Sulfonium Analogs Research Articles

Inhibition of monoterpene cyclases by sulfonium analogs of presumptive carbocationic intermediates of the cyclization reaction.

The enzymatic cyclization of geranyl pyrophosphate to monoterpenes is thought to proceed through a series of carbocation-pyrophosphate anion paired intermediates. Sulfonium analogs of two putative carbocationic intermediates of the cyclization sequence were shown to be inhibitors of the conversion of the acyclic precursor to the bicyclic monoterpenes (+)-alpha-pinene and (+)-bornyl pyrophosphate by partially purified cyclase preparations from sage (Salvia officinalis). The sulfonium analog of the tertiary allylic, linalyl, intermediate (i.e. methyl-(4-methylpent-3-en-1-yl)vinyl-sulfonium perchlorate) provided respective Ki values of 2.5 microM and 3.0 microM against the cyclization to alpha-pinene and bornyl pyrophosphate at a substrate concentration of 5 microM, whereas the sulfonium analog of the monocyclic, alpha-terpinyl, intermediate (i.e. dimethyl-(4-methylcyclohex-3-en-1-yl) sulfonium iodide) exhibited respective Ki values of 3.4 microM and 3.9 microM against the same two cyclizations. The potency of inhibition in all cases increased with increasing substrate concentration, indicating that the affinity of the enzymes for the sulfonium analogs was increased by the presence of the pyrophosphate ester. Inorganic pyrophosphate at a concentration of 50 microM, which alone had little influence on the cyclizations, increased the effectiveness of inhibition of the sulfonium analogs severalfold, and the apparent Ki for inorganic pyrophosphate was reduced manyfold by the presence of either analog at 5 microM. That the combination of sulfonium analog and pyrophosphate provided synergistic inhibition of the electrophilic cyclizations indicated that the cyclases bind the paired species more tightly than either partner alone. Specificity studies suggested that inhibition by the above sulfonium ion:pyrophosphate pairs was due to both electronic and structural resemblance to intermediates of the reaction.

Behavioral effects of a dimethylsulfonium analog of dopamine after injection into the nucleus accumbens and the striatum

We have previously synthesized a chemical analog of dopamine (DA) in which the amine group has been replaced by a permanently charged dimethylsulfonium group. In the present study, we have determined whether this compound can exert DA agonist activity in the nucleus accumbens by comparing its effects with those of DA. When DA was injected into the nucleus accumbens of rats pretreated with nialamide, a monoamine oxidase inhibitor, there was marked stimulation of locomotor activity. Similarly, after intraaccumbens injection, the sulfonium analog also produced a marked stimulation of locomotor activity, and this effect was inhibited by the DA receptor antagonist, haloperidol (0.2 mg/kg, IP). However, the sulfonium analog did not stimulate locomotor activity when rats were pretreated with saline instead of nialamide. In addition, the stimulation of locomotor activity produced by the sulfonium analog in rats pretreated with nialamide was completely inhibited by the DA synthesis inhibitor, α-methyl-p-tyrosine. These results suggest that the stimulation of locomotor activity by the sulfonium analog is mediated indirectly through the release of DA. The sulfonium analog was able to produce marked contralateral circling after it was injected into the striatum of rats on the side of the brain in which DA nerve terminals were previously destroyed with 6-hydroxydopamine. Similarly, the sulfonium analog produced a marked stimulation of locomotor activity after it was injected into the nucleus accumbens of rats that were previously injected into this region with 6-hydroxydopamine. These results suggest that the sulfonium analog of dopamine can exert direct as well as indirect DA agonist activity.

Occurrence of phosphatidylsulfocholine, the sulfonium analog of phosphatidylcholine in some diatoms and algae

A survey of seven species of diatoms, one Euglena sp. and one dinoflagellate sp. for the presence of phosphatidylsulfocholine (PSC), the sulfonium analog of phosphatidylcholine (PC), was carried out using 1H-NMR spectroscopy and ammonia desorption chemical ionization mass spectrometry. PSC alone was found only in a non-photosynthetic diatom, Nitzschia alba. PSC, together with PC, was found in four of the diatoms ( Nitzschia angularis, Cylindrotheca fusiformis, Phaeodactylum tricornutum and Navicula pelliculosa) in proportions of 6–24% of the total PC + PSC fraction, but little or no PSC (less than 2%) was detected in the remaining two ( Cyclotella nana and Navicula incerta). Little or no PSC (less than 2%) was detected in a Euglena sp. by 1H-NMR but its presence was confirmed by 35S-labeling. The amount of PSC, if any, in the dinoflagellate ( Amphidinium carterae) was below the level of detection by 1H-NMR.

Crystal structures of two intermediates in the synthesis of sulfonium analogs of levorphanol and isolevorphanol

Crystal structures of two intermediates in the synthesis of sulfonium analogs of levorphanol and isolevorphanol

Effect of a sulfonium analog of dopamine on the depolarization-induced release of [ 3H]acetylcholine from mouse striatal slices

We have synthesized a chemical analog or dopamine in which the amino group has been replaced by a charged dimethylsulfonium group. The dopaminergic activity of this drug was evaluated by determining its ability to inhibit the depolarization-evoked release of [ 3H]acetylcholine from mouse striatal slices. The slices were preincubated with [ 3H]choline (0.1 μM) and then superfused in physiological medium. [ 3H]Acetylcholine release was induced by exposure of the slices to a high potassium medium (12.5 mM) for 5 min. The sulfonium analog of dopamine, dopamine, and apormorphine inhibited the evoked [ 3H]acetylcholine release with IC 50 values of approximately 10, 2.0, and 0.3 μM respectively. The inhibition by the sulfonium analog was reversed by fluphenazine (1 μM), suggesting that the inhibition of [ 3H]acetylcholine release was due to the activation of dopaminergic receptors. The sulfonium analog also inhibited the uptake of [ 3H]dopamine into striatal slices and caused the release of exogenously taken up [ 3H]dopamine from these slices. The release of [ 3H]dopamine by the sulfonium analog was inhibited by cocaine (3 μM), suggesting that the drug-induced release of [ 3H]dopamine was dependent on the carrier-mediated uptake of the sulfonium analog into dopaminergic neurons. The inhibition of the evoked [ 3H]acetylcholine release by high concentrations (30 and 60 μM) of the sulfonium analog did not appear to be mediated by endogenous dopamine release, since the analog still inhibited [ 3H]acetylcholine release from slices after reserpine-α- methyl-p- tyrosine treatment, However, the inhibitory effect of the sulfonium analog at 10 μM was reduced by reserpine-α- methyl-p- tyrosine treatment, suggesting that the inhibition at lower concentrations was mediated through endogenous DA release. These results suggest that a charged compound can act as a substrate for the dopamine carrier and can activate the dopamine receptor regulating acetylcholine release. They also indicate that the nitrogen on the dopamine molecule is not essential for dopamine agonist activity.

Osmotic behavior of liposomes of phosphatidylcholine and phosphatidylsulfocholine as a function of lipid concentration

A relationship between the initial rate of liposome swelling, d(1/ A)/ dt and the reciprocal of the lipid concentration of the liposomes has been derived and then utilized to describe the osmotic swelling behavior of serially diluted liposomes and chloroplasts exposed to hypertonic urea solutions. The slopes of plots of d(1/ A)/ dt vs. the reciprocal of the lipid concentration of liposomes were not affected by differences in the initial absorbance of phosphatidylcholine-sterol bilayers, and were used to assess the ability of sterols to reduce the initial rates of urea permeation through dimyristoylphosphatidylcholine (DMPC) bilayers in the liquid-crystalline state. Multilamellar liposomes and sonicated vesicles were prepared from dimyristoylphosphatidylsulfocholine (DMPSC), in which the quaternary ammonium group of choline is replaced by -S +(CH 3) 2. Cholesterol reduced the initial rate of osmotic urea penetration into liposomes and the rate of 6-carboxyfluorescein efflux from vesicles at 35°C. The effect of cholesterol on bilayers of phosphatidylsulfocholine and phosphatidylcholine was very similar, suggesting that no strict structural requirements need be met in the choline moiety for lecithin-cholesterol interaction. The sulfonium analog could thus functionally replace phosphatidylcholine in natural membranes.

Comparative physical studies of phosphatidylsulfocholine and phosphatidylcholine. Calorimetry, fluorescence polarization and electron paramagnetic resonance spectroscopy

Transition temperatures of phosphatidylsulfocholines (PSCs; di-14 : 0-, di-16 : 0-, di-18 : 0- and di-18 : 1-) were compared with those of the corresponding phosphatidylcholines (PCs) using the techniques of differential scanning calorimetry, fluorescent polarization with diphenylhexatriene (DPH) and cis- and trans- parinaric acids as probes, and electron paramagnetic resonance (EPR) with 5-doxyl stearic acid as probe. Liposomal dispersions of the sulfonium analogs showed the typical multibilayer structure by electron microscopy (EM) and were in general very similar in physical behaviour to those of the corresponding PCs. However, the fully hydrated saturated PSCs consistently showed sharp main transitions 2–4°C above those of the corresponding PCs, by all three techniques used; the unsaturated PSC (di-18 : 1) had a transition 2–3°C below that of di-18 : 1-PC and only the di-14 : 0-PSC and di-18 : 1-PSC showed a well-defined pretransition. Fluorescence polarization studies with cis- and trans-parinaric acids showed that the PSC bilayers were less ordered than the corresponding PC bilayers in both the gel and liquid crystalline states. These results provide a rationale for the observed ability of the sulfonium analogs to substitute for PC in some natural membranes.

Replacement of mouse LM fibroblast choline by a sulfonium analog: Effects on membrane properties as determined by virus probes

A sulfonium analog of choline (‘sulfocholine’, a natural phospholipid constituent of diatoms) was metabolically incorporated into mouse LM fibroblasts cultured in serum-free medium. Subconfluent cultures of LM cells were able to utilize sulfocholine as sole choline source and to increase in cell number for 3 days of incubation; thereafter a decrease in cell number was observed. In contrast, cultures of LM cells seeded to confluency showed no decrease in cell number up to at least 10 days when maintained, with daily medium changes, in medium containing either choline or the sulfonium analog. Such confluent cultures, maintained for 7 days in sulfocholine-containing medium, showed virtually complete replacement of cellular phosphatidylcholine and greater than 50% replacement of cellular sphingomyelin by their respective sulfonium analogs. The functional exchangeability of natural phosphatidylcholine and sphingomyelin with their sulfonium analogs to participate in normal cell membrane-mediated activities was demonstrated by comparatively assaying the abilities of sulfocholine- and choline-maintained cells to incorporate and replicate certain animal viruses known to possess membrane-dependent steps in various phases of their replication cycles. No difference was detected between the abilities of sulfocholine- and choline-maintained cells to take up vesicular stomatitis virus or mengo virus, or to replicate vesicular stomatitis virus, mengo virus or mouse hepatitis virus.

Studies on substrate specificity of S-adenosylmethionine: protein-carboxyl methyltransferase from calf brain.

Kinetic properties of protein methylase II (S-adenosylmethionine:protein-carboxyl methyltrans- ferase, EC 2.1.1.24), which methylates the free carboxyl groups of protein substrates, were studied with various analogs and derivatives of S-adenosyl-l-methionine (AdoMet) and S-adenosyl-l- homocysteine (AdoHcy), using corticotropin as methyl-accepting polypeptide. Experiments with methyl-labelled structural analogs of AdoMet showed that the replacement of the amino groups of AdoMet by hydroxyl groups, as well as the removal of the carboxyl group, results in a loss of methylating ability of the molecule. Deaminated and decarboxylated derivatives were also inactive as inhibitors. Among the sulfonium analogs tested, only S-adenosyl-l- (2-amino-4-carboxymethylthio)butyric acid exerted a significant inhibition. AdoHcy, the demethylated product of AdoMet, exerts a competitive inhibition on the reaction (Ki= 0.65 μM); the probable regulatory role of this inhibition will be discussed. The removal of the adenine amino group of the thioether resulted in a loss of the inhibitory effect. Experiments with the D-isomer of AdoHcy showed the relevance of the steric configuration of the α-carbon in the binding to the enzyme protein. 5′-Methylthioadenosine, a metabolic product of AdoMet, in- hibited competitively the reaction (Ki= 41 μM) while 5′-methylthioadenosine derivatives, such as n-butylthioadenosine, isobutylthioadenosine and thioethanoladenosine, failed to exert any in- hibition. Three synthetic polypeptides differing in amino acid composition and in chain length have also been tested as methyl-acceptor substrates and as inhibitors for the reaction. Only the copolymer of l-glutamic acid and l-tyrosine [poly(Glul1.16, Tyrl)] (Mr= 22600) exerts a relevant non-com- petitive inhibition, while none of the tested synthetic polypeptides is active as substrate.

Studies on the biosynthesis of sulfolipids in the diatom Nitzschia alba

Labeling of sulfolipids in Nitzschia alba was studied after growth of the cells in media containing ll-[ 35S] cystine, l-[ 35S] cysteine, l-[ 35S]-methionine or a mixture of l-[ Me- 3H] methionine and l-[ 35S] methionine. [ 35S] Cysteine or [ 35S] cystine labeled the deoxyceramide sulfonate and the sulfonium analog, phosphatidylsulfocholine (and its lyso derivative) but not the sterol sulfate nor the sulfoquinovosyl diglyceride; [ 35S] methionine labeled only the phosphatidylsulfocholine and its lyso derivative. With the [ 35S] - and [ Me- 3H] methionine mixture ( 3H 35S ratio 1.0) the phosphatidylsulfocholine had a 3H 35S ratio of 1.5 indicating that both sulfonium methyl groups were derived from methionine. Probable biosynthetic pathways for these novel sulfolipids are discussed.

Chemical synthesis of sn-3-phosphatidyl sulfocholine, a sulfonium analog of lecithin.

A sulfonium analog of lecithin has been reported to replace the ubiquitous phosphatidyl choline in a non-photosynthetic diatom, Nitzschia alba. The structure of this sulfonium analog has now been established by chemical synthesis using the following methods: (i) condensation of sn-3-phosphatidic acid (dimyristoyl-, dipalmitoyl-, distearoyl-, distearoyl-, and dioleoyl-) with sulfocholine chloride in the presence of triisopropylbenzenesulfonylchloride in chloroform-pyridine (9:1); and (ii) phosphorylation of 1,2-dipalmitoyl-sn-glycerol with monophenylphosphoryl-dichloridate followed by a reaction with sulfocholine in the presence of pyridine and finally removal of the blocking phenyl group by catalytic hydrogenolysis. The desired synthetic products were obtained in overall yields of 50-70% and 11% for methods (i) and (ii), respectively, and were characterized by elemental analyses; infrared spectroscopy, nuclear magnetic resonance spectrometry, and mass spectrometry; optical rotation; and thin-layer chromatography mobilities. Comparison of the synthetic analogs with the natural sulfolecithin showed them to be identical, except for the nature of the fatty acid chains, thus establishing the natural product as sn-3-phosphatidyl sulfocholine.

The rate of action of cyclic ammonium and sulfonium analogues of acetylcholine

The rate of action of cyclic acetylcholine analogues in the 4-acetoxypiperidine and 4-acetoxythiacyclohexane series has been determined by using the isolated left guinea-pig atrium. The kinetic data obtained has been correlated with the experimental ED50-value on the muscarinic receptor.

Identification of the sulfolipids in the non-photosynthetic diatom nitzschia alba

The four major sulfolipids in the non-photosynthetic marine diatom, Nitzschia alba, were isolated in pure form and their structures were established spectrometrically and by identification of their hydrolysis products as (a) 24-methylene cholesterol sulfate, (b) 1-deoxyceramide-1-sulfonate, (c) phosphatidyl sulfocholine (a sulfonium analogue of phosphatidylcholine) and (d) sulfoquinovosyi diglyceride. The major characteristic fatty acids of the sulfolipids were: for the deoxyceramide sulfonate, 16:0 (26%) and 16:1- Δ 3-trans (64%); for the sulfonium analogue, 14:0 (30%), 18:1 (12%), 18:2 (8%), 20:5 (27%) and 22:6 (4%); and for the sulfoquinovosyl diglyceride (two species, respectively), 14:0 (9%, 22%), 16:0 (16%, 28%), 18:1 (8%, 22%), 20:5 (42%, 23%) and 22:6 (14%, 2%). Traces of lyso-derivatives of sulfoquinovosyl diglyceride and phosphatidyl sulfocholine were also detected. The deoxyceramide sulfonate and the phosphatidyl sulfocholine represent novel membrane lipid components not previously detected in other organisms. They may however have a widespread distribution in marine diatoms and perhaps in marine organisms generally.

Biochemical and pharmacological studies on the sulfonium analogues of choline and acetylcholine

Sulfocholine was found to be a substrate for choline acetyltransferase and acetylsulfocholine was a substrate for acetylcholinesterase and cholinesterase. Sulfocholine, like choline, was taken up by an active transport mechanism into brain slices. When 14C-labelled sulfocholine was injected into mice, formation of labelled acetylsulfocholine in the brain was demonstrated. The equipotent cholinomimetic molar ratio of acetylcholine and acetylsulfocholine on the tibialis anterior preparation of the cat was 6.6 : 1. The response elicited by sulfocholine on the stimulated tibialis anterior preparation was similar to that of choline, and was antagonized by D-tubocurarine. Sulfocholine had a restorinng action on the hemicholinium-inhibited tibialis anterior preparation, although weaker than that of choline. It is concluded, that the action of sulfocholine on neuromuscular transmission consists mainly of a stimulating effect on the motor end-plate, but a presynaptic action, leading to an increased output of acetylcholine, is also suggested.

Notes- Synthesis of Certain Sulfonium Analogs of Meperidine and of the Methadone Class of Analgesics

Notes- Synthesis of Certain Sulfonium Analogs of Meperidine and of the Methadone Class of Analgesics

Additions and Corrections: Synthesis of Certain 3-Hydroxy-3-phenylpropylsulfonium Salts. Sulfonium Analogs of Artane (Trihexyphenidyl) and Pathilon (Tridihexethyl Iodide).

Additions and Corrections: Synthesis of Certain 3-Hydroxy-3-phenylpropylsulfonium Salts. Sulfonium Analogs of Artane (Trihexyphenidyl) and Pathilon (Tridihexethyl Iodide).

The Synthesis and Pharmacology of Some Polymethylene Bisonium Compounds

The sulfonium analogs of pentaméthonium and hexaméthonium and a series of S,S -polymethylenebisthiuronium salts have been prepared.These compounds have been tested for hypotensive, spasmolytic, local anesthetic, and anticoagulant activity.They showed a variable hypotensive activity of short duration, a weak spasmolytic activity, and were found to be devoid of local anesthetic properties._ Only S,S ’-hexamethylenebis (thiuronium bromide) had any anticoagulant activity.