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PubMed1988

A study of the metal complexation behaviour of some penicillins, cephalosporins and their derivatives.

The metal complexation behaviour of several beta-lactam antibiotics and derivatives is explained, based on the results of potentiometric titrations. The (organo)metal ions used were (organic derivatives of) transition elements and elements with a filled d-subshell. The emphatic class b (organo)metal ions Ag(I), Hg(II) and C6H5Hg(I) form the most stable complexes with the studied ligands: Hg(II) is the most suited ion. The alkaline degradation products and hydroxamic acid derivatives of penicillins and cephalosporins are very similar to penicillamine in their complexation behaviour. This emphasizes the dominant role of the thiol group as site of complexation. A scheme for stepwise complex formation with Hg(II) and Ag(I) is presented. The availability of the thiol group is used to explain small differences in complexation behaviour between penicillin derivatives on the one hand, and cephalosporin derivatives and penicillamine on the other.

Cephalosporins↗
PubMed2007

Histone deacetylase inhibitors increase neuronal differentiation in adult forebrain precursor cells.

Chromatin modification plays a key role in fate decision of neural stem cells. Here, we explored the impact of epigenetic remodelling onto neuronal fate determination using specific inhibitors of histone deacetylases (iHDAC). Adult subventricular zone (SVZ) precursor cells were expanded as neurospheres and treated in vitro with second generation iHDAC MS-275, M344 and suberoylanilide hydroxamic acid (SAHA). All tested compounds revealed a significant increase of betaIII-tubulin positive neurons (ranging from 258 to 431%) in a concentration-dependent manner. The number of oligodendrocytes was decreased by almost 50%, accompanied by a reduction of Olig2 mRNA expression. In contrast, astrocyte quantity remained unaffected after iHDAC treatment. Both control and iHDAC treated cells expressed markers of mature GABAergic and dopaminergic neurons. Increased expression levels of NeuroD, Cyclin D2 and B-lymphocyte translocation gene 3 (Btg3) point to a shift towards neuronal fate determination targeted by HDAC inhibitors.

Age Factors↗
PubMed2007

Bioconversion of butyronitrile to butyramide using whole cells of Rhodococcus rhodochrous PA-34.

Butyramide is an important chemical commodity, which is used for the synthesis of hydroxamic acids and electrorheological fluids and for the preparation of beta-amodoorganotin compounds. The nitrile hydratase (Nhase) of Rhodococcus rhodochrous PA-34 catalyzed the conversion of butyronitrile to butyramide. The maximum Nhase activity [18 U/mg dry cell weight (dcw)] of whole cells of R. rhodochrous PA-34 was observed at pH 7.0 with 10% (v/v) butyronitrile and 1 mg cells (dcw)/ml reaction mixture at 10 degrees C. The cells of R. rhodochrous PA-34 retained almost 50% activity when incubated for 1 h in the presence of 85% (v/v) butyronitrile. A yield of 597 g of butyramide (6.8 M) was obtained using 60% (v/v) butyronitrile, 1 g cells (dry weight) in a 1-l batch reaction at 10 degrees C for 6 h.

Amides↗
PubMed2006

Ex vivo therapy of malignant melanomas transplanted into organotypic brain slice cultures using inhibitors of histone deacetylases.

Disease progression in patients suffering from malignant melanomas is often determined by metastatic spreading into brain parenchyma. Systemic chemotherapy regimens are, therefore, mandatory for successful treatment. Most recently, inhibitors of histone deacetylases (HDACi) have been shown to significantly inhibit melanoma progression. Here, mouse as well as human melanoma cells were transplanted into rodent hippocampal slice cultures in order to translate and microscopically confirm promising in vitro chemotherapeutic propensities of HDACi within the organotypic brain environment. In our ex vivo model, tumor progression was significantly inhibited by administration of low micromolar concentrations of second generation HDACi MS-275 over a period of 8 days. In contrast, HDACi treatment with suberoylanilide hydroxamic acid was less efficient ex vivo, although both compounds were successful in the treatment of tumor cell monolayer cultures. Protein levels of the cell cycle inhibitor p21(WAF1) were significantly increased after HDACi treatment, which points to enhanced G1 arrest of tumor cells as confirmed by cytofluorometric analysis. Considering the ability of MS-275 to cross the blood-brain barrier, our experimental model identifies the benzamide MS-275 as a promising therapeutic compound for targeting epigenetic chromatin modulation as systemic treatment of metastatic melanomas.

Animals↗
PubMed1997

Matrix metalloproteinase inhibitors reduce phorbol ester-induced cutaneous inflammation and hyperplasia.

Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteases which play key roles in extracellular matrix remodeling, connective tissue damage, inflammation and cell proliferation in a variety of tissues. Since MMP inhibitors have been recently shown to decrease proliferation of vascular smooth-muscle cells, and to prevent neutrophil infiltration in response to alkali burns, we sought to determine whether MMPs play a role in the pathogenesis of inflammatory or hyperproliferative skin disorders. The effects of a specific MMP inhibitor and its analogues on phorbol dibutyrate (PdiBu)-induced inflammation and epidermal hyperplasia in murine skin were assessed. Topical GM 6001, a hydroxamic acid analog with potent inhibitory activity against several MMPs, markedly inhibited PdiBu-induced increases in both ear thickness and ear punch-biopsy weight in a dose-dependent manner 30 h after topical application of PdiBu. Maximal inhibition (75%) was obtained at a dose of 100 micrograms/cm2 (P < 0.01). Moreover, histologic analysis revealed that GM 6001 decreased both the inflammatory cellular infiltrates and epidermal hyperplasia induced by PdiBu. Whereas similar results were found for GM 1489, an analog of GM 6001, acetohydroxamic acid, containing the critical metal ligand group but without the amino acid side chains necessary for binding to the MMPs, did not alter the response to PdiBu inflammation/hyperplasia. These results show that the MMP inhibitors, GM 6001 and GM 1489, are effective in reducing both the inflammatory and hyperproliferative responses that occur following topical phorbol ester application, suggesting a potential role for MMPs in cutaneous inflammatory dermatoses. Moreover, the delivery of this class of inhibitors across intact stratum corneum implies that MMP inhibition could provide an approach to the topical treatment of inflammatory dermatoses.

Animals↗
PubMed2005

Heterocyclic zinc-binding groups for use in next-generation matrix metalloproteinase inhibitors: potency, toxicity, and reactivity.

In an effort to improve the zinc-chelating portion of matrix metalloproteinase (MMP) inhibitors, we have developed a family of heterocyclic zinc-binding groups (ZBGs) as alternatives to the widely used hydroxamic acid moiety. Elaborating on findings from an earlier report, we performed in vitro inhibition assays with recombinant MMP-1, MMP-2, and in a cell culture assay using neonatal rat cardiac fibroblast cells. In both recombinant and cell culture assays, the new ZBGs were found to be effective inhibitors, typically 10-100-fold more potent than acetohydroxamic acid. The toxicity of these chelators was examined by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt cytotoxicity assays, which demonstrate that most of these compounds are nontoxic at concentrations of almost 100 microM. To address the possible interaction of sulfur-containing ZBGs with biological reductants, the reactivity of these chelators with 5,5'-dithiobis(2-nitrobenzoic acid) was examined. Finally, thione ZBGs were shown to be effective inhibitors of cell invasion through an extracellular matrix membrane. The data presented herein suggest these heterocyclic ZBGs are potent, nontoxic, and biocompatible compounds that show promise for incorporation into a new family of MMP inhibitors.

Animals↗
PubMed2006

Design of iron chelators: syntheses and iron (III) complexing abilities of tripodal tris-bidentate ligands.

The interest in synthetic siderophore mimics includes therapeutic applications (iron chelation therapy), the design of more effective agents to deliver Fe to plants and the development of new chemical tools in order to study iron metabolism and iron assimilation processes in living systems. The design of ligands needs a rational approach for the understanding of the metal ion complexing abilities. The octahedral arrangement of donor atoms is the most favourable geometry, allowing the maximum possible distance between their formal or partial negative charges. Hexadentate chelators, usually of the tris-bidentate type, can accommodate the metal coordination sphere and are well-suited to obtain high pFe values. The first part of this review is dedicated to selected synthetic routes, taking into account (i) the nature of the chelating subunits, connecting groups and spacers, (ii) the water-solubility and hydrophilic/lipophilic balance, (iii) the chirality and (iv) the possibility of grafting probes or vectors. In the second part, we discuss the role of the molecular design on complexing abilities (thermodynamics and kinetics). The bidentate 8-hydroxyquinoline moiety offers an alternative to the usual coordinating hydroxamic acids, catechols and/or alpha-hydroxycarboxylic acids groups encountered in natural siderophores. The promizing results obtained with the tris-hydroxyquinoline-based ligand O-TRENSOX are summarized. O-TRENSOX exhibits a high and selective affinity for Fe(III) complexation. Its efficiency in delivering Fe to plants, iron mobilization, cell protection, and antiproliferative effects has been evidenced. Other chelators derived from O-TRENSOX (mixed catechol/8-hydroxyquinoline ligands, lipophilic ligands) are also described. Some results question the relevance of partition coefficients to foresee the activity of iron chelators. The development of probes (fluorescent, radioactive, spin labelled) based on the O-TRENSOX backbone is in progress in order to get insights in the complicated iron metabolism processes.

Drug Design↗
PubMed2006

Inhibition of histone deacetylase enhances the anti-proliferative action of antiestrogens on breast cancer cells and blocks tamoxifen-induced proliferation of uterine cells.

Here we report a novel potential therapeutic strategy using histone deacetylase (HDAC) inhibitors to enhance the action of hormonal therapy agents in estrogen receptor alpha (ER alpha)-positive breast cancer. HDAC inhibitors [trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA)], inhibited proliferation of MCF-7 breast cancer cells and, in combination with tamoxifen inhibited proliferation better than with either agent alone. VPA, an anti-convulsant drug with HDAC inhibitory activity, enhanced tamoxifen action at doses within the concentration range used for anti-convulsive therapy. VPA cooperated with tamoxifen in a variety of ER alpha-positive cell lines and was also effective when combined with other antiestrogens, and with aromatase inhibition. VPA enhanced antiestrogen action by promoting cell death via apoptosis without affecting cell cycling. Some of this action may be due to VPA's ability to induce the pro-apoptotic gene Bik, which is also induced by antiestrogens. Remarkably, VPA blocked the undesirable pro-proliferative action of tamoxifen on uterine endometrial cells. Our in vitro results suggest that VPA and other HDAC inhibitors have the potential to enhance hormonal therapy for ER alpha-positive breast cancer and simultaneously reverse the adverse effects of antiestrogens in the uterus.

Aromatase↗
PubMed2006

Neutrophil activator of matrix metalloproteinase-2 (NAM).

We have isolated a novel soluble factor(s), neutrophil activator of matrix metalloproteinases (NAM), secreted by unstimulated normal human peripheral blood neutrophils that causes the activation of cell secreted promatrix metalloproteinase-2 (proMMP-2). Partially purified preparations of NAM have been isolated from the conditioned media of neutrophils employing gelatin-Sepharose chromatography and differential membrane filter centrifugation. NAM activity, as assessed by exposing primary human umbilical vein endothelial cells (HUVEC) or HT1080 cells to NAM followed by gelatin zymography, was seen within one hour. Tissue inhibitor of metalloproteinase-2 (TIMP-2) and hydroxamic acid derived inhibitors of MMPs (CT1746 and BB94) abrogated the activation of proMMP-2 by NAM, while inhibitors of serine and cysteine proteases showed no effect. NAM also produced an increase in TIMP-2 binding to HUVEC and HT1080 cell surfaces that was inhibited by TIMP-2, CT1746, and BB94. Time-dependent increases in MT1-MMP protein and mRNA were seen following the addition of NAM to cells. These data support a role for NAM in cancer dissemination.

Adult↗
PubMed2004

Effect of host defense chemicals on clonal distribution and performance of different genotypes of the cereal aphid Sitobion avenae.

Five microsatellite loci were used to study the genetic variability and population structure of Sitobion avenae (Hemiptera: Aphididae) on some of its host plants. Individuals were collected in Chile from different cultivated and wild Poaceae. Forty-four multilocus genotypes were found among the 1052 aphids analyzed, of which four represented nearly 90% of the sample. No specialist genotypes were found, although some preferred hosts endowed with chemical defenses, i.e., hydroxamic acids (Hx), while others preferred comparatively undefended hosts. Performances of some predominant and some rare genotypes were evaluated on plants differing in their Hx levels. Significant differences in performance were found among clones, the two most common genotypes showing no differences in performance among all hosts tested, and the rare genotypes showing enhanced performance on the host with highest Hx level. A hypothesis is proposed whereby the appearance of rarer genotypes is in part related to the presence of Hx.

Animals↗
PubMed2006

Tubulin must be acetylated in order to form a complex with membrane Na(+),K (+)-ATPase and to inhibit its enzyme activity.

In cells of neural and non-neural origin, tubulin forms a complex with plasma membrane Na(+),K(+)-ATPase, resulting in inhibition of the enzyme activity. When cells are treated with 1 mM L-glutamate, the complex is dissociated and enzyme activity is restored. Now, we found that in CAD cells, ATPase is not activated by L-glutamate and tubulin/ATPase complex is not present in membranes. By investigating the causes for this characteristic, we found that tubulin must be acetylated in order to associate with ATPase and to inhibit its catalytic activity. In CAD cells, the acetylated tubulin isotype is absent. Treatment of CAD cells with deacetylase inhibitors (trichostatin A or tubacin) caused appearance of acetylated tubulin, formation of tubulin/ATPase complex, and reduction of membrane ATPase activity. In these treated cells, addition of 1 mM L-glutamate dissociated the complex and restored the enzyme activity. Cytosolic tubulin from trichostatin A-treated but not from non-treated cells inhibited ATPase activity. These findings indicate that the acetylated isotype of tubulin is required for interaction with membrane Na(+),K(+)-ATPase and consequent inhibition of enzyme activity.

Acetylation↗
PubMed1977

A study of the primary effect of the uncoupler carbonyl cyanide m-chlorophenylhydrazone on membrane potential and conductance in Riccia fluitans.

1. In the presence of 10(-5) to 10 (-8) M carbonyl cyanide m-chlorophenylhydrazone (CCCP) the membrane potential of thallus cells of the aquatic liverwort Riccia fluitans responds to changes of the external pH between 5.5 and 8.3. This occurs in the light and dark, and also if respiration is abolished by addition of 10(-4) M KCN and 10 (-5) M salicyl-hydroxamic acid. 2. The ATP-level of the thallus is reduced, independently of the external pH, by greter than or equal to 10 (-6) M CCCP to 30--40% of the control level of about 1.1 nmol ATP per mg dryweight within 5 min. 3. Upon addition of 10 (-4) M CCCP at 20 degrees C the ATP-level declines exponentially with a half time of about 20--30 s, whereas the membrane potential declines exponentially with a half time of about 2--3 s. 4. At pH 7.2 the electrical membrane conductance yields a sigmoid curve as a function of the logarithm of the CCCP concentration between 10 (-8) and 3 - 10 (-6) M. On the other hand, at 3 - 10(-7) M M CCCP the gm (electrical slope conductance, muS - cm-2 = 10 (-6)-omega-1-cm-2) versus pH-curve displays an optimum between pH 6.5 and 7.5. 5. We conclude that CCCP acts upon membrane potential and conductance in Riccia predominantly by inducing a passive proton permeability of the cell membrane, i.e. CCCP raises the permeability ratio, PH/PK, more than 100-fold above its control level of about 10.

Adenosine Triphosphate↗
PubMed1994

Sulphation of N-hydroxy-4-aminobiphenyl and N-hydroxy-4-acetylaminobiphenyl by human foetal and neonatal sulphotransferase.

Sulphation of the genotoxic compounds N-hydroxy-4-aminobiphenyl (N-OH-4ABP) and N-hydroxy-4-acetylaminobiphenyl (N-OH-4AABP) was determined in cytosolic preparations of human foetal, neonatal and adult liver and foetal and neonatal adrenal gland. Sulphotransferase (ST) activity capable of sulphating these compounds was present in foetal liver and adrenal gland by 14 weeks of gestation. Sulphation of N-OH-4ABP was higher in foetal and neonatal adrenal cytosol than was sulphation of N-OH-4AABP and in general, N-OH-4ABP ST activity was also greater than that towards 1-naphthol. In foetal and neonatal liver cytosol the sulphation of N-OH-4ABP was also higher than that of N-OH-4AABP (approximately 2-fold). In adult liver cytosols, however, N-OH-4AABP ST activity was higher than that for N-OH-4ABP and 1-naphthol sulphation. Aromatic hydroxylamines and hydroxamic acids are known to be converted by sulphotransferase into reactive, electrophilic compounds capable of reacting with DNA. Our data show that the human foetus and neonate have the capacity to sulphate these compounds and thus is able to produce the reactive mutagenic metabolites. Therefore, this class of genotoxic compounds may be bioactivated by humans during development--a time when they are most vulnerable to the effects of genotoxins.

Adrenal Glands↗
PubMed1996

Investigation of mechanism-based inhibitors of complement targeting the activated thioester of human C3.

An intramolecular thioester bond in complement protein C3 is vital for covalent attachment of C3b (the proteolytically activated form of C3) to biological surfaces and for activation of the complement system. Proteolytic removal of C3a from C3 activates the thioester in the C3b fragment. Activated C3b primarily forms ester bonds with hydroxyl groups of carbohydrates on complement activating surfaces, but it has also been shown to react with the hydroxyl group of tyrosine and with specific Ser and Thr residues on IgG and on complement protein C4b. To examine the reactivity of the thioester, several families of hydroxylated compounds were examined. Reactivity of a series of substituted phenols varied over two orders of magnitude and demonstrated a linear correlation between reactivity and the Hammett substituent constants. Hydroxylated drugs including members of the L-DOPA/epinephrine family and hydroxamic acids also were examined. Compounds were identified that were 20,000 times more reactive than carbohydrates. These compounds were found to inhibit both the classical and alternative pathways of complement activation. Although the specificity of the thioester for its natural biological targets appears to be determined by many structural features, the data presented here demonstrate that increasing the nucleophilic character of the target hydroxyl group can increase the potency of a synthetic inhibitor many orders of magnitude.

Complement C3↗