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J Stanek

Publications and source records attributed to J Stanek.

At least 37 records · Page 2Linked to original sources
PubMed1995

Mixed valence state in ironporphyrin aggregates.

In biological systems, metalloporphyrins play a central role in energy and electron transfer process. Our aim is to understand the influence of ligands and iron coordination of ironporphyrin on the electron transfer. The lyophilized ironporphyrin, enriched in 57Fe up to 90% has been studied by Mössbauer spectroscopy between 2.8 and 313 K. Above room temperature the bounded diffusion of the ferric iron was observed. Below 293 K a part of iron appears in mixed Fe+3<==>Fe+2 valence state with 10 meV activation energy for the electron trapping. Below 4 K a part of iron shows magnetic ordering with a broad distribution of the hyperfine field. The results are discussed in terms of metalloporphyrin aggregation process.

Electrochemistry↗
PubMed1994

CGP 48664, a new S-adenosylmethionine decarboxylase inhibitor with broad spectrum antiproliferative and antitumor activity.

Inhibitors of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (SAMDC), derived from methylglyoxal-bis(guanylhydrazone) (MGBG), have been shown to have significant antitumor activity in several human solid tumor systems (U. Regenass et al., Cancer Res., 52:4712-4718, 1992). From an ongoing effort to synthesize derivatives with increased enzyme specificity and potency and improved antitumor efficacy, we have now identified CGP 48664, a 4-amidinoindan-1-one 2'-amidinohydrazone (J. Stanek et al., J. Med. Chem., 36:2168-2171, 1993). The compound displays potent inhibition of SAMDC (50% inhibitory concentration, 5 nM), modest inhibition of diamine oxidase (50% inhibitory concentration, 4 microM), and no detectable inhibition of ornithine decarboxylase. CGP 48664 inhibits the growth of a panel of human and mouse tumor cell lines, including one which expresses the multidrug resistance phenotype, with 50% inhibitory concentrations ranging between 0.3 and 3 microM. CGP 48664 does not seem to utilize the polyamine transport carrier system since it competes poorly with spermidine for uptake into L1210 cells (Ki 161 microM) and inhibits the growth of polyamine transport-deficient Chinese hamster ovary cells. Relative to MGBG or previously described MGBG analogues, CGP 48664 accumulates to much lower intracellular concentrations. Treatment of the L1210 cell for 48 h with 3 microM CGP 48664 decreases SAMDC activity to < 10% of control and initiates a compensatory 3-fold rise in ornithine decarboxylase. Consistent with SAMDC inhibition, putrescine pools increase 10-fold, whereas spermidine and spermine pools fall to < 10% of control. In contrast to MGBG, CGP 48664 displays attenuated antimitochondrial activity as indicated by a lack of effect on pyruvate oxidation and mitochondrial DNA levels under treatment conditions which inhibit cell proliferation. Specificity of drug action was indicated further by prevention of L1210 cell growth inhibition by exogenous spermidine or spermine. More convincingly, Chinese hamster ovary cells made approximately 1000-fold resistant by chronic exposure to the analogue were found to selectively overexpress SAMDC mRNA due to gene amplification. The new SAMDC inhibitor showed potent antitumor activity against syngeneic tumors (B16 melanoma and Lewis lung carcinoma) and nude mouse human tumor xenografts (T-24 bladder carcinoma, SK MEL-24 melanoma, and MALME-3M melanoma). On the basis of its novel structure, its apparent specificity of action, and its potent antitumor activity, CGP 48664 is the candidate drug for further preclinical development.

Adenosylmethionine Decarboxylase↗
PubMed1993

4-Amidinoindan-1-one 2'-amidinohydrazone: a new potent and selective inhibitor of S-Adenosylmethionine decarboxylase.

Two isomeric amidino-2-acetylpyridine amidinohydrazones, 11 and 12, and 4-amidinoindanone amidinohydrazone, 17, have been synthesized and tested for inhibition of S-adenosylmethionine decarboxylase (SAMDC) and diamine oxidase and for antiproliferative activity against T24 human bladder carcinoma cells. Compound 11 inhibited SAMDC with an IC50 of 10 nM and was 140- and > 500-fold more potent than methylglyoxal bis(guanylhydrazone) (MGBG) and 12, respectively. The difference in potency between 11 and 12 was interpreted with the help of molecular modeling and appeared to be associated with two different low-energy conformations of the compounds. Compound 17 which represents a conformationally constrained analogue of 11, was superior to the latter and MGBG with respect to selective inhibition of SAMDC and antiproliferative activity, and is of interest as a potential anticancer agent and a drug for the treatment of protozoal and Pneumocystis carinii infections.

Adenosylmethionine Decarboxylase↗
PubMed1993

S-adenosylmethionine decarboxylase inhibitors: new aryl and heteroaryl analogues of methylglyoxal bis(guanylhydrazone).

A series of 3-acylbenzamidine (amidino)hydrazones 7a-h, the corresponding (hetero)aromatic congeners 7i-p, and 3,3'-bis-amidino-biaryls 25a-e were synthesized. The hydrazones 7a-p were prepared by conversion of the corresponding acyl nitriles 1a,c-d,i,n-p to the imido esters 3a,c-d,i and the amidines 5a,c-d,h-i, followed by a reaction with aminoguanidine, or vice versa. Similarly, the biaryl 3,3'-dinitriles 23a-e were converted, via the imino esters 24a-c or the imino thioesters 27d-e, to the diamidines 25a-e. These new products are conformationally constrained analogues of methylglyoxal bis(guanylhydrazone) (MGBG). They are up to 100 times more potent as inhibitors of rat liver S-adenosylmethionine decarboxylase (SMDC) and generally less potent inhibitors of rat small intestine diamine oxidase (DAO) than MGBG. Some of these SAMDC inhibitors, e.g., compounds 7a, 7e, 7i, 25a, and 25d, have shown antiproliferative effects against T24 human bladder carcinoma cells. These products, whose structure-activity relationships are discussed, are of interest as potential anticancer agents and drugs for the treatment of protozoal and Pneumocystis carinii infections.

Adenosylmethionine Decarboxylase↗
PubMed1993

Fine-needle aspiration diagnosis of ectopic thyroid: report of one case.

Fine-needle aspiration (FNA) of a mass of the floor of the mouth in a teenage woman showed many foamy and pigmented histiocytes, cholesterol crystals, and few sheets of follicular cells with paravacuolar granules and cytoplasmic flares. The cytologic findings were consistent with adenomatous thyroid tissue. This was confirmed by subsequent surgical excision and histologic diagnosis of the surgical specimen. The differential diagnosis and value of preoperative diagnosis by FNA of lesions of the floor of the mouth in general and ectopic thyroid in particular, are briefly discussed.

Adolescent↗
PubMed1993

Pharmacological properties of the ornithine decarboxylase inhibitor 3-aminooxy-1-propanamine and several structural analogues.

Analogues of 3-aminooxy-1-propanamine proved to be highly potent and selective inhibitors of ornithine decarboxylase (ODC). The compounds competed with ornithine for the substrate binding site of ODC, but resulted in progressive and apparently irreversible inactivation of the enzyme. Diamine oxidase was inhibited by these compounds to a lesser extent than ODC; the compounds were not metabolized by this enzyme. Several derivatives were growth-inhibitory for human T24 cells and for other mammalian cells, the most active compound being 3-aminooxy-2-fluoro-1-propanamine (AFPA). Growth-arrested cells were largely depleted of putrescine and spermidine. Cellular growth arrest could be antagonized by supplementation with spermidine. Selection for resistance against AFPA led to cells with amplified ODC genes and overexpression of the message. Some of the derivatives were tumoristatic at well-tolerated doses in mice bearing solid T24 tumours. The antiproliferative activity of these compounds appears to be mediated by polyamine depletion.

Animals↗
PubMed1993

p53 mutations in human immortalized epithelial cell lines.

Although rodent cells have been immortalized following transfection with a mutant p53 gene, the role of p53 in the immortalization of human cells is unknown. Therefore, human epithelial cell lines were examined for p53 mutations in exons 4-9 which include the evolutionarily conserved regions. A spontaneously immortalized skin keratinocyte cell line, HaCat, and three ras-transfected clones, have a p53 mutational spectrum that is typical of ultraviolet light induced mutations. A normal finite lifespan cell strain (184) and two benzo[a]pyrene immortalized mammary epithelial cell lines derived from 184 (184A1 and 184B5) contain wild type p53 sequences in exons 4-9, although elevated levels of nuclear p53 indicate an alteration in the stability of the normally transient protein. Wild type p53 was found in human bronchial, esophageal and hepatic epithelial cells immortalized by SV40 T antigen gene and human renal epithelial cells immortalized by adenovirus 5. BEAS-2B, an SV40 T antigen immortalized bronchial epithelial cell line and two subclones, have a germline polymorphism at codon 47. Inactivation of p53 by mechanisms such as mutation or complexing with proteins of DNA tumor viruses appears to be important in the immortalization of human epithelial cells.

Base Sequence↗
PubMed1992

New S-adenosylmethionine decarboxylase inhibitors with potent antitumor activity.

Methylglyoxal bis(guanylhydrazone) (MGBG) has been studied clinically as an antitumor and antileukemic agent and is recognized as a potent but nonspecific inhibitor of the key polyamine biosynthetic enzyme, S-adenosylmethionine decarboxylase (SAMDC). A series of four SAMDC inhibitors with structural features similar to MGBG have been found to have improved potency and specificity toward the target enzyme, SAMDC. Relative to MGBG, the new derivatives were much more effective in inhibiting partially purified preparations of SAMDC (50% inhibitory concentration, 10 to 100 nM), much less effective at inhibiting diamine oxidase, and inactive toward ornithine decarboxylase. The inhibitors varied relative to MGBG in their ability to compete with spermidine for uptake, with two being similar and two being less effective. Against L1210 leukemic cells and T24 bladder carcinoma cells, the compounds were slightly less effective than MGBG at inhibiting cell growth, with 50% inhibitory concentration values of 1 to 10 microM as compared with 0.5 and 1.1 microM, respectively, for MGBG. Under 50% growth-inhibitory conditions, the inhibitors decreased SAMDC activity, increased ornithine decarboxylase activity and putrescine pools, and markedly depleted spermidine and spermine pools of L1210 cells. At the same time, mitochondrial integrity as assessed by whole-cell pyruvate oxidation and mitochondrial DNA content was not affected as it was with MGBG. At doses less than one tenth that of the maximally tolerated dose, all of the new inhibitors strongly suppressed the growth of B16 melanoma in vivo with minimal weight loss or toxicity. At doses less than one sixth the maximally tolerated dose, they effectively inhibited the growth of T24 human bladder carcinoma xenografts. In these same systems, MGBG showed only marginal antitumor activity. These studies identify two potent and efficacious inhibitors of SAMDC as potential antitumor agents and reaffirm the importance of SAMDC as a target in anticancer drug discovery.

Adenosylmethionine Decarboxylase↗
PubMed1992

2-substituted 3-(aminooxy)propanamines as inhibitors of ornithine decarboxylase: synthesis and biological activity.

1-Amino-3-(aminooxy)-2-propanol (6a) has been synthesized and found to inhibit rat liver ornithine decarboxylase (ODC) with an IC50 in the nanomolar range. Compound 6a served as a basis for the design of new enzyme inhibitors, which led to the identification of 3-(aminooxy)-2-fluoropropanamine (15) as a new powerful enzyme blocker. Compound 15 inhibited ODC at 3 times lower concentrations than 6a and 3-(aminooxy)propanamine (APA), and it was superior to APA as an antiproliferative agent in inhibiting the growth of human T24 bladder carcinoma cells in vitro.

Animals↗
PubMed1991

Mutagenic activity of 6-azido deoxyhexoses and azido alcohols in Salmonella typhimurium and its inhibition by a structure-similar carbon source in the medium.

6-Azido-6-deoxy (AZd) derivatives of D-glucose, D-mannose, D-altrose, D-allose, L-idose, D-galactose, D-galactonic acid and D-galactitol, 3-azido-1,2-propanediol (azidoglycerol), 3,1-diazido-2-propanol (diazidoglycerol) and (at much higher doses) 2-azidoethanol were mutagenic in Salmonella typhimurium strains TA100 and TA1535. The mutagenic response was similar to that induced by sodium azide, i.e., the azido compounds failed to induce mutations in strain TA98, and mutagenesis was independent of plasmid pKM101, and independent of external activation. The specific mutagenicity (his+ rev/mmole) of AZd-glucose and AZd-galactose was decreased with increasing concentrations of D-glucose or D-galactose in the minimal agar medium and enhanced 100-fold or more when 0.2% citrate rather than 0.2% glucose served as the carbon source in the medium. Similarly, the mutagenic efficiency of azidoglycerol was inhibited by glycerol but not by D-glucose or D-galactose; however, the mutagenicity of sodium azide was not influenced by any of these carbon sources in the medium. The inhibition of the mutagenic action of azido hexoses and azido alcohols by non-azido structural analogs is assumed to reside in competition in transmembrane transport or for the metabolic pathways.

Alcohols↗
PubMed1991

Synthesis and aromatase inhibitory activity of novel 1-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane- and -[3.1.1]heptane-2,4- diones.

The synthesis of 3-(cyclohexymethyl)-1-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane-2, 4-dione (1h), with its optical enantiomers, and a series of novel achiral 1-(4-aminophenyl)-3-azabicyclo[3.1.1]haptane-2,4-diones (2a-i,k) is described. These compounds were tested in vitro for inhibition of human placental aromatase, a cytochrome-P450-dependent enzyme responsible for the conversion of androgens to estrogens. All of them displayed enzyme-inhibiting activity, and 3-cyclohexyl derivative 2g and 3-cyclohexylmethyl derivative 1h both proved more potent (greater than 140-fold) than the clinically effective agent aminoglutethimide [3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione, AG]. As with AG and its derivatives, the 1R-(+)-enantiomer of 1h was responsible for the enzyme inhibitory activity. These novel compounds are of interest as potential drugs for endocrine therapy of hormone-dependent tumors, e.g. breast cancer.

Aniline Compounds↗
PubMed1990

Morphological evidence for an apparent lysosomotropic activity by unsaturated putrescine analogues.

Treatment of cultured L1210 cells with the putrescine analogue, 2,5-diamino-3-hexyne, at 0.5 nM resulted in the rapid (1-2 h) appearance of numerous cytoplasmic vacuoles which were highly visible by light microscopy. Ultrastructural examination revealed that the vacuoles contained numerous membrane vesicles and electron-dense structures resembling endosomal elements. Other cellular organelles were unaffected by the drug. The overall morphological effect by 2,5-diamino-3-hexyne was nearly identical to that produced in the same cells by the known lysosomotropic agent, chloroquine. Since the putrescine analogue, 1,4-diamino-2-butyne at 1.2 mM, also produced comparable cytoplasmic vacuolation, and putrescine itself failed to do so at concentrations as high as 5 mM, it was concluded that the apparent lysosomotropic activity of the putrescine analogues was probably due to their weaker basicity related to the presence of an internal triple bond. Although it is uncertain whether the effect of the analogues on the endosomal system is related to the natural function of polyamines, the finding points out the previously unrecognized potential for certain polyamine analogues to act in this manner.

Animals↗
PubMed1990

[Clinical diagnosis and laboratory study of acute respiratory diseases of viral origin in children].

The authors analyzed retrospectively a group of 477 children aged two months to 16 years (mean age 6 years and 5 months), hospitalized on account of acute respiratory disease and subjected to virological examination. The aetiology was revealed in 53% of the sick children. In the elucidation of the aetiology participated a number of respiratory viruses, in particular the respiratory syncytial virus. The clinical picture of the disease was very varied. It was confirmed that the clinical picture does not make it possible to express in a considerable proportion of patients suspicion of an actual infectious aetiology. A mixed aetiology of acute respiratory diseases and a varied clinical picture indicate the necessity of a rapid virological and bacteriological examination in hospital practice.

Acute Disease↗
PubMed1990

[Surveillance of acute respiratory diseases in the 1988/1989 season in Czechoslovakia].

The authors submit an analysis of results of surveillance of acute respiratory diseases during the 1988/1989 season in the CSSR. The influenza epidemic took place between the 4th and 11th calendar week with a peak in the 7th week. During the epidemic 19.7% of the population in the CSR contracted the disease. The influenza epidemic was preceded by a high incidence of infections caused by a respiratory syncytia virus. As to the aetiology, influenza viruses subtypes A/H1N1/, A/H3N2/ and type B participated practically equally in the epidemic. The authors discuss the observed changes in the influenza epidemiology in recent years in Czechoslovakia and neighbouring countries.

Acute Disease↗
PubMed1990

[What is surveillance?].

The authors give an account of the development of the definition and context of epidemiological surveillance during the past decades in Czechoslovakia and in the world. They analyze views of epidemiologists who contributed in a major way to the modern concept of surveillance. The concept of surveillance reflects social conditions in the widest sense of the word and its contents are and probably will also in future be the subject of lively discussions. The authors assume that in the near future a more important part will be played by an active approach to surveillance of infections, as no modern system of health care can do without its development. Contemporary social changes will play a decisive role.

Humans↗
PubMed1990

Epidemiological analysis of acute respiratory disease (ARD) and characteristics of the influenza epidemic in Bohemia during the season 1986/1987.

The authors analyze the findings of epidemiological and virological surveillance of ARD in Bohemia during the season 1986/1987. In all, 57.5% of the Czech population was affected by acute respiratory disease (ARD). There were 5,950,832 cases reported, 124,444 complications (2.1% of the overall morbidity rate) and 5,374 deaths due to influenza, bronchitis, pneumonia and chronic pulmonary affection. The influenza epidemic commenced during the 48-th calendary week (CW) and lasted 5 weeks till the 52-nd CW. The epidemic was due to an influenza virus strain of the subtype A(H1N1) antigenically related to the drift variant A (Singapore) 6/86. Within an extremely short period of the epidemic, 1,094,865 influenza cases were reported and 22,313 cases of complications. 10.7% of the CSR population were affected during the epidemic in whose etiology noninfluenza respiratory viruses were significantly implicated, especially adenoviruses (41.7%) and the RS virus (26.9%). There was no excessive mortality in the course of the epidemic. The authors discuss the atypical nature of this particular influenza epidemic and the etiological role of respiratory viruses.

Acute Disease↗