Mechanism of action of 2-aryloxy-2-thio-1,3,2-oxazaphosphorinane pesticides

The interaction of 2-aryloxy-2-thio-1,3,2-oxazaphosphorinanes exhibiting nematocide, insecticide/acaricide, and synergetic activities with monoamine oxidases and the interaction of the corresponding oxones, 2-aryloxy-2-oxo-1,3,2-oxazaphosphorinanes, with various cholinesterases, carboxyl esterases, and monoamine oxidases were studied. We showed that the thioderivatives inhibited monoamine oxidases, whereas oxones, which are, as a rule, weak cholinesterase inhibitors, strongly inhibited carboxyl esterases of the American cockroach and were transformed with monoamine oxidases into the strong cholinesterase inhibitors, acyclic phosphamidates. This allowed us to explain the low toxicity of the thioderivatives, the high toxicity of the oxoderivatives, and the great difference in toxicities of thio- and oxocompounds in the 1,3,2-oxazaphosphorinane series. The capacity of thioderivatives to inhibit monoamine oxidases and of oxoderivatives and their further activation products to inhibit carboxyl esterases, i.e., both enzymes responsible for pyrethroid detoxication in insects, explains the synergetic activity of the 1,3,2-oxazaphosphorinane series.     

Effect of Heating Temperature on Sulfhydryl and disulfide Contents and State of Aromatic Amino Acid Residues in Soybean Protein

The optical isomers of ten kinds of insecticidal 1,3,2-oxazaphospholidine 2-sulfides (OS) and two kinds of 1,3,2-benzodioxaphosphorin 2-sulfides (BS), including the commercial insecticide salithion, were synthesized in high optical purity by using two optically active aryl methyl phosphorochloridothionates (AMPC) as chiral two-step phosphorylating reagents. Their con-figurations were assigned according to the reaction mechanisms and supported by proton NMR information.     

Synthesis of Some Nucleoside Cyclic Ethylene Phosphothionates

Abstract

This communication describes the synthesis of 5′-deoxy-5′-chloro-3′-(2-thio-1,3,2-dioxaphosphorinanyl)thymidine, N⁴,2′,3′-triacetyl-5′-(2-thio-1,3,2-dioxaphosphorinanyl)-1-β-D-arabinosyl-cytosine and N⁴-acetyl-5′-(2-thio-1,3,2-dioxaphosphorinanyl)-1-β-D-arabinosylcytosine.     

Piperidine levels in the brain and peripheral organs in rats during cold exposure

Piperidine is one of biogenic amines possessing nicotine-like synaptotropic actions on the nervous systems. Since piperidine produces multiplex pharmacological actions, a role for the amine as a modulator in neuroendocrine as well as neuronal functions has been supposed. In the present study, piperidine levels in the brain and peripheral organs in rats during cold exposure were examined by use of a mass fragmentographic technique and it was found that piperidine concentrations in the brain and peripheral endocrine glands significantly increased at 180 min following exposure to 4°C. The significance of the findings is discussed with respect to the neurohormone-releasing effect of piperidine.     

Core modification of substituted piperidines as Novel inhibitors of HDM2–p53 protein–protein interaction

The discovery of 3,3-disubstituted piperidine 1 as novel p53–HDM2 inhibitors prompted us to implement subsequent SAR follow up directed towards piperidine core modifications. Conformational restrictions and further functionalization of the piperidine core were investigated as a strategy to gain additional interactions with HDM2. Substitutions at positions 4, 5 and 6 of the piperidine ring were explored. Although some substitutions were tolerated, no significant improvement in potency was observed compared to 1. Incorporation of an allyl side chain at position 2 provided a drastic improvement in binding potency.     

Inhibition of acetylcholinesterase by derivatives of 1,3,2-dioxaphosphorinane 2-oxide.

Cholinesterases are inhibited by 2-fluoro-1,3,2-dioxaphosphorinane 2-oxide by a mechanism that involves a slow association step followed by a very slow phosphorylation step. No phosphorylation step was observed for the interaction between acetylcholinesterase and 2-S-[2'-(NN-diethylamino)ethyl]thio-1,3,2-dioxaphosphorinane 2-oxide.     

Formation of an unstable covalent intermediate during the inhibition of electric-eel acetylcholinesterase with 1,3,2-dioxaphosphorinane 2-oxides.

The kinetics of interaction of eel acetylcholinesterase (EC 3.1.1.7) with 1,3,2-dioxaphosphorinane 2-oxides were investigated. It was demonstrated that the rate of spontaneous re-activation as well as the re-activation profile in the presence of 2-pyridine aldoxime methiodide of the inhibited enzyme are irrespective of the leaving group of three inhibitors and exhibit the same values. The dissociation constant of the corresponding Michaelis complex was evaluated by two independent methods and the results were found to be in close agreement. It was shown that the active site is essential for interaction between the enzyme and the various dioxaphosphorinanes. The mixed anhydride of diethyl phosphoric acid and 2-hydroxy-1,3,2-dioxaphosphorinane 2-oxide behaves exactly as would be predicted from a typical diethyl phosphate inhibitor. Enxyme that was incubated with the cyclic acid or the corresponding methyl ester recovered immediately upon extensive dilution. Inhibition of enzyme in the presence of high concentratasions of the corresponding 2-chloro and 2-fluoro derivatives decreased the regeneration rates as well as the maximal amount of the re-activated enzyme. This observation could not be explained in terms of a classical aging process. On the basis of the kinetics observations it is suggested that an unstable covalent phospho-enzyme intermediate is formed during the reaction between acetylcholinesterase and 1,3,2-dioxaphosphorinane 2-oxides.     

Plant alkaloids that cause developmental defects through the disruption of cholinergic neurotransmission

The exposure of a developing embryo or fetus to alkaloids from plants, plant products, or plant extracts has the potential to cause developmental defects in humans and animals. These defects may have multiple causes, but those induced by piperidine and quinolizidine alkaloids arise from the inhibition of fetal movement and are generally referred to as multiple congenital contracture‐type deformities. These skeletal deformities include arthrogyrposis, kyposis, lordosis, scoliosis, and torticollis, associated secondary defects, and cleft palate. Structure‐function studies have shown that plant alkaloids with a piperidine ring and a minimum of a three‐carbon side‐chain α to the piperidine nitrogen are teratogenic. Further studies determined that an unsaturation in the piperidine ring, as occurs in gamma coniceine, or anabaseine, enhances the toxic and teratogenic activity, whereas the N‐methyl derivatives are less potent. Enantiomers of the piperidine teratogens, coniine, ammodendrine, and anabasine, also exhibit differences in biological activity, as shown in cell culture studies, suggesting variability in the activity due to the optical rotation at the chiral center of these stereoisomers. In this article, we review the molecular mechanism at the nicotinic pharmacophore and biological activities, as it is currently understood, of a group of piperidine and quinolizidine alkaloid teratogens that impart a series of flexure‐type skeletal defects and cleft palate in animals. Birth Defects Research (Part C) 99:235–246, 2013. Published 2013 Wiley Priodicals, Inc.     

Synthetic flavors: efficiency and safety factors for sweaty and fishy odorants

Rat feeding trials were conducted with two pairs of food additiveswhich exhibit similar odor qualities but vastly different odorintensities. The maximum no-adverse-effect dietary levels ina 90-day trial were as follows: isovaleric acid, 5% 2-ethylbutyricacid, 0.6% trimethylamine, 0.16% piperidine, 0.08%. In viewof these no-effect levels, the concentrations of trimethylamineand piperidine used in human food sometimes infringe the Federal100-fold practical safety factor. In the maximum concentrationsused in food, purified 2-ethylbutyric acid and piperidine couldbe neither tasted nor smelled by human observers, and appearto serve no useful purpose as flavorings. Calculations are presentedwhich suggest that, when their widely differing odor thresholdsare taken into consideration, isovaleric acid has about 22,000times greater theoretical safety factor than 2-ethylbutyricacid for producing a given intensity of a sweaty aroma. By similarconsiderations, trimethylamine has about 260,000 times greatertheoretical safety factor than piperidine for generating a fishyodor.     

Synthesis and structure-activity relationships of piperidine-based melanin-concentrating hormone receptor 1 antagonists

Isosteric replacement of the urea group of lead compound 1 led to novel substituted piperidine phenylamide analogues. SAR on the electron-induced effects of various linkers as well as substituents on the phenyl rings and the piperidine nitrogen has been investigated. Many single-digit nanomolar MCH R1 antagonists have been identified from this series.     

Novel inhibition of porcine pepsin by a substituted piperidine. Preference for one of the enzyme conformers

Pepsin inhibition by 3-alkoxy-4-arylpiperidine (substituted piperidine; (3R,4R)-3-(4-bromobenzyloxy)-4-[4-(2-naphthalen-1-yl-2-oxo-ethoxy)phenyl]piperidine) has been studied using steady-state kinetic and pre-equilibrium binding methods. Data were compared with pepstatin A, a well known competitive inhibitor of pepsin. Steady-state analysis reveals that the substituted piperidine likewise behaves as a competitive inhibitor. Pre-equilibrium binding studies indicate that the substituted piperidine can displace a fluorescently labeled statine inhibitor from the enzyme active site. Simulation of the stopped-flow fluorescence transients provided estimates of the K(d) values of 1.4 +/- 0.2 microm and 39 +/- 2 nm for the piperidine and the fluorescently labeled statine, respectively. The effects of combinations of these two inhibitors resulted in a series of parallel lines when plotted by the method of Yonetani and Theorell (Yonetani, T., and Theorell, H. (1964) Arch. Biochem. Biophys. 106, 234-251), suggesting that the two inhibitors bind in a mutually exclusive fashion to pepsin. Fitting of the entire data set to the appropriate equation yielded an alpha factor of 8 +/- 1. The magnitude of this factor ( infinity > alpha > 1) can be explained by a conformational distinction between the enzyme species that bind each inhibitor. The effects of pH on the inhibition constants for pepstatin A and the substituted piperidine also suggest that the inhibitors bind to distinct conformational forms of the enzyme. No inhibition by the piperidine was observed at acidic pH, while pepstatin A inhibition is maximal at low pH values. Inhibition by the piperidine was maximal when a group with pK 4.8 +/- 0.2 was deprotonated and another group with pK 5.9 +/- 0.2 was protonated. Most likely these two groups are the catalytic aspartates with perturbed ionization properties as a result of a significant and unique conformational change. Taken together, these data suggest that the enzyme can readily interconvert between two conformers, one capable of binding substrate and pepstatin A and the other capable of binding the substituted piperidine.     

8-Phosphorus substituted isosteres of purine and deazapurines.

Synthesis of 8-phosphorus substituted isosteres of purine [pyrimidino (4,5-d)-1,3,2-diazaphosphole], 1-deazapurine [pyridino (2,3-d)-1,3,2-diazaphosphole] and 3-deazapurine [pyridino (4,5-d)-1,3,2-diazaphosphole] has been achieved by the reaction of equimolar amounts of triphenylphosphite and 4,5-diaminopyrimidine, 2,3-diaminopyridine and 3,4-diaminopyridine, respectively. These compounds hydrolyzed (cleavage of the phosphorus-nitrogen bounds) in aqueous solutions to provide the corresponding diaminopyrimidine or diaminopyridines. These three new basic ring systems constitute the first reported synthesis of purines in which ring carbon atom is substituted with a phosphorus atom. 8-Phosphorus substituted purine at a concentration of 4 X 10(-4)M caused a 50% inhibition in the growth of leukemia L1210 cells in culture. The biochemical rationale for the synthesis of these compounds is discussed.     

Chemical tools to distinguish the fire ant species Solenopsis invicta and S. saevissima (Formicidae: Myrmicinae) in Southeast Brazil

Morphologically similar fire ants Solenopsis invicta and Solenopsis saevissima are broadly sympatric in southeastern Brazil. Chemistry from venom (2,6-dialkyl piperidine alkaloids) and cuticular hydrocarbons have been reported as potentially important tools for differentiating Solenopsis species. We have analysed two chemical classes in widely separated populations of S. invicta and S. saevissima and find that both piperidine alkaloids and cuticular hydrocarbons separate the two species. Piperidine alkaloids clustered S. invicta but not S. saevissima. Cuticular hydrocarbons strongly clustered both S. invicta and S. saevissima. One population morphologically identified as S. invicta presented piperidine alkaloids and cuticular hydrocarbons markedly different from either species. The distinctive piperidine alkaloid differences among populations of S. saevissima and the marked difference in piperidine alkaloid and hydrocarbon profiles of the anomalous population of S. invicta suggest undescribed species fire ant in southeastern Brazil.     

Non-aromatic A-ring replacement in the triaryl bis-sulfone CB2 receptor inhibitors

The triaryl bis-sulfone 1 was modified by converting the aryl A-ring to a piperidine ring. The piperidine ring was further elaborated to a spirocyclopropyl piperidine moiety. The effect on CB2 binding potency, rat calcium channel affinity, and CYP 2C9 inhibition is described.     

Synthesis and activity of quinolinylmethyl P1′ α-sulfone piperidine hydroxamate inhibitors of TACE

A series of α-sulfone piperidine hydroxamate TACE inhibitors 11a–n bearing a quinolinyl methyl P1′ group was prepared, and their activity was compared to analogous α- and β-sulfone piperidine hydroxamates with a butynyloxy P1′ group. The quinolinyl methyl P1′ group affords increased inhibitory enzyme activity relative to the corresponding butynyloxy P1′ analogs in the α-sulfone piperidine hydroxamate series, and greater selectivity than the corresponding butynyloxy P1′ analogs in the β-sulfone piperidine hydroxamate series.     

Synthesis and structure-activity relationships of a new series of 2alpha-substituted trans-4,5-dimethyl-4-(3-hydroxyphenyl)piperidine as mu-selective opioid antagonists

Structure-activity relationships at the 2alpha-position of the piperidine ring of the trans-4,5-dimethyl-4-(3-hydroxyphenyl)piperidine mu-opioid antagonist series were investigated. This study showed that only small linear alkyl groups (methyl, propyl) are tolerated at the 2alpha-position of the piperidine ring of this series.     

Synthesis and biological evaluation of phenyl piperidine derivatives as CCR2 antagonists

A series of phenyl piperidine derivatives possessing potent and selective CCR2 antagonist activity is reported. Structure-activity relationship (SAR) studies have established that incorporation of a second ring system adjacent to the aryl piperidine plays an important role in determining the CCR2 potency. Both a second piperidine ring and a 1,3-substituted cyclopentylamine have been probed as linkers. For the cyclopentylamine series, the 1S,3R-configuration exhibits much higher affinity for hCCR2 than the 1R,3S-configuration. Compound 3g shows good selectivity over CCR1, CCR3, 5-HT and has an excellent P450 profile.     

The measurement of nanogram amounts of piperidine in tissues by gas chromatography.

A gas chromatographic method is presented which allows the determination of piperidine in tissue in nanogram quantities. Reaction of the perchloric acid tissue extracts with 3,5-dinitro-4-chloro-benzotrifluoride followed by extraction with hexane, results in a derivative of piperidine suitable for electron capture detection. The specificity of the procedure is confirmed by combined gas chromatography - mass spectrometry. Using this procedure the mean concentration of piperidine in whole mouse brain was found to be 219 pmoles per gram of tissue. No significant difference between the concentration of piperidine in the brains of active and behavioral sleeping mice could be found.     

Design and synthesis of novel CCR3 antagonists

As part of our investigation into the development of potent CCR3 antagonists, a series of piperidine analogues was designed and prepared. Exploration of the piperidine core examined both the basicity and the location of a nitrogen, as well as conformational variants. The bicyclo-piperidine 24c was found to be the most potent inhibitor of CCR3 with an IC(50) of 0.0082 microM in the binding assay and 0.0024 microM in the chemotaxis assay.     

Pipecolic acid in the dog brain

Pipecolic acid is an intermdiary metabolite of lysine and is decarboxylated to produce piperidine, an endogenous synaptotropic substance. In the present study, the existence of pipecolic acid in the dog brain was confirmed. It was present in highest concentration in the cerebellum followed by the diencephalon and caudate nucleus, and this distribution resembles that of piperidine in dog brain. It seems to be evident that pipecolic acid is a precursor of piperidine in the brain.