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PubMed1999

Phosphoryl oxime inhibition of acetylcholinesterase during oxime reactivation is prevented by edrophonium.

Reactivation of organophosphate (OP)-inhibited acetylcholinesterase (AChE) is a key objective in the treatment of OP poisoning. This study with native, wild-type, and mutant recombinant DNA-expressed AChEs, each inhibited by representative OP compounds, establishes a relationship between edrophonium acceleration of oxime-induced reactivation of OP-AChE conjugates and phosphoryl oxime inhibition of the reactivated enzyme that occurs during reactivation by pyridinium oximes LüH6 and TMB4. No such recurring inhibition could be observed with HI-6 as the reactivator due to the extreme lability of the phosphoryl oximes formed by this oxime. Phosphoryl oximes formed during reactivation of the ethoxy methylphosphonyl-AChE conjugate by LüH6 and TMB4 were isolated for the first time and their structures confirmed by (31)P NMR. However, phosphoryl oximes formed during the reactivation of the diethylphosphoryl-AChE conjugate were not sufficiently stable to be detected by (31)P NMR. The purified ethoxy methylphosphonyl oximes formed during the reactivation of ethoxy methylphosphonyl-AChE conjugate with LüH6 and TMB4 are 10- to 22-fold more potent than MEPQ as inhibitors of AChE and stable for several hours at pH 7.2 in HEPES buffer. Reactivation of both ethoxy methylphosphonyl- and diethylphosphoryl-AChE by these two oximes was accelerated in the presence of rabbit serum paraoxonase, suggesting that organophosphorus hydrolase can hydrolyze phosphoryl oxime formed during the reactivation. Our results emphasize that certain oximes, such as LüH6 and TMB4, if used in the treatment of OP pesticide poisoning may cause prolonged inhibition of AChE due to formation of phosphoryl oximes.

Acetylcholinesterase↗
PubMed1996

Antiradiation compounds. 24. Stability of copper (II) complexes of bis(methylthio) and methylthio amino derivatives of 1-methylpyridinium- and 1-methylquinolinium-2-dithioacetic acids in the presence of amino acids, simple peptides, and a protein.

The radiation-protective bis(methylthio) and methylthio amino derivatives of 1-methylpyridinium- and 1-methylquinolinium-2-dithioacetic acids, a series of non-thiol sulfur-containing compounds, have been examined for their ability to complex Cu(II) ion and remain stable in the presence of alpha-amino acids, peptides, and a protein. Copper-binding stability constants were found that were considered sufficiently large to be capable of existence under cellular conditions, with log K beta values in the range of 13-15. Copper-binding constants for alpha-amino acids are comparable to those for the radioprotective ligands, but overall binding constants for simple peptides are usually 10(4)-10(6) lower in magnitude. Essentially no change was found in the UV spectra of the Cu(II) complexes in the presence of alpha-amino acids and simple peptides, and the binding capacity to bovine serum albumin was quite low for two Cu(II) complexes of the best protective ligands, with values of 10(-6)-10(-7) M. The possibility that these radioprotectors may act in vivo as copper complexes, possibly as superoxide dismutase mimics, is thus feasible. The magnitude of the copper-binding stability constants, the lack of copper exchange between the radioprotective ligands and amino acids or peptides, and the very low tendency of the copper complexes of the radioprotective ligands to bind to a protein indicate the potential of the complexes to contribute to the radioprotective ability of the ligands.

Amino Acids↗
PubMed2001

Probing the ubiquinone reduction site in bovine mitochondrial complex I using a series of synthetic ubiquinones and inhibitors.

Studies of the structure-activity relationships of ubiquinones and specific inhibitors are helpful to probe the structural and functional features of the ubiquinone reduction site of bovine heart mitochondrial complex I. Bulky exogenous short-chain ubiquinones serve as sufficient electron acceptors from the physiological ubiquinone reduction site of bovine complex I. This feature is in marked contrast to other respiratory enzymes such as mitochondrial complexes II and III. For various complex I inhibitors, including the most potent inhibitors, acetogenins, the essential structural factors that markedly affect the inhibitory potency are not necessarily obvious. Thus, the loose recognition by the enzyme of substrate and inhibitor structures may reflect the large cavity like structure of the ubiquinone (or inhibitor) binding domain in the enzyme. On the other hand, several phenomena are difficult to explain by a simple one-catalytic site model for ubiquinone.

Animals↗
PubMed1995

Amino acid residues controlling reactivation of organophosphonyl conjugates of acetylcholinesterase by mono- and bisquaternary oximes.

Single and multiple site mutants of recombinant mouse acetylcholinesterase (rMoAChE) were inhibited with racemic 7-(methylethoxyphosphinyloxy)-1-methylquinolinium iodide (MEPQ) and the resulting mixture of two enantiomers, CH3PR,S(O)(OC2H5)-AChE(EMPR,S-AChE), were subjected to reactivation with 2-(hydroxyiminomethyl)-1-methylpyridinium methanesulfonate (P2S) and 1-(2'-hydroxyiminomethyl-1'-pyridinium)-3-(4"-carbamoyl-1"- pyridinium)-2-oxapropane dichloride (HI-6). Kinetic analysis of the reactivation profiles revealed biphasic behavior with an approximate 1:1 ratio of two presumed reactivatable enantiomeric components. Equilibrium dissociation and kinetic rate constants for reactivation of site-specific mutant enzymes were compared with those obtained for wild-type rMoAChE, tissue-derived Torpedo AChE and human plasma butyrylcholinesterase. Substitution of key amino acid residues at the entrance to the active-site gorge (Trp-286, Tyr-124, Tyr-72, and Asp-74) had a greater influence on the reactivation kinetics of the bisquaternary reactivator HI-6 compared with the monoquaternary reactivator P2S. Replacement of Phe-295 by Leu enhanced reactivation by HI-6 but not by P2S. Of residues forming the choline-binding subsite, the E202Q mutation had a dominant influence where reactivation by both oximes was decreased 16- to 33-fold. Residues Trp-86 and Tyr-337 in this subsite showed little involvement. These kinetic findings, together with energy minimization of the oxime complex with the phosphonylated enzyme, provide a model for differences in the reactivation potencies of P2S and HI-6. The two kinetic components of oxime reactivation of MEPQ-inhibited AChEs arise from the chirality of O-ethyl methylphosphonyl moieties conjugated with Ser-203 and may be attributable to the relative stability of the phosphonyl oxygen of the two enantiomers in the oxyanion hole.

Acetylcholinesterase↗
PubMed1987

Interaction of the nonintercalative antitumour drugs SN-6999 and SN-18071 with DNA: influence of ligand structure on the binding specificity.

Binding to DNA's of the non-intercalative ligands SN-6999 and SN-18071 has been studied by means of circular dichroism, UV absorption, thermal melting and for SN-6999 by viscosity measurements. Both antitumour drugs show a preference for dA.dT rich DNA's, but the base pair selectivity of SN-18071 is lower as indicated by some affinity to dG.dC containing duplex DNA. The dA.dT base pair specificity of SN-6999 is comparable to that of netropsin. It forms very stable complexes with dA.dT containing duplex DNA and competes with netropsin binding on DNA. The ligands SN-18071 and pentamidine are totally released from their complexes with poly(dA-dT).poly(dA-dT) by competitive netropsin binding. The results demonstrate that hydrogen bonding capacity of the ligand in addition to other factors strongly contribute to the base sequence specificity in the recognition process of the ligand with DNA. A binding model of SN-6999 with five dA.dT pairs in the minor groove of B-DNA is suggested.

Antineoplastic Agents↗
PubMed1996

Different effects of nonintercalative antitumor drugs on DNA triple helix stability: SN-18071 promotes triple helix formation.

The interaction of the nonintercalating bisquaternary ammonium heterocyclic drugs SN-18071 and SN-6999 with a DNA triple helix has been studied using thermal denaturation and CD spectroscopy. Our data show, that both minor groove binders can bind to the triple helix of poly(dA).2poly(dT) under comparable ionic conditions, but they influence the stability of the triplex relative to the duplex structure of poly(dA).poly(dT) in a different manner. SN-18071, a ligand devoid of forming hydrogen bonds, can promote triplex formation and thermally stabilizes it up to 500 mM Na+ concentration. SN-6999 destabilizes the triplex to duplex equibilirium whereas it stabilizes the duplex. The binding constant of SN-18071 is found to be greater than that to the duplex. The stabilizing effect of SN-18071 is explained by electrostatic interactions of three ligand molecules with the three grooves of the triple stranded structure. From the experiments it is concluded that SN-6999 binds to the triplex minor groove thereby destabilizing the triplex similar as previously reported for netropsin.

Antineoplastic Agents↗
PubMed1996

Inhibition of restriction endonucleases by DNA sequence-reading ligands.

DNA sequence-reading bisquaternary ammonium heterocycles SN 6570, SN 6999, SN 6053, SN 6132, SN 6131, SN 18071 and the non-specific binders SN 6113, SN 5754, SN 6324, and SN 4094 influence the enzymatic activity of restriction endonucleases in different manners. A prerequisite for sequence-specific ligand interaction is a dAdT run of at least four base pairs. The sequence-specific binders inhibit the cleavage activity of restriction endonucleases EcoRI, SspI, and Dral with four and six dAdT base pairs in their restriction sites, while the activity of SalI and BamHI with less than four dAdT base pairs in their recognition motifs remains unaffected. On the contrary, the non-specific binding DNA ligands are incapable of suppressing the digestion for restriction nucleases under research. These results are in line with our footprint data. The inhibitory effect is independent of the number of cleavage sites in DNA and of whether the macromolecule exists in the ccc or lds conformation. Sequence specific binding of the ligand SN 6053 in close vicinity to the cleavage sites of restriction endonuclease Dral also interferes with enzyme inhibition.

Base Sequence↗
PubMed1997

Sequence-specific interactions of minor groove binders with the 154 base pair HindIII-RsaI restriction fragment of cDNA of the human Tau 40 protein involved in pathology of Alzheimer's disease.

The DNA minor groove binders netropsin, distamycin and four structurally related bisquaternary ammonium heterocycles (BQA), SN 6999, SN 6570, SN 6132 and SN 6131, were investigated for sequence-specific interactions with the 154 base pair fragment of cDNA of the human Tau 40 protein (h Tau 40 protein), involved in pathology of Alzheimer's disease. The base sequences 5' AATCTT 3', 5' AATATT 3' and 5' TTTCAATCTTTTTATTT 3' were identified as ligand specific binding sites and demonstrate the obvious dA.dT binding preference. Footprinting titration experiments were performed to estimate sequence-specific binding constants (KA). The KA-values were in the order of 10(6)M-1 and dependent on DNA base sequence as well as ligands used. The highest values estimated were for netropsin (KA = 5.0 x 10(6)M-1) and the quinoline derivative SN 6999 (KA = 6.2 x 10(6)M-1) binding to the sequence 5' ATAAT 3'. Microscopic binding constants are determined by the base sequence rather than by the length of dA.dT stretches. In the extended dA.dT run, 5' TTTCAATCTTTTTATTT 3', netropsin and distamycin binding tolerates the presence of two dG.dC base pairs, as indicated by nearly unaffected footprints. In contrast, the failure of BQAs to form footprints demonstrates their significantly decreased binding selectivity.

Alzheimer Disease↗
PubMed2000

Down-regulation of H tau 40 protein expression by minor groove binders.

The DNA minor groove binders SN6999, SN6570, and SN6113, structurally related to netropsin and distamycin, were investigated for sequence-specific interactions with the 154 base pair cDNA fragment of the human tau 40 protein, involved in pathology of Alzheimer's disease. Footprinting results indicated that both the former compounds displayed a pronounced AT-preference, while the latter SN-derivative bound to DNA in a non-sequence specific manner. The influence of these ligands on the protein synthesis was analysed using monoclonal antibodies against h tau protein. Both sequence specific binders markedly impeded protein synthesis. The non-specific binder, however, did not affect protein biosynthesis.

Alzheimer Disease↗
PubMed1997

Minor groove binding of a bis-quaternary ammonium compound: the crystal structure of SN 7167 bound to d(CGCGAATTCGCG)2.

The X-ray crystal structure of the complex between the synthetic antitumour and antiviral DNA binding ligand SN 7167 and the DNA oligonucleotide d(CGCGAATTCGCG)2 has been determined to an R factor of 18.3% at 2.6 A resolution. The ligand is located within the minor groove and covers almost 6 bp with the 1-methylpyridinium ring extending as far as the C9-G16 base pair and the 1-methylquinolinium ring lying between the G4-C21 and A5-T20 base pairs. The ligand interacts only weakly with the DNA, as evidenced by long range contacts and shallow penetration into the groove. This structure is compared with that of the complex between the parent compound SN 6999 and the alkylated DNA sequence d(CGC[e6G]AATTCGCG)2. There are significant differences between the two structures in the extent of DNA bending, ligand conformation and groove binding.

Antineoplastic Agents↗
PubMed2003

Groove-binding unsymmetrical cyanine dyes for staining of DNA: dissociation rates in free solution and electrophoresis gels.

The rates of dissociation of three non-intercalative unsymmetrical cyanine dyes, BEBO, BETO and BOXTO from mixed-sequence DNA have been studied with the DNA either free in solution or in confining porous agarose gels. The properties of the new dyes were compared to the related intercalating dyes BO, BO-PRO, TO-PRO and YO-PRO. With DNA in solution, BEBO dissociates more slowly than the monovalent BO and interestingly also more slowly than the divalent dye BO-PRO. Similarly, both BETO and BOXTO exhibit considerably slower dissociation than TO-PRO. The new dyes show biexponential dissociation kinetics in mixed-sequence DNA. The average rate of dissociation increases with increasing ionic strength, but the salt dependence of the dissociation is weaker than for the corresponding intercalating dye. The rate of dye-dissociation decreases by a factor of about 10(5) in the gel. The rates for the dyes generally follow the pattern that we observe with the DNA in free solution, however a more accentuated stabilization was seen for intercalators than for groove-bound dyes. The results show that, in particular, BOXTO is a promising candidate as a preferentially groove-bound DNA-stain with a large enhancement of the fluorescence quantum yield upon binding to DNA, and which exhibits slow and salt-insensitive dissociation compared to corresponding intercalative dyes.

Animals↗
PubMed1991

Dopaminergic neurotoxicity in vivo and inhibition of mitochondrial respiration in vitro by possible endogenous pyridinium-like substances.

Elucidation of the mechanism(s) by which 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP+) cause parkinsonism in humans and other primates has prompted consideration of possible endogenous MPTP/MPP(+)-like neurotoxins in the etiology of idiopathic Parkinson's disease. Here we examined inhibition of mitochondrial respiration in vitro and neurotoxicity in rats in vivo produced by beta-carbolinium compounds that are presumed to form following Pictet-Spengler cyclization of serotonin. We also evaluated N-methylisoquinolinium, a putative endogenous neurotoxin, in the same manner. The latter compound exhibited MPP(+)-like mitochondrial respiratory inhibition, whereas the beta-carbolinium compounds, although more potent inhibitors of electron transport, exhibited weak accumulation-dependent enhancement of inhibition in intact mitochondria. It is interesting that the beta-carbolinium compounds inhibited succinate- as well as glutamate-supported respiration, and are best described as inhibitor-uncouplers. The results of partitioning experiments suggest that both the low accumulation potential and the inhibition of succinate respiration may be a consequence of the beta-carboliniums being in equilibrium with neutral "anhydro" bases. Relative to MPP+, all compounds tested had weak dopaminergic uptake activity in vitro and weak dopaminergic toxicity in vivo, consistent with other findings of relatively low neurotoxic potential for presumed endogenous pyridiniums.

1-Methyl-4-phenylpyridinium↗
PubMed1980

Micellar properties and surface activity of some bolaform drugs in aqueous solution.

The micellar properties of a series of dicationic drugs with structures resembling those of the bolaform electrolytes have been examined using light scattering, surface tension and conductivity techniques. The compounds investigated included, demecarium bromide, ambenonium chloride, dequalinium acetate, distigmine bromide and chlorhexidine acetate. Demecarium and dequalinium formed micelles at critical concentrations of 9 x 10(-3) and 4 x 10(-3) mol kg-1 respectively. No significant association of chlorhexidine acetate could be detected, contrary to previous reports.

Ambenonium Chloride↗
PubMed1980

The pH dependence of xanthine oxidase catalysis in basic solution.

The steady-state kinetics of the oxidation of the following six heteroaromatic substrates by xanthine oxidase have been investigated over the range pH 9.0--11.1 at 25 degrees C, ionic strength 0.1: 1-methylquinolinium, 6-methoxy-1-methylquinolinium, 1-methylnicotinamide, 3-acetyl-1-methylpyridinium, and 1-(4-methoxyphenyl)pyridinium cations and 1-methylnicotinate zwitterion. For the first four o these species, kc and Km were evaluated as a function of pH while only kc/Km was accessible in the latter two cases. Where available, kc is pH independent, whereas plots of log log (kc/Km) vs. pH are linear with slopes in the range 0.54--1.17. The rates of enzymic oxidation of the 1-methylquinolinium cation and its 2-deuterio derivative were investigated and kinetic isotope effects were calculated at pH 9.8 and 10.6: kcH/kcD = 1.7 and KmH/KmD = 0.4 at each pH. Detailed comparisons of the oxidation of heteroaromatic cations and xanthine-derived substrates indicate that similar rate-determining steps control the enzymic oxidations of these two classes of substrate.

Deuterium↗
PubMedDate not supplied

Action of platelet-activating factor (PAF) antagonists on the bronchopulmonary effects of PAF in the guinea-pig.

Intravenous injection of BN 52021 in anesthetized guinea-pigs, 5 min before challenge, inhibited in a dose-dependent fashion with an IC50 of 0.90 mg/kg the bronchoconstriction induced by PAF (60 ng/kg i.v.). However, BN 52021 did not prevent the leukopenia following PAF injection but significantly inhibited the thrombocytopenia induced by PAF. The dioxolan compound, BN 52111, dose-dependently reduced the bronchoconstriction (IC50 = 0.27 mg/kg) and at doses higher than 1 mg/kg partially antagonized the decrease in the number of circulating platelets and leukocytes induced by PAF. BN 52115 also markedly inhibited the bronchoconstriction (IC50 = 0.36 mg/kg) as well as the thrombocytopenia induced by PAF, but was without significant effect on the leukopenia. These results demonstrate that the two dioxolan compounds, BN 52111 and BN 52115, are more potent than BN 52021 in inhibiting the in vivo bronchopulmonary alterations induced by PAF. Since these alterations are related to the activation of platelets by the autacoid, these blood elements are probably the targets of BN 52111 and BN 52115. Injection of PAF (10 and 100 ng) via the pulmonary artery of ventilated and perfused guinea-pig lungs induced dose-dependent increases in pulmonary inflation pressure (PIP) and pulmonary perfusion pressure (PPP), associated with a dose-dependent release of thromboxane B2 (TxB2). Addition of BN 52021, BN 52111 or BN 52115 (0.1, 1 or 10 microM) to the perfusion medium, 15 min before challenge, dose-dependently inhibited the bronchopulmonary effects of PAF. Although BN 52111 was the more potent in inhibiting the PAF-induced increase in PIP, BN 52021 was the more active with respect to the PAF-evoked generation of TxB2, suggesting that the two phenomena are not directly related.

Animals↗