20 nM enhanced further the FdUrd (10 and 32 nM) cytotoxicity against DLD-1 by 76 and 77%, respectively, and HCT-15 by 31 and 48%, respectively. BBBA also potentiated the chemotherapeutic efficacy of FdUrd in anti-thymocyte serum immunosuppressed mice bearing DLD-1 xenografts with no apparent host toxicity. At a low tumor burden (2.5 x 10(6) cells/mouse), 2 days treatment with FdUrd alone (50 mg/kg/day x 2) did not result in significant reduction in tumor volume. Coadministration of BBBA at 5 and 10 mg/kg/day x 2 did not potentiate the efficacy of FdUrd over that achieved by FdUrd alone, but it significantly reduced the tumor volume by 27 and 32%, respectively, when compared with untreated controls. FdUrd alone at 150 mg/kg/day x 2 reduced the tumor volume by 29%. This reduction in tumor volume was enhanced 1.8-fold by coadministration of BBBA (10 mg/kg/day x 2). At a higher tumor burden (5 x 10(6) cells/mouse) and 4 days treatment, BBBA at 10 and 30 mg/kg/day x 4 reduced further the tumor volume produced by FdUrd alone (200 mg/kg/day x 4) by 1.2- and 1.4-fold, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)
In view of the tumor inhibitory activity of various pyrimidine derivatives, investigations aimed at the structure modification of barbituric acids were performed. In accordance with the aminomethinylation principle, barbituric acids (2) are converted into 5-formimidoylbarbituric acids (4) by s-triazine (1). Aside from the free barbituric acid (2a), both 1-substituted (2b, d, and f) and 1,3-di-substituted (2c, e, and g) barbituric acids are amenable to this reaction. After introduction of the formimidoyl group into 5-position of the barbituric acid ring system, marked tumor inhibitory effects against lymphoma, lymphocytical leukemia, and luekemia L-1210, are ascertainable.
The crystal structure of barbituric acid dihydrate (C4H4N2O3*2H2O) has twice been reported as orthorhombic, space group Pnma, with all atoms (except for CH(2) H atoms) lying on the mirror plane [Al-Karaghouli et al. (1977). Acta Cryst. B33, 1655-1660; Jeffrey et al. (1961). Acta Cryst. 14, 881-887]. The present study has found that at low temperatures, below 200 K, the crystal structure is no longer orthorhombic but is non-merohedrally twinned monoclinic, space group P2(1)/n. This phase is stable down to 100 K. Above 220 K the crystal structure is orthorhombic, and between 200 and 220 K the structure undergoes a phase change, with the monoclinic-to-orthorhombic phase transition itself taking place at around 216-217 K. The size of the beta angle in the monoclinic structure is temperature dependent; at 100 K beta is around 94 degrees and it decreases in magnitude towards 90 degrees as the temperature increases. Although the hydrogen-bonding motifs are the same for both crystal systems, there are significant differences in the crystal packing, in particular the out-of-plane displacement of the two water molecules and the sp3-hybridized C atom of barbituric acid.