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At least 19 recordsLinked to original sources
PubMed1988

Effect of pyridoxal isonicotinoyl hydrazone and other hydrazones on iron release from macrophages, reticulocytes and hepatocytes.

A model consisting of 59Fe-labelled macrophages was developed for screening potential iron-chelating drugs. Mouse peritoneal macrophages, induced by previous intraperitoneal injections of 3% thioglycollate, were labelled in vitro by their exposure to immune complexes of 59Fe-transferrin-antitransferrin antibody. Optimal conditions for macrophage labelling and subsequent 59Fe release were established. Sixty-two aromatic hydrazones, the majority of which had iron binding structures similar to pyridoxal isonicotinoyl hydrazone, were synthesized by condensation of aromatic aldehydes (pyridoxal, salicylaldehyde, 2-hydroxy-1-naphthylaldehyde and 2-furaldehyde) with various acid hydrazides prepared by systematic substitutions on the benzene ring. These compounds were examined for their potential to stimulate 59Fe release from 59Fe-labelled macrophages and also from reticulocytes and hepatocytes loaded with non-heme 59Fe. The majority of hydrazones derived from pyridoxal, salicylaldehyde and 2-hydroxy-1-naphthylaldehyde seemed to be equally effective in both the macrophage and reticulocyte testing systems. However, the pyridoxal hydrazones were much more active in hepatocytes than the other groups of hydrazones. Several compounds proved to be very potent in mobilizing 59Fe. These included hydrazones derived from 2-hydroxy-1-naphthylaldehyde and benzoic acid hydrazide, p-hydroxybenzoic acid hydrazide, 2-thiophenecarboxylic acid hydrazide, and also pyridoxal benzoyl hydrazone, pyridoxal m-fluorobenzoyl hydrazone and pyridoxal 2-thiophenecarboxyl hydrazone.

Animals↗
PubMed1992

Evaluation of the iron chelation potential of hydrazones of pyridoxal, salicylaldehyde and 2-hydroxy-1-naphthylaldehyde using the hepatocyte in culture.

A range of new analogues of the promising iron chelator pyridoxal isonicotinoyl hydrazone was prepared and assessed for activity in reducing hepatocyte iron, mechanism of action and potential in iron-chelation therapy. A total of 45 compounds were synthesized by condensation of aromatic aldehydes (pyridoxal, salicylaldehyde and 2-hydroxy-1-naphthylaldehyde) with various acid hydrazides prepared by systematic substitutions on the benzene ring or by the replacement of the ring with an acetyl, pyridyl, furoyl or thiophene moiety. The effects of these compounds on 59Fe uptake and intracellular distribution in hepatocytes in culture and on 59Fe mobilization from prelabeled hepatocytes were assessed. Toxicity, lipophilicity and the ability to chelate plasma transferrin-bound 59Fe were also evaluated. Several compounds were much more active than pyridoxal isonicotinoyl hydrazone and may have clinical potential. These included pyridoxal benzoyl hydrazone, pyridoxal p-methoxybenzoyl hydrazone, pyridoxal m-fluorobenzoyl hydrazone and pyridoxal 2-pyridyl hydrazone. All were more effective at reducing iron uptake than mobilizing hepatocyte iron; they also may act primarily on the transit iron pool rather than on storage iron. Other compounds (e.g., salicylaldehyde p-t-butyl-benzoyl hydrazone) redistributed ferritin-59Fe to different intracellular sites but had little net effect on hepatocyte iron levels.

Animals↗
PubMed1976

Phosphorus-nitrogen compounds. 20. Thiophosphorus hydrazones.

Six pyridine-2-carboxaldehyde, one pyridine N-oxide 2-carboxaldehyde, and five diketone thiophosphoric hydrazones, three thiophosphoric hydrazides, and two cupric chelates were synthesized. The chelates and nine of the hydrazones were tested against Ehrlich ascites carcinoma. Seven of these latter agents were administered concurrently with either cupric and/or ferrous salts to mice bearing this tumor. The greatest activity was found with the chelate, cimethyl pyridine-2-carboxyaldehyde phosphorothioic hydrazone-copper (1:1). The hydrazone portion of this chelate also formed a ligand-copper (2:1) complex. Although all of the hydrazones but one were inactive when evaluated alone, the concurrent injection of cupric ion increased survival times by an avoli alkaline phosphatase was found to be inhibited by two thiosemicarbazones in a manner similar to that previously reported by these agents against alkaline phosphatase derived from Sarcoma 180-6-thiopurine resistant ascites cells. None of the 14 hydrazides or hydrazones tested against E. coli enzyme displayed significant inhibition.

Alkaline Phosphatase↗
PubMed1978

Interference in assays for hydralazine in humans by a major plasma metabolite, hydralazine pyruvic acid hydrazone.

The present study showed that published spectrophotometric and GLC methods for hydralazine in plasma do not distinguish between the drug and a major plasma metabolite, hydralazine pyruvic acid hydrazone. These methods involve the acid treatment of the sample, which hydrolyzes that hydrazone back to hydralazine. A specific GLC assay for the hydrazone was developed and involves its selective extraction from plasma and transformation to 3-trifluoromethyl-s-triazolo[3,4-a]phthalazine. This derivative could be sensitively measured by GLC using an electron-capture detector. With this procedure, it was shown that most "apparent hydralazine" in plasma is the hydrazone, which forms rapidly from hydralazine and endogenous pyruvic acid. Previous work indicated that the hydrazone was inactive when administered intravenously to rabbits.

Chromatography, Gas↗
PubMed1989

Pyridoxal isonicotinoyl hydrazone and analogues. Study of their stability in acidic, neutral and basic aqueous solutions by ultraviolet-visible spectrophotometry.

The ultraviolet-visible absorption spectra of the orally effective iron chelator, pyridoxal isonicotinoly hydrazone (PIH), and three analogues, pyridoxal benzoyl hydrazone (PBH), pyridoxal p-methoxybenzoyl hydrazone (PpMBH) and pyridoxal m-fluorobenzoyl hydrazone (PmFBH) have been measured in aqueous solution with various concentrations of added acid or alkali. Assignment of absorption bands to various molecular species in equilibrium in aqueous solution is made by reference to their acid ionisation constants. All four hydrazones were stable at physiologial pH, but hydrolysed in strongly acidic and basic solutions, resulting in the liberation of pyridoxal and the acid hydrazide. In acidic solutions this resulted in a dramatic decrease in the intensity of absorption at wavelengths of 225 nm and above 300 nm, allowing a quantitative estimate of the degree of acid-catalysed hydrolysis of the ligands. These results indicate that for oral administration the chelator should be administered with calcium carbonate or provided with an enteric coating to minimise acid-catalysed hydrolysis in the stomach. At high pH, base-catalysed hydrolysis occurred, resulting in a decrease in the absorption at a wavelength of 387 nm.

Drug Stability↗
PubMed1979

Mutagenic activity of cytostatic methyl hydrazones with different strains of Salmonella typhimurium.

Experiments are performed to ascertain the mutagenic properties of four new cytostatic methyl-hydrazones in the Ames test using different strains of Salmonella typhimurium. As could be demonstrated all four hydrazones are mutagenic per se without a metabolic activation through rat liver microsomes (S-9 fraction). Whereas the beta-chloroethyl hydrazones B1 and B2 cause a base-pair substitution with the strains TA100 and TA1535 the methyl-hydrazones EB4 and CyB4 both cause base-pair substitution with TA100 and frameshift mutation with TA98. At both strains the mutagenic activity of Cy84 ist powerful. Furthermore, no relation could be detected between the mutagenic properties of the methyl-hydrazones and their alkylating behaviour on 4-(4-nitrobenzyl)-pyridine.

Methylhydrazines↗
PubMed1986

Preparation of protein conjugates via intermolecular hydrazone linkage.

Proteins can be modified at their amino groups under gentle conditions to contain an average of three to six aryl aldehyde or acyl hydrazide groups. These two types of modified proteins at about 10 microM concentration condense with each other at pH approximately 5 to form conjugates linked by hydrazone bonds. Under proper conditions conjugates mainly of dimers and trimers in size or, if desired, higher oligomers can be obtained. The conjugates can be dissociated to their individual protein components by an exchange reaction with an excess of acetyl hydrazide. The reversible hydrazone bonds of conjugates can be reduced with NaCNBH3 to give stable hydrazide bonds. The stability of protein-hydrazone conjugates was found to be significantly greater than that of the model compound, the N-acetylhydrazone of p-carboxybenzaldehyde. This difference is believed to result from the presence of multiple hydrazone linkages in protein conjugates.

Aldehydes↗
PubMed1978

Identification of hydrallazine and hydrallazine hydrazone metabolites in human body fluids and quantitative in vitro comparisons of their smooth muscle relaxant activity.

1 Serum and urine from hypertensive subjects on chronic oral hydrallazine therapy were studied using gas chromatographic/mass spectrometry techniques. 2 Metabolites resulting from acetylation, hydrolysis and conjugation reactions were detected. The acetone, pyruvate and alpha-ketoglutarate hydrazone were identified. 3 The activity of the pyruvate and alpha-ketoglutarate hydrazones were compared with that of hydrallazine using isolated rabbit aortic strips. 4 Both hydrazones were active under in vitro conditions, producing smooth muscle relaxant effects equal to those of hydrallazine. 5 It is concluded that hydrazone metabolites will contribute to the hypotensive effects of hydrallazine therapy in proportion to their relative abundance, persistence in vascular tissues and intrinsic activity.

Animals↗
PubMed1978

[Newer antimycotics. IV. Aryl-hydrazones of mesoxalic-acid-seminitril-hydrazid (author's transl)].

The author produced a number of aryl-hydrazones of mesoxalic-acid-seminitril-hydrazide and their N2-acyl-derivatives, farther the halogeno-substituted phenyl-hydrazones of mesoxalic-acid-seminitril-hydrazones, and investigated their fungistatic efficiency in vitro. From the author's results it can be concluded, that 2-, 3- and 4-chloro-phenyl-hydrazones of mesoxalic-acid-siminitril-hydrazide exert a strong fungistatic effect on Trichophyton- and Epidermophyton-species, but they are inactive on other fungi-strains. Their N2-acyl-derivatives, farther with aldehydes and ketones formed derivatives of the previous compounds exert any fungistatic effect neither on Trichophyton- and Epidermophyton-species, nor on other fungi-strains. From this it can be concluded, that the fungistatic activity of the investigated compounds is strong structur-specific.

Antifungal Agents↗
PubMed1978

Interaction of hydralazine and hydrazone derivatives with contractile mechanisms in rabbit aortic smooth muscle.

The mechanism of action and relative potency of hydralazine (H) and tow hydrazone derivatives were investigated using isolated rabbit aortic strips. H, hydralazine acetone hydrazone (HA) and hydralazine butanone hydrazone (HBH) relaxed established K+ and norepinephrine (NE) contractures, and inhibited the development of contractures to these two agents on preincubation. H, HA and HBH increased the threshold to Ca++ and decreased the maximum tension responses during K+-Ca++-contractures (HA greater than H, P less than .05; HBH greater than H P less than .01). The Ca++-dependent and Ca++-independent components of NE contractures were both inhibited by H, HA and HBH. NE contractures were more sensitive to the effects of H than K+ contractures. These results are consistent with the conclusion that H and hydrazone derivatives produce effects on vascular muscle both by interactions with the fluxes of Ca++ from the extracellular space and effects on release from cell stores. However, other possibilities need to be assessed experimentally.

Animals↗
PubMed1989

Iron chelators of the pyridoxal isonicotinoyl hydrazone class. III. Formation constants with calcium(II), magnesium(II) and zinc(II).

Formation constants for the calcium(II), magnesium(II) and zinc(II) complexes of the orally effective iron chelator, pyridoxal isonicotinoyl hydrazone (PIH) and three analogues, pyridoxal benzoyl hydrazone (PBH), pyridoxal p-methoxybenzoyl hydrazone (PpMBH) and pyridoxal m-fluorobenzoyl hydrazone (PmFBH) have been determined by potentiometry at 25 degrees C and I = 0.1 M [KNO3]. The four ligands bind calcium(II) weakly and magnesium(II) only slightly more strongly, as a 1:1 complex which is formed at pH greater than 8. The chelation of zinc(II) for all the ligands studied was greater than that for calcium(II) and magnesium(II), with complexation generally becoming significant at about pH 5. Thus, chelation of zinc(II) but not calcium(II) or magnesium(II) at physiological pH, 7.4 may be expected. Calculated values of the concentration of uncomplexed metal ion indicate that the selectivity of these ligands towards Fe(III) is comparable to that of the clinically used chelator desferrioxamine.

Calcium↗
PubMed1985

Iron chelation by pyridoxal isonicotinoyl hydrazone and analogues in hepatocytes in culture.

Pyridoxal isonicotinoyl hydrazone (PIH) and several analogues were synthesized and assessed in the rat hepatocyte culture for their potential in iron chelation therapy. Pyridoxal isonicotinoyl hydrazone and pyridoxal benzoyl hydrazone were as effective as desferrioxamine (DFO) in reducing both net uptake of rat transferrin-59Fe and incorporation into ferritin by hepatocytes. Dialysis studies showed that this was due to a cellular action and not to the extracellular chelation of transferrin-bound 59Fe. The analogues of PIH were more effective in mobilization studies than PIH and DFO, releasing more 59Fe from ferritin as well as from the stroma-mitochondrial membranes in hepatocytes prelabelled using transferrin-59Fe. Chelator action was dependent on incubation time, concentration, temperature and lipophilicity. Pyridoxal benzoyl hydrazone, the most effective iron chelator, was also the most lipophilic, suggesting that access to cellular iron compartments as well as iron-binding affinity is important in effective iron chelation.

Animals↗
PubMed1978

Spectrophotometric determination of isoniazid in presence of its hydrazones.

A spectrophotometric determination of isoniazid in the presence of its hydrazones was developed. The method involves the reaction between isoniazid and 2,3-dichloro-1,4-naphthoquinone in the presence of ammonia in an ethanolic medium. The colored product has an absorbance maxium at 640 nm. The Lambert-Beer law is obeyed in the 1--14-microgram/ml range. The proposed method was applied to the analysis of isoniazid tablets. In commercial tablets, hydrazone formation due to the reaction between isoniazid and lactose was detected by TLC. The analysis of lactose-containing isoniazid tablets showed 10--22% lower recovery than that obtained by the official method. Hydrazone formation in tablets probably interferes with isoniazid bioavailability.

Color↗
PubMed1986

Hydrazone formation of 2,4-dinitrophenylhydrazine with pyrroloquinoline quinone in porcine kidney diamine oxidase.

Homogeneous diamine oxidase (EC 1.4.3.6) from porcine kidney was treated with the inhibitor 2,4-dinitrophenylhydrazine (DNPH). The coloured compounds formed were detached with pronase and purified to homogeneity. When the reaction with DNPH was conducted under an O2 atmosphere, the product (obtained in a yield of 55%) was the C(5)-hydrazone of pyrroloquinoline quinone (PQQ) and DNPH, as revealed by its chromatographic behaviour, absorption spectrum and 1H-NMR spectrum. Only 6% of this hydrazone was formed under air, the main product isolated being an unidentified reaction product of DNPH with the enzyme. Porcine kidney diamine oxidase is the second mammalian enzyme shown to have PQQ as its prosthetic group. In view of the requirements for hydrazone formation with DNPH, it is incorrect to assume that inhibition of this type of enzymes with common hydrazines is simply due to blocking of the carbonyl group of its cofactor.

Amine Oxidase (Copper-Containing)↗
PubMed1991

Formation of methyl radicals during the catalase-mediated oxidation of formaldehyde hydrazone.

It has been suggested that formaldehyde hydrazone, a condensation product of hydrazine with formaldehyde, plays an important role in hydrazine-promoted DNA methylation in vivo. The present study demonstrated by spin-trapping experiments with 5,5-dimethyl-1-pyrroline-N-oxide and tert-nitrosobutane that catalase-mediated oxidation of formaldehyde hydrazone generates methyl radicals. Both the use of two spin-traps and parallel studies of oxygen consumption were important for excluding possible artefacts of spin-trapping experiments with tert-nitrosobutane. Hydrazine was also oxidized by catalase but only hydroxyl radicals were detected. Metabolic activation of formaldehyde hydrazone to methyl radicals may be of importance in regard to hydrazine-mediated toxicity and carcinogenicity.

Catalase↗