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Biomedical subjects

E Hajdu

Publications and source records attributed to E Hajdu.

At least 19 recordsLinked to original sources
PubMed2000

Flavopiridol binds to duplex DNA.

Flavopiridol, the first potent cyclin-dependent kinase inhibitor to enter clinical trials, was recently found to be cytotoxic to noncycling cells. The present studies were performed to examine the hypothesis that flavopiridol, like several other antineoplastic agents that kill noncycling cells, might also interact with DNA. Consistent with this possibility, treatment of A549 human lung cancer cells with clinically achievable concentrations of flavopiridol resulted in rapid elevations of the DNA damage-responsive protein p53. In further studies, the binding of flavopiridol to DNA was examined in vitro by four independent techniques. Absorption spectroscopy revealed that addition of DNA to aqueous flavopiridol solutions resulted in a red shift of the flavopiridol lambda(max) from 311 to 344 nm, demonstrating an isosbestic point typical of changes seen with DNA-binding compounds. Reverse-phase high-performance liquid chromatography demonstrated that flavopiridol binds to genomic DNA to a similar extent as ethidium bromide and Hoechst 33258. Nuclear magnetic resonance spectroscopy revealed that DNA caused extreme broadening of flavopiridol 1H nuclear magnetic resonance signals that could be reversed by addition of ethidium bromide or by DNA melting, suggesting that flavopiridol binds to (and likely intercalates into) duplex DNA. Equilibrium dialysis demonstrated that the equilibrium dissociation constant of the flavopiridol-DNA complex (5.4+/-3.4 x 10(-4) M) was in the same range observed for binding of the intercalators doxorubicin and pyrazoloacridine to DNA. Molecular modeling confirmed the feasibility of flavopiridol intercalation into DNA and analysis of the effects of flavopiridol in the National Cancer Institute tumor cell line panel using the COMPARE algorithm demonstrated that flavopiridol most closely resembles cytotoxic antineoplastic intercalators. Collectively, these data suggest that DNA might be a second target of flavopiridol, providing a potential explanation for the ability of this agent to kill noncycling cancer cells.

Acridines↗
PubMed2000

Novel polycyclic guanidine alkaloids from two marine sponges of the genus Monanchora.

Two marine sponges of the genus Monanchora (Poecilosclerida, Crambeidae) have been found to contain new polycyclic guanidine alkaloids bearing the (5,6,8b)-triazaperhydroacenaphthylene skeleton. Their structures have been determined by detailed spectroscopic analysis. Dehydrobatzelladine C (1) has been isolated from M. arbuscula and crambescidins 359 (2) and 431 (3) from M. unguiculata. The chemotaxonomic implications of these findings are discussed.

Alkaloids↗
PubMed2000

Arenosclerins A-C and haliclonacyclamine E, new tetracyclic alkaloids from a Brazilian endemic Haplosclerid sponge Arenosclera brasiliensis.

Arenosclerins A (2), B (3), and C (4), as well as haliclonacyclamine E (1), are new tetracyclic alkylpiperidine alkaloids isolated from a new species of marine sponge belonging to the order Haplosclerida, Arenosclera brasiliensis, a species endemic to the southeastern Brazilian coast. The alkaloids were isolated as their hydrochloride salts and identified by analysis of spectroscopic data. Data obtained from (1)H-(1)H COSY, HMBC, and HSQC-TOCSY NMR experiments allowed complete assignment of the (1)H and (13)C resonances, and analysis of the NOESY and ROESY spectra showed that the only differences between 2, 3, and 4 were the relative stereochemistries of the bispiperidine ring system. Arenosclerins A-C are the first haliclonacyclamine/halicyclamine-related alkaloids with a hydroxy group in the bridging alkyl chain.

Alkaloids↗
PubMed2000

Characterization of 2'-deoxyadenosine adducts derived from 4-oxo-2-nonenal, a novel product of lipid peroxidation.

Analysis of the reaction between 2'-deoxyadenosine and 4-oxo-2-nonenal by liquid chromatography/mass spectrometry revealed the presence of three major products (adducts A(1), A(2), and B). Adducts A(1) and A(2) were isomeric; they interconverted at room temperature, and they each readily dehydrated to form adduct B. The mass spectral characteristics of adduct B obtained by collision-induced dissociation coupled with multiple tandem mass spectrometry were consistent with those expected for a substituted etheno adduct. The structure of adduct B was shown by NMR spectroscopy to be consistent with the substituted etheno-2'-deoxyadenosine adduct 1' '-[3-(2'-deoxy-beta-D-erythropentafuranosyl)-3H-imidazo[2, 1-i]purin-7-yl]heptane-2' '-one. Unequivocal proof of structure came from the reaction of adducts A(1) and A(2) (precursors of adduct B) with sodium borohydride. Adducts A(1) and A(2) each formed the same reduction product, which contained eight additional hydrogen atoms. The mass spectral characteristics of this reduction product established that the exocyclic amino group (N(6)) of 2'-deoxyadenosine was attached to C-1 of the 4-oxo-2-nonenal. The reaction of 4-oxo-2-nonenal with calf thymus DNA was also shown to result in the formation of substituted ethano adducts A(1) and A(2) and substituted etheno adduct B. Adduct B was formed in amounts almost 2 orders of magnitude greater than those of adducts A(1) and A(2). This was in keeping with the observed stability of the adducts. The study presented here has provided additional evidence which shows that 4-oxo-2-nonenal reacts efficiently with DNA to form substituted etheno adducts.

Aldehydes↗
PubMed2000

Metabolism and excretion of [(14)C]celecoxib in healthy male volunteers.

We determined the disposition of a single 300-mg dose of [(14)C]celecoxib in eight healthy male subjects. The [(14)C]celecoxib was administered as a fine suspension reconstituted in 80 ml of an apple juice/Tween 80/ethanol mixture. Blood and saliva samples were collected at selected time intervals after dosing. All urine and feces were collected on the 10 consecutive days after dose administration. Radioactivity in each sample was determined by liquid scintillation counting or complete oxidation and liquid scintillation counting. Metabolic profiles in plasma, urine, and feces were obtained by HPLC, and metabolites were identified by mass spectrometry and NMR. [(14)C]Celecoxib was well absorbed, reaching peak plasma concentrations within 2 h of dosing. [(14)C]Celecoxib was extensively metabolized, with only 2.56% of the radioactive dose excreted as celecoxib in either urine or feces. The total percentage of administered radioactive dose recovered was 84.8 +/- 4.9%, with 27.1 +/- 2.2% in the urine and 57.6 +/- 7.3% in the feces. The oxidative metabolism of celecoxib involved hydroxylation of celecoxib at the methyl moiety followed by further oxidation of the hydroxyl group to form a carboxylic acid metabolite. The carboxylic acid metabolite of celecoxib was conjugated with glucuronide to form the 1-O-glucuronide. The percentages of the dose excreted in the feces as celecoxib and the carboxylic acid metabolite were 2.56 +/- 1.09 and 54.4 +/- 6.8%, respectively. The majority of the dose excreted in the urine was the carboxylic acid metabolite (18.8 +/- 2.1%); only a small amount was excreted as the acyl glucuronide (1.48 +/- 0.15%).

Administration, Oral↗
PubMed1997

1,3-Dimethylisoguanine, a new purine from the marine sponge Amphimedon viridis.

A new purine, 1,3-dimethylisoguanine (1), has been isolated from the marine sponge Amphimedon viridis and identified by analysis of spectroscopic data. Compound 1 increased the contractions obtained by transmural electrical stimulation in the guinea pig longitudinal muscle/myenteric plexus in a dose-dependent manner.

Animals↗
PubMed1996

Chemical and pharmacological characterization of halitoxin from Amphimedon viridis (Porifera) from the southeastern Brazilian coast.

The halitoxin complex from the marine sponge Amphimedon viridis, collected in the São Sebastião channel (southeastern Brazilian coast), was isolated by gel-filtration chromatography on Sephadex LH-20. Spectroscopic data (1H, 13C and 2D-NMR) of halitoxin from A. viridis indicated that it has the same two alkylpyridine monomers composition of the previously isolated halitoxin from Amphimedon compressa (as Haliclona rubens). Nevertheless, analysis by High Performance Gel Permeation Chromatography indicated that the halitoxin complex of A. viridis has a lower molecular weight (500, 2000 and 5000 Da; the major component corresponding to the fraction of 2000 Da MW) when compared to the previously isolated halitoxin complex from A. compressa. Some pharmacological properties of the halitoxin complex from A. viridis were evaluated in terms of lethality, antimitosis, hemolysis and neurotoxicity. The possible chemotaxonomic value of alkyl pyridine alkaloids is discussed.

Action Potentials↗
PubMed1996

Isolation and identification of metabolites of leukotriene A4 hydrolase inhibitor SC-57461 in rats.

The metabolic fate of SC-57461, N-methyl-N-[3-[4-(phenylmethyl)-phenoxy]propyl]-beta-alanine, a potent and specific inhibitor of the leukotriene A4 hydrolase, was determined by LC/MS/MS, NMR and GC/MS in male Sprague-Dawley rats. The major metabolites of SC-57461 in rats were the desmethyl metabolite, the hydroxylated metabolite, the N-oxide metabolite, the hydroxylamine metabolite, and the propionic acid metabolite. The N-oxide metabolite was found to be stable in the rat plasma and urine, but was unstable in most organic solvents (methanol, acetonitrile, and methylene chloride, etc.) because of the classic Cope reaction of the N-oxide, which led to the formation of the corresponding hydroxylamine product and acrylic acid. The hydroxylamine metabolite and acrylic acid were reactive in the biomatrix and could not be isolated in the in vivo samples. However, formation of the hydroxylamine metabolite and acrylic acid from the N-oxide metabolite in methylene chloride was verified by NMR. The propionic acid metabolite was found to be the common metabolite shared by SC-57461, N-oxide metabolite, as well as the hydroxylamine metabolite, which suggested a sequential metabolism of SC-57461 in rats. The ultimate fate of the propionic acid metabolite was incorporation into rat glycerolipid metabolism as a result of its structural similarity to aryl-substituted propionic acid, a known class of compounds that can be incorporated into rat glycerolipid metabolism. Finally, the isolated hydroxylated metabolite and the N-desmethyl metabolite were found to have excellent inhibitory effects toward leukotriene A4 hydrolase and therefore were the major active metabolites of SC-57461 in rats.

Administration, Oral↗
PubMed1982

Echocardiographic criteria for the diagnosis of congestive (dilated) cardiomyopathy.

M-mode echocardiograms of 29 patients with congestive cardiomyopathy verified by either complete angiographic study or autopsy were compared with those of normal persons in order to find indices which separate individual cases. Three indices to be used as echocardiographic criteria of congestive cardiomyopathy are proposed: E-point separation over 10 mm, left ventricular end-diastolic dimension over 55 mm, and per-cent fractional shortening below 20%. It is suggested that segmental wall motion disturbances cannot be considered as criteria for congestive cardiomyopathy. In 76 patients with clinically suspected congestive cardiomyopathy the diagnosis was supported by the combination of the above-mentioned criteria. The authors recommend the use of these criteria for screening of the disease in the population.

Adult↗
PubMed1980

Dianhydrogalactitol and neural tumors: an in vitro, in vivo preclinical evaluation.

The effects of dianhydrogalactitol on human neuroblastomas in vitro and in vivo as heterotransplants in nude mice were determined. Four neuroblastoma lines and three primitive neuroectodermal tumor lines were found, in vitro, to have different sensitivities to the drug. The most sensitive in in vitro assays was the neuroblastoma line SK-N-Mc. Tumors from patients resistant to cyclophosphamide were sensitive to dianhydrogalactitol in vitro and in nude mice. The lack of increased cytotoxicity in vitro with concentrations greater than 12 micrograms/ml and the lowered degree of weight loss in mice treated with 6 mg/kg/day x 5 consecutive days compared to 15 mg/kg/day x 2 days (either in sequence or with a 3-day interval) suggest that clinical trials with 5-day courses or constant infusions may be more effective than intermittent pulsed doses.

Animals↗
PubMed1979

Correlation of cytology and cystoscopy.

A total of 152 patients had cytology and cystoscopy performed for either initial or recurrent bladder tumors and postoperative control examinations. Positive cytology was found in 97 per cent of patients with pathologically proved bladder tumors. However, 23 per cent of the patients with negative cytology had positive cystoscopic and pathologically proved findings. Without cystoscopic examination a significant number of recurrent tumors may be missed because of a negative cytology.

Cystoscopy↗