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PubMedDate not supplied

[Inhibition of cholinesterases by quaternary phosphonium compounds].

Alkyl tributylphosphonium and triphenylphosphonium derivatives as well as tetraphenylphosphonium were first studied as inhibitors of acetylcholinesterase of human blood erythrocytes and butyrylcholinesterase of horse blood serum. The inhibition is reversible, of mixed type, with a different contribution of competitive and uncompetitive components. The value of the inhibitory effect is essentially dependent on the structure of phosphonium compounds, especially in experiments with butyrylcholinesterase: allyltriphenylphosphonium is 290 times as strong enzyme inhibitor as methyltributylphosphonium. Hexyltributylphosphonium is identical to hexyltributylammonium in both the pattern and efficiency of the inhibitory action on cholinesterases.

Acetylcholinesterase↗
PubMed1995

Analysis of glutamate receptors in primary cultured neurons from fetal rat forebrain.

In order to further analyze the development of glutamatergic pathways in neuronal cells, the expression of excitatory amino acid receptors was studied in a model of neurons in primary culture by measuring the specific binding of L-[3H]glutamate under various incubation conditions in 8-day-old intact living neurons isolated from the embryonic rat forebrain, as well as in membrane preparations from these cultures and from newborn rat forebrain. In addition, the receptor responsiveness to glutamate was assessed by studying the uptake of tetraphenylphosphonium (TPP+) which reflects membrane polarization. In the presence of a potent inhibitor of glutamate uptake, the radioligand bound to a total number of sites of 36.7 pmol/mg protein in intact cells incubated in a Tris buffer containing Na+, Ca2+, and Cl-, with a Kd around 2 microM. In the absence of the above ions, [3H]glutamate specific binding diminished to 14.2 pmol/mg protein with a Kd-value of 550 nM. Under both of the above conditions, similar Kd were obtained in membranes isolated from cultures and from the newborn brain. However, Bmax-values were significantly lower in culture membranes than in intact cells or newborn membranes. Displacement studies showed that NMDA was the most potent compound to inhibit [3H]glutamate binding in membranes obtained from cultured neurons as well as from the newborn brain, whereas quisqualate, AMPA, kainate and trans-ACPD were equally effective.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Iodonium ion-assisted synthesis of a haptenic tetrasaccharide fragment corresponding to the inner cell-wall glycopeptidolipid of Mycobacterium avium serotype 4.

Condensation of ethyl 2,4-di-O-benzoyl-1-thio-alpha-L-rhamnopyranoside with ethyl 3-O-benzyl-4-O-chloroacetyl-2-O-methyl-1-thio-beta-L-fucopyranoside in the presence of iodonium di-sym-collidine perchlorate afforded exclusively ethyl 2,4-di-O-benzoyl-3-O-(3-O-benzyl-4-O- chloroacetyl-2-O-methyl-alpha-L-fucopyranosyl)-1-thio-alpha-L-rhamnop yra noside. This disaccharide derivative was extended at C-1 with 3-benzyloxycarbonylaminopropyl 6-deoxy-3,4-O-isopropylidene-alpha-L- talopyranoside, using N-iodosuccinimide and triflic acid as the catalyst, to furnish 3-benzyloxycarbonylaminopropyl 6-deoxy-2-O-[2,4-di-O-benzoyl-3-O-(3-O-benzyl-4-O-chloroacetyl-2-O-me thy l- alpha-L-fucopyranosyl)-alpha-L-rhamnopyranosyl]-3,4-O-isopropylidene-alp ha-L- talopyranoside (20). Selective removal of the chloroacetyl group from 20, followed by condensation with ethyl 2,3-di-O-benzoyl-4-O-methyl-1-thio-alpha-L- rhamnopyranoside in the presence of the same thiophilic promoter, yielded a fully protected tetrasaccharide derivative. Deprotection of the latter gave the target compound 3-aminopropyl 6-deoxy-2-O-[3-O-[2-O- methyl-(4-O-methyl-alpha-L-rhamnopyranosyl)-alpha-L-fucopyranosyl]-alpha -L- rhamnopyranosyl]-alpha-L-talopyranoside (1).

Carbohydrate Sequence↗
PubMed1994

A protein that activates expression of a multidrug efflux transporter upon binding the transporter substrates.

Multidrug transporters are membrane proteins which, by an unknown mechanism, recognize diverse toxic compounds and efflux them from cells. We found that two substrates of the Bacillus subtilis multidrug transporter Bmr, rhodamine 6G and tetraphenylphosphonium (TPP), enhance Bmr expression at the level of transcription. Gene knock-out experiments demonstrated that an open reading frame located immediately downstream of the bmr gene is required for this enhancement. The protein product of this open reading frame, BmrR, shows distinct sequence homology to several known bacterial transcription activator proteins, such as MerR and TipAL. Gel-mobility shift and DNase protection assays indicated that BmrR binds specifically, as a dimer, to the bmr gene promoter. Furthermore, the affinity of this binding was enhanced by rhodamine and TPP, thus suggesting that these structurally dissimilar molecules interact directly with BmrR. Indeed, we found that BmrR bound rhodamine 6G stoichiometrically, one rhodamine molecule/BmrR dimer, and that TPP competed with rhodamine for this binding. Our results indicate that the enhancement of Bmr expression by some of its substrates is due to the ability of the regulatory protein, BmrR, to bind structurally dissimilar compounds resulting in enhanced transcription of the transporter gene.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Prevention of mitochondrial oxidative damage using targeted antioxidants.

Mitochondrial-targeted antioxidants that selectively block mitochondrial oxidative damage and prevent some types of cell death have been developed. These antioxidants are ubiquinone and tocopherol derivatives and are targeted to mitochondria by covalent attachment to a lipophilic triphenylphosphonium cation. Because of the large mitochondrial membrane potential, these cations accumulated within mitochondria inside cells, where the antioxidant moiety prevents lipid peroxidation and protects mitochondria from oxidative damage. The mitochondrially localized ubiquinone also protected mammalian cells from hydrogen peroxide-induced apoptosis while an untargeted ubiquinone analogue was ineffective against apoptosis. When fed to mice these compounds accumulated within the brain, heart, and liver; therefore, using these mitochondrial-targeted antioxidants may help investigations of the role of mitochondrial oxidative damage in animal models of aging.

Animals↗
PubMed2003

Synthesis and characterization of cationic iodonium macrocycles.

A synthetic strategy for the high-yield preparation of iodonium containing macrocycles such as rhomboids, a square, and a pentagon is described, with the long-term objective of preparing iodonium compounds for potential molecular electronics applications. Two cationic rhomboid shaped molecules were prepared for the first time (55-70%) by the treatment of compounds 11 and 12a or 12b with Me3SiOTf. The reaction of dication 8 with 6 in the presence of Me3SiOTf gave an iodonium containing molecular square in 70% yield. In addition, a pentagon-shaped macromolecule was prepared in 60% yield. These iodonium-containing charged macromolecules were characterized by multinuclear NMR, mass spectrometry, and physical means.

Cations↗
PubMed1997

The IncP plasmid-encoded cell envelope-associated DNA transfer complex increases cell permeability.

IncP-type plasmids are broad-host-range conjugative plasmids. DNA translocation requires DNA transfer-replication functions and additional factors required for mating pair formation (Mpf). The Mpf system is located in the cell membranes and is responsible for DNA transport from the donor to the recipient. The Mpf complex acts as a receptor for IncP-specific phages such as PRD1. In this investigation, we quantify the Mpf complexes on the cell surface by a phage receptor saturation technique. Electrochemical measurements are used to show that the Mpf complex increases cell envelope permeability to lipophilic compounds and ATP. In addition it reduces the ability of the cells to accumulate K+. However, the Mpf complex does not dissipate the membrane voltage. The Mpf complex is rapidly disassembled when intracellular ATP concentration is decreased, as measured by a PRD1 adsorption assay.

Adenosine Triphosphate↗
PubMed2000

N-Hydroxyguanidine compound 1-(3,4-dimethoxy- 2-chlorobenzylideneamino)-3-hydroxyguanidine inhibits the xanthine oxidase mediated generation of superoxide radical.

We here show that the novel N-hydroxyguanidine derivative PR5 (1-(3, 4-dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine) is acting as an alternative electron acceptor in xanthine oxidase catalyzed oxidation of xanthine. The reduction product is the corresponding guanidine derivative 1-(3, 4-dimethoxy-2-chlorobenzylideneamino)guanidine (PR9). The reaction occurs under both anaerobic and aerobic conditions. Moreover, EPR measurements show that the action of PR5 is associated with the inhibition of superoxide radical formation seen under aerobic conditions. PR5 also supports xanthine oxidase catalyzed anaerobic oxidation of NADH. Kinetic studies indicate that increasing xanthine concentration significantly increases the apparent K(m) of PR5, but it remains unaltered by changing NADH concentration. Moreover, the molybdenum center inhibitor allopurinol inhibits the PR5-sustained oxidation of xanthine and NADH equally well, whereas the flavin adenine dinucleotide site inhibitor diphenyliodonium (DPI) markedly inhibits only the PR5-sustained oxidation of NADH. We suggest that PR5 binds and becomes reduced at the molybdenum center of the xanthine oxidase. We also found that both PR5 and its reduction product PR9 can inhibit the oxygen-sustained xanthine oxidase reaction. The properties of PR5 suggest that it is a member of a novel class of compounds which we have termed xanthine oxidase electron acceptor-inhibitor drugs. The potential use of xanthine oxidase electron acceptor-inhibitors in the prevention of free radical mediated tissue damage in organ ischemia-reperfusion diseases is discussed.

Allopurinol↗
PubMed2004

Stable compounds of cigarette smoke induce endothelial superoxide anion production via NADPH oxidase activation.

OBJECTIVE: Endothelial dysfunction is an early manifestation of cigarette smoke (CS) toxicity. We have previously demonstrated that CS impairs nitric oxide (NO)-mediated endothelial function via increased generation of superoxide anion (O2*). In these studies, we investigated whether stable compounds present in CS activate specific pathways responsible for the increased endothelial O2* production. METHODS AND RESULTS: Short exposure of bovine pulmonary artery endothelial cells (BPAECs), human pulmonary artery endothelial cells, and rat pulmonary arteries to CS extracts (CSEs) resulted in a large increase in O2* production (20-fold, 3-fold, and 2-fold increase, respectively; P<0.05 versus control), which was inhibited by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors diphenyleneiodinium, apocynin, and gp91 docking sequence-tat peptide but not by oxypurinol, the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester, or the mitochondrial respiration inhibitor rotenone. Exposure of BPAECs to acrolein, a stable thiol-reactive agent found in CS, increased O2* production 5-fold, which was prevented by prior inhibition of NADPH oxidase. CONCLUSIONS: These studies demonstrate that thiol-reactive stable compounds in CS can activate NADPH oxidase and increase endothelial O2* production, thereby reducing NO bioactivity and resulting in endothelial dysfunction. Clinically, these studies may contribute to the development of agents able to mitigate CS-mediated vascular toxicity.

Acetophenones↗
PubMed1976

Synthesis and properties of 2-S-(N,N-dialkylamino)ethyl)thio-1,3,2-dioxaphosphorinane 2-oxide and of the corresponding quaternary derivatives as potential nontoxic antiglaucoma agents.

A new series of cyclic organophosphorus esters, 2-S-[2'-N,N-dialkylamino)ethyl]thio-1,3,2-dioxaphosphorinane 2-oxide and their quaternary derivatives, was synthesized and studied as potential antiglaucoma agents. Thes compounds inhibit acetylcholinesterase (E.C.3.1.1.7)at a bimoecular rate constant (ki) in the range of 10(3)-10(4) M-1 min-1. Values of the affinity (K) and phosphorylation (k') rate constants for this enzyme indicate that k' is responsible for the relatively low values of ki as compared with similar data for the open-chain analogues, O,O-diethyl phosphorothiolates (10(6) M-1 min-1). The mammalian toxicity of the new compounds in terms of acute LD50 values in mice is 1-3 x 10(3) less than that of phospholine, an open-chain analogue. In an initial clinical trial, one member of the new series (alkyl = C2H5) caused a significant decrease of intraocular pressure in aphakic glaucoma, while phospholine proved to be ineffective.

Animals↗
PubMed1985

Effects of alkyl and aryl substitution on the myocardial specificity of radioiodinated phosphonium, arsonium, and ammonium cations.

Several radioiodinated iodopentenyl-trisubstituted phosphonium, arsonium, and ammonium iodides have been prepared and evaluated in rats to determine the effects of structural variations of the cations on myocardial uptake and retention. The synthesis of (E)-(1-iodo-1-penten-5-yl)-trisubstituted phosphonium, arsonium, and ammonium iodides via the condensation of trisubstituted phosphine, arsine, and amine precursors, respectively, with (E)-1,5-diiodopentene is described. In some cases a second route involved condensation with (E)-1-borono-5-iodo-1-pentene followed by iodination. In the phosphonium series, the compounds triphenyl 1, dicyclohexylphenyl 5, tricyclohexyl 6, and dimethyl-n-octyl 8 were prepared. The triphenylarsonium 10 and triethylammonium 11 compounds were also prepared. The corresponding radioiodinated analogues were prepared and tissue distribution studies performed in rats. The results (percent dose/gram, 30 min) demonstrate that replacement of phosphorus with arsenic (1, 3.99%; 10, 3.17%) or the replacement of the phenyl ring with the cyclohexyl ring system (6, 2.67%) has no apparent effect on heart uptake. In the series of compounds studied, replacement of the cyclic ring system with alkyl groups, however, significantly decreased heart uptake with both the phosphorus (8, 1.95%) and nitrogen agents (11, 1.11%). Gamma camera imaging studies with [123I]-5 and [123I]-8 further substantiated the decreased heart uptake with alkyl substitution and the apparent hepatobiliary clearance of 8.

Alkylation↗
PubMed1995

FAD is a further essential cofactor of the NAD(P)H and O2-dependent zeaxanthin-epoxidase.

In chloroplasts of plants the xanthophyll cycle is suggested to function as a protection mechanism against photodamage. Two enzymes catalyze this cycle. One of them, violaxanthin de-epoxidase, transforms violaxanthin (Vio) to zeaxanthin (Zea) via antheraxanthin (Anth) and is bound to the lumenal surface of the thylakoid vesicles, when being in its active state. The other enzyme, Zea-epoxidase, is responsible for the backward reaction (Zea-->Anth-->Vio) and is active at the stromal side of the thylakoid. For the epoxidation of Zea this enzyme requires NAD(P)H and O2 as cosubstrates. Using isolated thylakoid membranes we found that FAD enhances the epoxidase activity (decrease of apparent Km for NAD(P)H and two-fold increase of Vmax). The flavin functions as a third cofactor which is partially lost during the isolation procedure of thylakoids. Other flavins, such as FMN or riboflavin are without effect. The involvement of FAD in the enzymatic reaction is also demonstrated by the inhibitory action of diphenyleneiodoniumchloride (DPI) (IC50 = 2.3 microM), a compound that blocks the reoxidation of reduced flavins within enzymes. The Zea-epoxidase is a multi-component enzyme system which can be classified as FAD-containing, NAD(P)H- and O2-dependent monooxygenase that is able to epoxidize 3-hydroxy beta-ionone rings of xanthophylls in the 5,6 position.

Carotenoids↗
PubMed1990

The use of diphenylene iodonium, an inhibitor of NADPH oxidase, to investigate the antimicrobial action of human monocyte derived macrophages.

Diphenylene iodonium is an inhibitor of the respiratory burst-generating NADPH oxidase of phagocytes. The effect of this compound on human monocyte-derived macrophages and its usefulness in exploring the antimicrobial mechanisms of phagocytes was examined. 1 microM diphenylene iodonium inhibited hydrogen peroxide production by human macrophages and the activity of these cells against Toxoplasma gondii. At this concentration macrophage degranulation was unaffected.

Acetylglucosaminidase↗
PubMed1998

KATP channel blocking actions of quaternary ions play no role in their antiproliferative action on mouse leukaemia and rat vascular smooth muscle cells in vitro.

1. The aim of the present study was to investigate the possibility that, in the two cell lines examined, alterations in cell growth caused by lipophilic quaternary ions may involve KATP channels. We examined the effect of tetraphenylphosphonium (TPP), tetraphenylboron (TPB), rhodamine 123, dequalinium chloride (DECA) and the non-quaternary ion cisplatin on the proliferation of L1210 mouse leukaemia cells and rat smooth muscle cells in vitro. The KATP channel opener levcromakalim (LKM) and the KATP channel antagonist glibenclamide were also tested. 2. From growth-inhibition studies, the rank order of potency (based on pIC50 values) using L1210 leukaemia cells was: DECA (6.61) > cisplatin (6.09) = rhodamine 123 (6.01) > TPP (5.61) > TPB (4.25). Levcromakalim and glibenclamide were found to be inactive at the maximum concentrations used (100 mumol/L). A different rank order of potency was obtained in rat aortic smooth muscle cells: cisplatin (6.33) > DECA (5.67) > TPP (4.96) > rhodamine 123 (4.1). Tetraphenylboron (30 mumol/L), LKM (100 mumol/L) and glibenclamide (100 mumol/L) were found to be inactive. 3. When the negatively charged TPB (30 mumol/L) was combined with some of the active agents, the potency of the active agents was increased. Thus, in L1210 cells, rhodamine 123, DECA and TPP were all more potent at inhibiting cell growth in the presence of TPB. Tetraphenylboron had no effect on cisplatin in this cell line. In rat smooth muscle cells, TPB (30 mumol/L) potentiated the effect of rhodamine 123 but had no effect on the actions of cisplatin, DECA or TPP. 4. In functional studies, rhodamine 123 was a weak antagonist of the vasorelaxant responses to the KATP channel opener LKM in the porcine right circumflex artery in vitro. The pKB value obtained for rhodamine 123 at 100 mumol/L was 4.95. Dequalinium chloride was inactive. 5. We found no correlation between the actions of the compounds tested to antagonise KATP channels and their ability to inhibit cell proliferation. In addition, compounds known to regulate KATP channel activity failed to influence proliferative rates. These results suggest that KATP channels are not involved in the antiproliferative action of TPP and other quaternary ions in the two cell lines studied.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1977

In search of anti-Trypanosoma cruzi drugs: new leads from a mouse model.

Nine of 25 carefully selected compounds (from a stock of more than 200 000 chemical species amassed principally as a result of testing against other parasitic diseases) were found to have significant suppressive activity against the parasites in the blood of a Trypanosoma cruzi mouse model. Eight of these compounds evaluated in this model had suppressive activity equal to or greater than the reference compound, nifurtimox. For the first time, suppressive activity against T. cruzi is reported for a 7-aminoquinoline, a phosphonium salt, and TAC pamoate; The biological model is believed to be able to serve as a means of identifying other new "leads* in seeking drugs broadly effective against T=ruzi infections in man.

5-Amino-3-((5-nitro-2-furyl)vinyl)-1,2,4-oxadiazol↗
PubMed1989

Effect of cocaine and cocaine congeners on veratridine-induced depolarization in mouse cerebrocortical synaptoneurosomes.

Structure-activity relationships were determined for cocaine congeners in counteracting the depolarization induced by the action of veratridine on voltage-dependent sodium channels of synaptoneurosomes from mouse brain cortex, and their potency was compared to those determined previously on Na+ uptake and batrachotoxinin binding. Cocaine, norcocaine, (+)-pseudococaine, (-)-pseudococaine, (+)-neopseudococaine, benzoyltropine, benzoylpseudotropine, ecgonine methylester, atropine, WIN-35,428, WIN-35,140, WIN-35,065-3, WIN-35,004, and procaine were tested for their potency in inhibiting depolarization as measured by the distribution of the lypophilic cation [3H]triphenylmethylphosphonium across the membrane. All of the tested compounds inhibited the veratridine-induced depolarization in a competitive manner. The structure-activity relationships were similar to those for inhibition of 22Na+ uptake in mouse brain homogenates, and the potency of these local anesthetics in inhibiting veratridine-induced uptake of [3H]triphenylmethylphosphonium correlated well with their potency in inhibiting [3H]batrachotoxinin A 20-alpha-benzoate binding in mouse brain synaptosomes.

Anesthetics, Local↗
PubMed2006

Reaction mechanism of the acidic hydrolysis of highly twisted amides: Rate acceleration caused by the twist of the amide bond.

We present an ab initio study of the acid hydrolysis of a highly twisted amide and a planar amide analogue. The aim of these studies is to investigate the effect that the twist of the amide bond has on the reaction barriers and mechanism of acid hydrolysis. Concerted and stepwise mechanisms were investigated using density functional theory and polarizable continuum model calculations. Remarkable differences were observed between the mechanism of twisted and planar amide, due mainly to the preference for N-protonation of the former and O-protonation of the latter. In addition, we were also able to determine that the hydrolytic mechanism of the twisted amide will be pH dependent. Thus, there is a preference for a stepwise mechanism with formation of an intermediate in the acid hydrolysis, whereas the neutral hydrolysis undergoes a concerted-type mechanism. There is a nice agreement between the characterized intermediate and available X-ray data and a good agreement with the kinetically estimated rate acceleration of hydrolysis with respect to analogous undistorted amide compounds. This work, along with previous ab initio calculations, describes a complex and rich chemistry for the hydrolysis of highly twisted amides as a function of pH. The theoretical data provided will allow for a better understanding of the available kinetic data of the rate acceleration of amides upon twisting and the relation of the observed rate acceleration with intrinsic differential reactivity upon loss of amide bond resonance.

Acids↗
PubMed1974

Inhibition and uncoupling of photophosphorylation in isolated chloroplasts by organotin, organomercury and diphenyleneiodonium compounds.

1. Trialkyltin, triphenyltin and diphenyleneiodonium compounds inhibited ADP-stimulated O(2) evolution by isolated pea chloroplasts in the presence of phosphate or arsenate. Tributyltin and triphenyltin were the most effective inhibitors, which suggests a highly hydrophobic site of action. Phenylmercuric acetate was a poor inhibitor of photophosphorylation, which suggests that thiol groups are not involved. 2. Triethyltin was a potent uncoupler of photophosphorylation by isolated chloroplasts in media containing Cl(-), but had little uncoupling activity when Cl(-) was replaced by NO(3) (-) or SO(4) (2-), which are inactive in the anion-hydroxide exchange. It is suggested that uncoupling by triethyltin is a result of the Cl(-)-OH(-) exchange together with a natural uniport of Cl(-). Tributyltin, triphenyltin and phenylmercuric acetate had low uncoupling activity, probably because in these compounds the uncoupling activity is partially masked by inhibitory effects. 3. At high concentrations the organotin compounds caused inhibition of electron transport uncoupled by carbonyl cyanide m-chlorophenylhydrazone or NH(4)Cl. At these high concentrations the organotin compounds may be producing a detergent-like disorganization of the membrane structure. In contrast, diphenyleneiodonium sulphate inhibited uncoupled electron transport at low concentrations; however, this inhibition is less than the inhibition of photophosphorylation, which suggests that the compound also inhibits the phosphorylation reactions as well as electron transport. 4. The effects of these compounds on basal electron transport were complex and depended on the pH of the reaction media. However, they can be explained on the basis of three actions: inhibition of the phosphorylation reactions, uncoupling and direct inhibition of electron transport. 5. The inhibition of cyclic photophosphorylation in the presence of phenazine methosulphate by diphenyleneiodonium sulphate shows that it inhibits in the region of photosystem 1.

Adenosine Diphosphate↗