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Biomedical subjects

H Elo

Publications and source records attributed to H Elo.

At least 19 recordsLinked to original sources
PubMed1999

Effect of Bis(guanylhydrazones) on Growth and Polyamine Uptake in Plant Cells.

In the present work the effect of several bis(guanylhydrazones) on the growth of Helianthus tuberosus tuber explants was studied. Different aliphatic congeners of glyoxal bis(guanylhydrazone) were tested. Most of the compounds displayed an inhibitory effect on growth, and a correlation between the structure of the molecule and the inhibitory activity was observed. Experiments carried out with glyoxal bis(guanylhydrazone) and its congeners methyl-, ethylmethyl-, and methylpropylglyoxal bis(guanylhydrazones) show that as the total number of side chain carbon atoms in the molecule increases, the inhibitory potency also increases. A depletion of spermidine levels was also found in the explants treated with ethylmethylglyoxal bis(guanylhydrazone), which turned out to be one of the most potent growth inhibitors. The addition of spermidine caused a significant reversion of the antiproliferative action of glyoxal bis(guanylhydrazone). The effect of these compounds on spermidine uptake in protoplasts isolated from carrot phloem parenchyma was also investigated. Only a slight competition was found when antagonists were present at concentrations 20 times higher than the polyamine, thus suggesting that bis(guanylhydrazones) do not share, at least at low concentrations, the polyamine transport system in plant cells.Key Words. Bis(guanylhydrazones)-Carrot protoplasts-Growth-Helianthus tuberosus-Polyamines-Uptakehttp://link.springer-ny.com/link/service/journals/00344/bibs/18n1p39.html

Journal Article↗
PubMed1996

Determination of the antileukemic drug mitoguazone and seven other closely related bis(amidinohydrazones) in human blood serum by high-performance liquid chromatography.

A reversed-phase (C18) HPLC method with diode-array detection was developed for the separation and determination of methylglyoxal bis(amidinohydrazone) (mitoguazone) and seven closely related aliphatic analogs thereof, namely the bis(amidinohydrazones) of glyoxal, dimethylglyoxal, ethylmethylglyoxal, methylpropylglyoxal, butylmethylglyoxal, diethylglyoxal and dipropylglyoxal. The mobile phase consisted of a non-linear binary gradient of methanol and 0.03 M aqueous sodium acetate buffer (pH 4.3). Good separation of the eight congeners was achieved. On increasing the methanol content of the eluent, the bis(amidinohydrazones) eluted in the order of increasing number of carbon atoms in the side-chains. The method was also applied to the quantitative analysis of the compounds in aqueous solution and, combined with ultrafiltration, for the separation of the eight congeners in spiked human blood serum. A separate simplified method for the quantitative determination of each of the compounds in spiked human blood serum samples was also developed. The methods developed made for the first time possible the simultaneous HPLC analysis of more than one bis(amidinohydrazones). The results obtained indicate that the bis(amidinohydrazones) studied obviously have a distinct tendency to form ion associates with acetate ions and probably also other carboxylate ions in aqueous solution. This aspect may be of biochemical significance, especially concerning the intracellular binding of the compounds. Each one of the compounds studied invariably gave rise to one peak only, this result supporting the theory that the conventional synthesis of each of the compounds gives rise to one geometrical isomer only. This result is completely in agreement with the results of previous proton and carbon NMR spectroscopic as well as X-ray diffraction studies.

Adult↗
PubMed1996

Biochemical and chemical characterization of phenylglyoxal bis(guanylhydrazone), an aromatic analogue of mitoguazone.

Since little has been known about the properties of aromatic analogues of the antineoplastic agent methylglyoxal bis(guanylhydrazone) (MGBG), an investigation was performed on phenylglyoxal bis(guanylhydrazone) (PhGBG). PhGBG competitively inhibited yeast adenosylmethionine decarboxylase (AdoMetDC) with a Ki of 65 microM. As compared to MGBG (Ki 0.23 microM), PhGBG is a much weaker inhibitor, being even weaker than the unsubstituted congener glyoxal bis(guanylhydrazone) (GBG, Ki 18 microM). PhGBG inhibited porcine kidney diamine oxidase (DAO) non-competitively, being a more potent inhibitor (Ki 0.12 microM) than GBG (Ki 0.17 microM) or MGBG (Ki 0.33 microM). Thus, PhGBG has an unfavourably high ratio of Ki(AdoMetDC)/Ki(DAO) for potential use for selectively inhibiting polyamine biosynthesis. This does not exclude the possibility that PhGBG or other aromatic congeners might have therapeutic value since the corresponding ratio of the antileukaemic congeners GBG and MGBG is also high as compared to many aliphatic non-antileukaemic analogues. The pKa1 and pKa2 values of PhGBG dication were found to be 6.39 +/- 0.02 and 8.64 +/- 0.02 respectively, their difference being distinctly larger than in the case of GBG or its C-alkylated analogues. This may result from decreased stability of the dication form, caused by the resonance effect or possibly by the inductive effect of the phenyl group. The species distribution of PhGBG (proportion of free base 5.5%, predominant species the monocation) at 37 degrees C resembles that of GBG and MGBG but is clearly different from that of non-antileukaemic C-alkylated analogues. These similarities suggest that PhGBG and its derivatives may be worth antitumour screening. Depending on the conditions used in the crystallization, three different types of crystals of PhGBG sulphate were obtained. Crystallography indicated that, in two of the types, the crystal consisted exclusively of the anti-anti isomer, i.e. the same isomer as has been observed in the case of GBG and its C-alkylated congeners. One crystal type, however, consisted of a different geometrical isomer (anti-syn), suggesting that PhGBG may isomerize more easily than its aliphatic analogues. Previous concepts on the isomerism of GBG and C-alkylated bis(guanylhydrazones) thus cannot be generalized to aromatic congeners. A theory based on resonance, inductive and hyperconjugative effects and electron transfers is presented that is capable of explaining the formation of the two geometrical isomers of PhGBG that were experimentally observed. A similar theory, based on hyperconjugation of C-F bonds, is presented that is capable of explaining the previous finding of the formation of the anti-syn isomer of trifluoromethylglyoxal bis(guanylhydrazone) (CF3GBG). Like that of CF3GBG, the anti-syn isomer of the PhGBG dication is stabilized by an internal hydrogen bond. The lack of structural rigidity may affect the biological properties of PhGBG, e.g. its ability to inhibit AdoMetDC.

Animals↗
PubMed1992

Determination of bis(amidinohydrazones) by micellar electrokinetic capillary chromatography.

A micellar electrokinetic capillary chromatography method was developed for the separation and determination of aliphatic congeners of bis(amidinohydrazones) in standard solution. Eight bis(amidinohydrazones) could be determined in less than 15 min at an applied voltage of 22 kV, using 0.05 M sodium phosphate as buffer (pH 7.0) together with 1 mM N-cetyl-N,N,N-trimethylammonium bromide. Hydrostatic sample injection was employed. The method exhibited good repeatability and a linear range of 2.5-100 micrograms ml-1. A detection limit of 1 micrograms ml-1 was achieved. The method also allows the determination of bis(amidinohydrazones) in human serum samples.

Chromatography↗
PubMed1990

Adenosylmethionine decarboxylase inhibitors--lack of activity against cytopathic effects of HIV.

Many bis(amidinohydrazones) are potent inhibitors of adenosylmethionine decarboxylase (AdoMetDC), a key enzyme of polyamine biosynthesis, and some of them are also known to be powerful antiviral agents. Therefore, seven bis(amidinohydrazones), including the two most potent inhibitors of eukaryotic AdoMetDC so far reported, were screened for antiviral activity against the human immunodeficiency virus (HIV). The screening was performed by incubating susceptible human leukemia cells in microculture plates in the presence or absence of test compounds for 7 days and by determining the number of viable cells at the end of the test. None of the compounds screened, however, displayed any detectable antiviral activity (i.e. none of them increased the viability of virus-infected cells) in these tests whose aim was to reveal potential activity against the cytopathic effects of HIV. This result suggests that inhibitors of AdoMetDC, at least when used alone, are devoid of value for the prevention of the cytopathic effects of HIV. However, the possibility cannot be totally excluded that some of them might decrease the amount of infectious progeny viruses formed, just as methylglyoxal bis(amidinohydrazone) is known to do in the case of vaccinia virus.

Adenosylmethionine Decarboxylase↗
PubMed1988

Diethylglyoxal bis(guanylhydrazone): a novel highly potent inhibitor of S-adenosylmethionine decarboxylase with promising properties for potential chemotherapeutic use.

Diethylglyoxal bis(guanylhydrazone) (DEGBG), a novel analog of the antileukemic agent methylglyoxal bis(guanylhydrazone) (MGBG) was synthesized. It was found to be the most powerful inhibitor of yeast S-adenosylmethionine decarboxylase (AdoMetDC) so far studied (Ki approx. 9 nM). This property, together with the finding that the compound is a weaker inhibitor of intestinal diamine oxidase than are MGBG and its glyoxal, ethylglyoxal and ethylmethylglyoxal analogs, makes the compound a promising candidate as a polyamine antimetabolite for chemotherapy studies. DEGBG was also found to potentiate the antiproliferative effect of the ornithine decarboxylase inhibitor alpha-difluoromethyl ornithine against mouse L1210 leukemia cells in vitro. DEGBG increased several-fold the intracellular putrescine concentration of cultured L1210 cells, just as MGBG and its ethylglyoxal analog are known to do. The results strongly suggest that DEGBG is worth further studies. Combined with previous studies, they also made possible the construction of some empirical rules concerning the structure-activity relationships of bis(guanylhydrazone) type inhibitors of AdoMetDC. The identity of DEGBG was confirmed by a single-crystal X-ray analysis and by 1H- and 13C-NMR spectroscopy. It consisted of the same isomer as MGBG and several of its analogs are known to consist of.

Adenosylmethionine Decarboxylase↗
PubMed1987

An antiproliferative salicylaldoximato type copper(II) chelate as an enhancer of the cytotoxicity of murine spleen cells to tumor cells in vitro.

The antiproliferative metal chelate bis(2,3,4-trihydroxybenzaldoxyimato)copper(II) (CuTRI2) was shown to distinctly enhance the cytotoxicity of the spleen effector cells of CBA/CA mice to YAC-1 tumor cells in vitro as measured using a 4-h 51Cr release test. The compound was either added directly to the assay system or the effectors were incubated in the presence of it for 2 h and washed before assay. The concentrations tested were 10, 20 and 40 mg/ml, the lowest concentration leading invariably to the strongest enhancement of cytotoxicity. The effector cells involved were very probably natural killer cells. The highest concentration had, if anything, a negative effect on the release of 51Cr from the target cells. In the same concentrations, CuTRI2 did not enhance the cytotoxicity of the spleen effector cells to K-562 tumor cells. Preliminary studies on the related chelate trans-bis(2,4-dihydroxybenzaldoximato)copper(II) are also reported. This paper is apparently the first report of a copper chelate that enhances the cytotoxicity of any sort of effector cells to tumor cells.

Animals↗
PubMed1987

Charge transfer-oxy radical mechanism for anticancer agents: mAMSA derivatives, rhodamine 123, and nickel salicylaldoximate.

The proposal is advanced that many anticancer agents may function via redox reactions resulting in generation of toxic oxy radicals which destroy neoplastic cells. Cyclic voltammetry was performed with some of the main types: iminium ions (protonated mAMSA derivatives), quinone derivatives (rhodamine 123) and metal complexes (nickel(II) salicylaldoximate). In addition, relevant literature data are provided. A rationale is offered that relates electrochemical data to physiological activity.

Amsacrine↗
PubMed1986

Charge transfer-oxy radical mechanism for anti-cancer agents.

The proposal is advanced that anti-cancer drugs generally function by charge transfer resulting in formation of toxic oxy radicals which destroy the neoplasm. Electrochemical studies were performed with some of the main types of agents: iminium ions (adenine iminium from alkylating species, iminium metabolite of 6-mercaptopurine, nitidine, other polynuclear iminiums) and metal complexes (Pt(II)diaquodiammine-guanosine, copper salicylaldoximes). Reduction potentials ranged from -0.4 to -1.2 V. Literature data for quinones are presented and radiation is discussed. Based on the theoretical framework, a rationale is offered for the carcinogen-anti-cancer paradox and the role of antioxidants.

Alkylation↗
PubMed1985

S-adenosylmethionine decarboxylase as target of chemotherapy.

Although ornithine decarboxylase under most conditions is the rate-controlling enzyme of polyamine biosynthesis and thus the most logical target for chemical intervention, the inhibition of the enzyme triggers a series of compensatory reactions all aimed to circumvent the inhibition. These include secondary induction of adenosylmethionine decarboxylase, enhanced accumulation of extracellular polyamines and an overproduction of ornithine decarboxylase resulting from enhanced expression and gene amplification. Thus chemotherapy based on an intervention of polyamine formation has also to be directed to reactions other than the decarboxylation of ornithine. Adenosylmethionine decarboxylase is the second natural target for chemotherapy. Virtually all effective inhibitors of this enzyme are members of the family of bis(guanylhydrazones). Small modifications, such as increased hydrophobicity at the glyoxal portion of the parent compound glyoxal bis(guanylhydrazone), greatly enhance the inhibition of adenosylmethionine decarboxylase and diminish the undesirable inhibition of diamine oxidase. However, although ethylglyoxal and propylglyoxal bis(guanylhydrazone) appear to utilize the putative polyamine carrier for their cellular entry, their cellular accumulation, in contrast to that of glyoxal and methylglyoxal bis(guanylhydrazone), is not stimulated by putrescine and spermidine deprivation produced by inhibitors of ornithine decarboxylase. It is obvious that the cellular accumulation of each of the bis(guanylhydrazones) is determined by their different efflux rates: GBG and MGBG are effectively retained whereas EGBG is rapidly excreted by the tumor cells. GBG and MGBG, but possibly not EGBG, behave as mitochondrial poisons and rapidly produce extensive morphological damage of the mitochondria. The bis(guanylhydrazones) likewise inhibit carnitine-dependent mitochondrial oxidation of long-chain fatty acids, competitively in respect to carnitine. It is possible that this inhibition has something to do with the mitochondrial damage, as carnitine protects tumor cells from the early mitochondrial damage produced by MGBG. Carnitine also protects experimental animals from MGBG-induced acute toxicity and death.

Adenosylmethionine Decarboxylase↗
PubMed1984

Glyoxal bis(guanylhydrazone) as an inhibitor of polyamine biosynthesis in tumour cells.

Glyoxal bis(guanylhydrazone), the parent compound of methylglyoxal bis(guanylhydrazone), was synthesized and tested for its ability to inhibit the biosynthesis of polyamines. It was found to be a powerful competitive inhibitor of adenosylmethionine decarboxylase (EC 4.1.1.50), yet the lack of the methyl group at the glyoxal portion increased the apparent Ki value for the enzyme by about 30-fold in comparison with methylglyoxal bis(guanylhydrazone). Glyoxal bis(guanylhydrazone) inhibited diamine oxidase (EC 1.4.3.6) activity as effectively as did methylglyoxal bis(guanylhydrazone). The cellular accumulation curves of glyoxal bis(guanylhydrazone) in L1210 cells were practically superimposable with those of methylglyoxal bis(guanylhydrazone), and the uptake of both compounds was distinctly stimulated by a prior treatment with 2-difluoromethylornithine. The drug decreased the concentration of spermidine in a dose-dependent manner and, in contrast with methylglyoxal bis(guanylhydrazone), without a concomitant accumulation of putrescine. The fact that putrescine concentrations were decreased in cells exposed to glyoxal bis(guanylhydrazone) was, at least in part, attributable to an inhibition of ornithine decarboxylase (EC 4.1.1.17) activity in cells treated with the compound. Under these experimental conditions equivalent concentrations of methylglyoxal bis(guanylhydrazone) [1,1'-[(methylethanediylidine)dinitrilo]diguanidine] elicited large increases in the enzyme activity. When combined with difluoromethylornithine, glyoxal bis(guanylhydrazone) potentiated the growth-inhibitory effect of that drug. Taking into consideration the proven anti-leukaemic activity of glyoxal bis(guanylhydrazone), its effectiveness to inhibit spermidine biosynthesis (without raising the concentration of putrescine) as well as its suitability for combined use with inhibitors of ornithine decarboxylase, this drug is apparently worthy of further testing in tumour-bearing animals, especially in combination with difluoromethylornithine or related inhibitors of ornithine decarboxylase.

Adenosylmethionine Decarboxylase↗
PubMed1984

Different efflux rates may determine the cellular accumulation of various bis(guanylhydrazones).

Three bis(guanylhydrazones) (those of methylglyoxal, glyoxal and ethylglyoxal) were compared for their affinity for the putative polyamine carrier and for their cellular retention in L1210 mouse leukaemia cells. All the bis(guanylhydrazones) inhibited equally effectively the uptake of spermidine by the tumour cells, indicating that the compounds had roughly equal affinity for the polyamine carrier. The fact that methylglyoxal bis(guanylhydrazone) and glyoxal bis(guanylhydrazone) were much more effectively concentrated in the animal cells than was ethylglyoxal bis(guanylhydrazone) was obviously attributable to the finding that the efflux rate of ethylglyoxal bis(guanylhydrazone) greatly exceeded that of the other bis(guanylhydrazones). The rate of efflux of the drugs was slowed down if the tumour cells were treated with 2-difluoromethylornithine before exposure to the bis(guanylhydrazones). These results suggest that intracellular binding of the bis(guanylhydrazones) determines their cellular accumulation.

Animals↗