Phenolic Substituents Research Articles

Phenolic replacements for cysteine in farnesyl transferase inhibitors based on CVFM

Compounds in which cysteine of the tetrapeptide CVFM has been replaced with a phenolic benzyl substituent inhibit farnesylation of H-ras protein by farnesyl transferase (FTase). In the most potent inhibitors (e.g., 5-chloro-2-hydroxybenzyl-VFM, IC 50 = 0.5 μM, approx. 8 times less active than CVFM) the phenolic hydroxyl is ortho to the methylene linker. Inhibitory activity is influenced by substitution on the phenol ring.

Inhibition of signal-regulated protein kinases by plant-derived hydrolysable tannins

A variety of hydrolysable tannins purified from Phyllanthus amarus are potent inhibitors of rat liver cyclic AMP-dependent protein kinase catalytic subunit (cAK) with IC 50 values (concentrations for 50% inhibition) in the range 0.2–1.7 μM. The three most effective compounds of this series of hydrolysable tannins have five phenolic substituents. These three compounds are also the most effective inhibitors of wheat embryo Ca 2+-dependent protein kinase (CDPK), rat brain Ca 2+- and phospholipid-dependent protein kinase C (PKC) and Ca 2+-calmodulin-dependent myosin light chain kinase (MLCK). The order of sensitivity for protein kinase inhibition by the hydrolysable tannins studied is cAK>CDPK>PKC>MLCK. Thus the IC 50 values for protein kinase inhibition by the most potent compound are 0.2 μM (for cAK), 1.8 μM (for CDPK), 26 μM (for PKC) and 56 μM (for MLCK) when protein kinase affinity is measured using synthetic peptide substrates. These hydrolysable tannin inhibitors found are the most specific and potent plant-derived inhibitors of cAK yet found.

Characterization of a Novel, Linear Radioiodinated Vasopressin Antagonist: An Excellent Radioligand for Vasopressin V<sub>1a</sub> Receptors

We report on the pharmacological properties of a potent and selective linear vasopressin (AVP) V1a receptor antagonist HO-Phenylacetyl1-D-Tyr(Me)2-Phe3-Gln4-Asn5-Arg6-Pro7-Arg8-NH2 (HO-LVA). Iodinated on the phenolic substituent at position 1, [125I]-HO-LVA displayed the highest affinity for rat liver V1a receptors (8 pM) ever reported. Furthermore, affinities of HO-LVA and I-HO-LVA for V1b, V2 and oxytocin (OT) receptors was 400- to 1,000-fold lower than for V1a receptors, rendering it a highly selective ligand. Both HO-LVA and its iodinated derivative are V1 antagonists, they potently inhibited AVP-induced inositol-phosphate accumulation in WRK1 cells, and also, although with a much lower potency, the AVP-induced ACTH release from freshly prepared pituitary cells. Using autoradiography [125I]-HO-LVA appeared to be the first radioligand to successfully identify and localize the presence of V1a receptors in rat liver and blood vessel walls. Moreover, several new brain regions expressing V1a receptors could be identified, in addition to those brain regions that were previously identified with other radiolabelled AVP analogues.

Serotoninergic behavioural effects induced by intrahippocampal infusion of 8-hydroxy-2-(DI-N-propylamino)tetralin (8-OH-DPAT) in the rat

Racemic 2-(di-n-propylamino)tetralin ((R,S)-DPAT), which lacks phenolic or other aromatic substituents, induces both dopaminergic (sniffing, licking and gnawing) and serotoninergic (forepaw treading and flat body posture) behavioural responses. The present study shows thats.c. administration of (R)-DPAT induces typical 5-HT1A receptor agonist behaviours. These effects are blocked by the 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin ((S)-UH-301). Administration of (S)-DPAT induces dopaminergic behaviours, which are fully antagonised by raclopride, a dopamine D2 receptor antagonist. Both enantiomers induce hypothermia, (R)-DPAT being antagonised by (S)-UH-301, whereas (S)-DPAT is antagonised by raclopride. The accumulation of 5-hydroxytryptophan and DOPA (3,4-dihydroxyphenylalanine) after decarboxylase inhibition that reflects presynaptic actions on 5-HT (5-hydroxytryptamine, serotonin) and dopamine neurons, respectively, are inhibited by both enantiomers of DPAT. (R)-DPAT is more potent than (S)-DPAT as an inhibitor of 5-hydroxytryptophan accumulation whereas (S)-DPAT is more potent than (R)-DPAT as an inhibitor of DOPA accumulation. Thus, in functional tests of postsynaptic actions (R)-DPAT behaves as a 5-HT1A receptor agonist and (S)-DPAT as a dopamine D2 receptor agonist. Presynaptically, (R)-DPAT shows selectivity for 5-HT1A receptors and (S)-DPAT for dopamine D2 receptors. Receptor binding studies, utilizing [3H]8-hydroxy-2-(di-n-propylamino)tetralin and [3H]quinpirole as radioligands for 5-HT1A and dopamine D2 receptors, respectively, showed (R)-DPAT to have a 3-fold higher affinity than (S)-DPAT for 5-HT1A receptors, whereas (S)-DPAT had a 6-fold higher affinity than (R)-DPAT for dopamine D2 receptors. Thus, the results from receptor binding studies support the conclusion that (R)- and (S)-DPAT are agonists showing selectivity for 5-HT1A and dopamine D2 receptors, respectively. Taken together, these findings may explain previous controversies with regard to the pharmacology of racemic DPAT and re-emphasise the necessity to study pure enantiomers of chiral compounds.

Role of presynaptic and postsynaptic 5-HT1A receptors in spatial learning of rats with impaired hippocampal cholinergic transmission

Racemic 2-(di-n-propylamino)tetralin ((R,S)-DPAT), which lacks phenolic or other aromatic substituents, induces both dopaminergic (sniffing, licking and gnawing) and serotoninergic (forepaw treading and flat body posture) behavioural responses. The present study shows thats.c. administration of (R)-DPAT induces typical 5-HT1A receptor agonist behaviours. These effects are blocked by the 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin ((S)-UH-301). Administration of (S)-DPAT induces dopaminergic behaviours, which are fully antagonised by raclopride, a dopamine D2 receptor antagonist. Both enantiomers induce hypothermia, (R)-DPAT being antagonised by (S)-UH-301, whereas (S)-DPAT is antagonised by raclopride. The accumulation of 5-hydroxytryptophan and DOPA (3,4-dihydroxyphenylalanine) after decarboxylase inhibition that reflects presynaptic actions on 5-HT (5-hydroxytryptamine, serotonin) and dopamine neurons, respectively, are inhibited by both enantiomers of DPAT. (R)-DPAT is more potent than (S)-DPAT as an inhibitor of 5-hydroxytryptophan accumulation whereas (S)-DPAT is more potent than (R)-DPAT as an inhibitor of DOPA accumulation. Thus, in functional tests of postsynaptic actions (R)-DPAT behaves as a 5-HT1A receptor agonist and (S)-DPAT as a dopamine D2 receptor agonist. Presynaptically, (R)-DPAT shows selectivity for 5-HT1A receptors and (S)-DPAT for dopamine D2 receptors. Receptor binding studies, utilizing [3H]8-hydroxy-2-(di-n-propylamino)tetralin and [3H]quinpirole as radioligands for 5-HT1A and dopamine D2 receptors, respectively, showed (R)-DPAT to have a 3-fold higher affinity than (S)-DPAT for 5-HT1A receptors, whereas (S)-DPAT had a 6-fold higher affinity than (R)-DPAT for dopamine D2 receptors. Thus, the results from receptor binding studies support the conclusion that (R)- and (S)-DPAT are agonists showing selectivity for 5-HT1A and dopamine D2 receptors, respectively. Taken together, these findings may explain previous controversies with regard to the pharmacology of racemic DPAT and re-emphasise the necessity to study pure enantiomers of chiral compounds.

Numerical and Monte Carlo simulations of phenolic polymerizations catalyzed by peroxidase

Numerical and Monte Carlo simulations of horseradish peroxidase-catalyzed phenolic polymerizations have been performed. Kinetic constants for the simulations were fit to data from the oxidation and polymerization of bisphenol A. Simulations of peroxidase-catalyzed phenolic polymerization were run as a function of enzyme concentration and radical transfer and radical coupling rate constants. Predictions were performed with respect to conversion vs. time and number average molecular weight and polydispersity vs. conversion. It is shown that the enzymatic polymerization of phenols can be optimized with respect to high molecular weights by employing low enzyme concentrations and phenols with low radical coupling rate constants coupled with relatively high radical transfer rate constants. Such phenols may be identified by using linear free energy relationships that relate radical reactivity to electron donating/withdrawing potential of the phenolic substituent.

Hydrogen Bonding Between Substituted Phenols and CH3COOCH3or CH2CICOOCH3: An FTIR Spectroscopic Study

Abstract The hydrogen bonded complexes between phenol derivatives and methyl acetate and methyl chloroacetate were studied in carbon tetrachloride solution by FTIR spectroscopy. Temperature variation studies were used to evaluate both formation constants and the enthalpies of complex formation. It is shown that the relative values of enthalpies associated with the hydrogen bonding process in the various studied systems depend mainly on the electron releasing ability of the phenol substituents as well as on the polarization state of the carbonyl bond of the ester. In addition, it is also shown that the observed shifts in the carbonyl stretching frequency upon complexation can be correlated with ΔH, thus providing a useful indirect way of measuring the strength of the hydrogen bond.

Synthesis and properties of sym-triazines. 10 Synthesis of 2,4-diamino-sym-triazines containing a sterically hindered phenol substituent

Condensation of N-(4-hydroxy-3,5-di-tert-butylphenyl)biguanide with esters in the presence of catalytic amounts of sodium ethylate gives 2-amino-4-(4-hydroxy-3,5-di-tert-butylanilino)-6-substituted sym-triazines. When the trichloroacetate ester is used the main product is 2-amino-4-(4-hydroxy-3,5-di-tert-butylanilino)-6-oxo-1(5)H-sym-triazine.

Prostaglandin H synthase kinetics. The effect of substituted phenols on cyclooxygenase activity and the substituent effect on phenolic peroxidatic activity.

A series of p- and m-substituted phenols were examined for their effect on the cyclooxygenase activity of prostaglandin H synthase in 0.1 M phosphate buffer at pH 8.0 and 25.0 +/- 0.1 degrees C. A biphasic response was observed. At low concentrations phenols stimulate, but at higher concentrations inhibit, cyclooxygenase activity. Both enhancement and inhibition are increased by phenolic substituents which are electron-donating, quantified by Hammett sigma constants, and hydrophobic, quantified by Hantsch tau constants. The same series of substituted phenols was also reacted with compound II of prostaglandin H synthase at 4.0 +/- 0.5 degrees C. The compound II data fit the Hammett rho sigma equation; no hydrophobicity factors are required. Phenols inhibit cyclooxygenase activity by interfering with the binding of arachidonic acid to compound I and by competing directly with arachidonic acid as reducing substrates for compound I. Phenols stimulate cyclooxygenase activity by acting as reducing substrates for compound II, thereby accelerating the peroxidatic cycle. Phenols also protect the enzyme from self-catalyzed inactivation, most likely by removing the free radical of prostaglandin G2 by reducing it to prostaglandin G2. Kinetic parameters Km and kcat for cyclooxygenase activity were determined in the presence of phenols. Identical values of Km (15.3 +/- 0.5 mM) and kcat (89 +/- 2 s-1) were obtained regardless of which phenol was employed. Therefore these represent the true Km and kcat values for cyclooxygenase activity.

Synthesis, characterization and electropolymerization of ferrocene monomers with aniline and phenol substituents

The synthesis and electrochemical properties of the ferrocene compounds (C 5H 5)Fe(C 5H 4 CH 2NHR n), where R nC 6H 5 ( 1), C 6H 4-3-NH 2 ( 2), C 6H 4-3-OH ( 3) and (CH 2) 2NHC 6H 5 ( 4), are described. All compounds polymerize upon electrochemical oxidation of the phenyl portion of the complex in a CH 3CN solution containing BU 4NClO 4 as supporting electrolyte. The phenol-substituted complex shows unique polymerization behavior: adding NEt 3 to the electrolysis solution greatly enhances the rate of film deposition. Electrochemical characterization of the films shows well-defined couples for the ferrocene but no indication that the polymer backbones are electroactive. Spectroelectrochemical measurements show changes in the visible region of the spectrum characteristic for formation of the ferricinium cation, 0λ max = 620 nm, upon oxidation. In the case of the polymer from 2 a moderately intense absorption at 480 nm is also recorded, which suggests that the polymer backbone may be electrochemically active.

Hydrogen bonding involving α,β-unsaturated carboxylic esters and substituted phenols: an infrared spectroscopic study

The hydrogen-bonded complexes between phenol derivatives and methyl acrylate, methyl trans- crotonate and methyl trans-cinnamate were studied in carbon tetrachloride solution by infrared spectroscopy. Temperature variation studies were used to evaluate both formation constants and the enthalpies of complex formation. It is shown that the relative values of enthalpies associated with the hydrogen bonding process in the various systems studied depend on the substituent constants of both the ester and phenol substituents. In addition, it is also shown that the observed shifts in the carbonyl stretching frequency upon complexation can be correlated with Δ H, thus providing a useful indirect way of measuring the strength of the hydrogen bond.

Über Pyridinium‐N‐phenolat‐Betaine und ihre Verwendung zur Charakterisierung der Polarität von Lösungsmitteln, XVI. Bestimmung der empirischen Lösungsmittelpolaritäts‐Parameter ET(30) und AN für 55 substituierte Phenole

Pyridinium N‐Phenoxide Betaines and Their Application for the Characterization of Solvent Polarities, XVI1). – Determination of the Empirical Parameters of Solvent Polarity ET(30) and AN for 55 Substituted PhenolsBy means of the negatively solvatochromic dyes 1 and 2, the empirical solvent polarity parameters ET(30) and AN (Acceptor Number) are determined for solutions of 55 substituted phenols in 1,2‐dichloroethane as inert solvent (Table 1). The ET(30) values and Acceptor Numbers are compared with each other and with corresponding literature values, determined in neat substituted phenols (Table 2). The influence of the phenolic substituents on both solvent parameters is discussed with respect to their electronic and steric effects as well as to the self‐association of phenols in solution. Polyhydroxybenzenes such as resorcinol and pyrogallol exhibit both high solvent polarity and acceptor properties, whereas substituents in positions 2 and 6 of phenols decrease their polarity and acceptor strength.

Synthèse et Identification des 4‐OXO‐1,4‐Dihydropyrimidines en vue des Applications Pharmacologiques

AbstractThere is described synthesis of 2,6‐dimethyl‐5‐phenyl‐4‐oxo‐1,4‐dihydropyrimidines and their perchlorates with phenolic or acetoxyphenolic substituent in the 1st position.All these compounds possess activities as tranquilizers and antidepressive and neuroleptic geants.

Linkage of phenolic acids to cell-wall polysaccharides of bamboo shoot

Hydrolysis of bamboo shoot cell walls with Driselase (a fungal enzyme preparation) gave xyloglucan and arabinoxylan oligosaccharides containing ferulic and p-coumaric acids, respectively. The structures of two oligosaccharides containing phenolic acids are here determined to be O-(4- O- trans-feruloyl-α- d-xylopyranosyl)-(1→6)- d-glucopyranose and O-[5- O-( trans-p-coumaroyl)-α- l-arabinofuranosyl]-(1→3)- O-β- d-xylopyranosyl-(1→4)- d-xylopyranose, on the basis of n.m.r. spectroscopy, methylation analysis, and f.a.b.-m.s. The possible role of phenolic acid substituents in cell-wall architecture is discussed.

Facile aerial oxidation of a porphyrin. Part 4. Unsymmetrical meso-tetra aryl porphyrins with 3,5-di-t-butyl-4-hydroxyphenyl and 4-hydroxyphenyl substituents

A series of porphyrins (2a)–(5a), unsymmetrically substituted in their meso-positions with 3,5-di-tbutyl-4-hydroxyphenyl(DtB4HP) and 4-hydroxyphenyl (4HP) groups, has been synthesised and characterised. The two di-DtB4HP di-4HP isomeric porphyrins, (3a) and (4a)(called ‘cis’ and ‘trans’, respectively), in particular are distinguishable by 1H n.m.r. spectroscopy. In basified dichloromethane (DCM) solutions, the porphyrins undergo drastic colour and u.v.–visible changes which, in 1 mol dm–3 methanolic potassium hydroxide, is indicative of irreversible aerial oxidation that is slower and less extensive than for the symmetrically tetrakis-DtB4H P substituted porphyrin (1). Cyclic voltammetry supports this, indicating that in basified DCM solutions, one-electron oxidation of porphyrins (2a)–(5a) becomes increasingly more difficult than for (1), as the DtB4HP groups are replaced by 4HP. An explanation of the relative redox activity of these porphyrins compared with (1), is offered in terms of the different electron-releasing properties of the two types of phenolic substituent.

Synthesis of a novel amphiphilic porphyrin carrying water-soluble polyether side chains of controlled chain length. Formation of a cofacial molecular assembly in aqueous media

A novel amphiphilic porphyrin carrying poly(oxyethylene) side chains of controlled chain length was obtained by polymerization of epoxyethane initiated by an aluminium porphyrin [(5,10,15,20-tetraphenylporphyrinato)-aluminium chloride] in the presence of a porphyrin with phenolic substituents [5,10,15,20-tetrakis(4′-hydroxyphenyl)porphyrin], and was found to form cofacial aggregates spontaneously in aqueous media.

Cellulose bound chlorophenols II: Preparation and characterization of phenyloxycarbonylpentanoyl celluloses dependence of substitution on chlorophenol structure

AbstractNew types of polymeric phenols (including the fungicide PCP) are prepared by linking phenol and different chlorophenols to cellulose via ester bonds using adipic acid as bridging molecule. Monophenylesteracid chlorides of adipic acid are prepared as intermediates. The yield of esterification of cellulose with these compounds depends in a complicated manner on size and chlorosubstitution pattern of the phenolic substituents. It is tentatively assumed that hydrogen bonding between chlorophenol and cellulose is an important factor. The polymeric PCP ester showed fungicidal activity in an agar plate test.

ChemInform Abstract: New Derivatives of Imidazoline‐3‐oxide and Thiazoline with 2,6‐Dialkylphenol Fragments.

AbstractDie aus 2,6‐Dialkylphenolen (I) durch Umsetzung mit Methylvinylketon (II) hergestellten 4‐Arylbutanone (III) cyclisieren mit Amino‐oximen (IV) zu Imidazolin‐oxiden (V).

13C NMR phenol substituent effect in acyclic alkanes

AbstractLiterature and unpublished data on phenols have been analysed to give phenol substituent effects for acyclic alkanes. The results are analysed in terms of the α‐branching of the alkyl phenol side chain.

New derivatives of imidazoline 3-oxide and thiazoline with 2,6-dialkylphenol fragments

(2,6-Dialkyl-4-hydroxyphenyl)-2-butanones and aminooxides were used to obtain the corresponding 3-imidazoline 3-oxides. Nitrosylation of 3-imidazoline 3-oxide containing a phenol substituent proceeds either at the imidazoline ring amino group or at the phenol fragment. Intermolecular cyclization of (2,6-di-tert-butyl-4-hydroxyphenyl)-2-butanone with sulfur and ammonia gave a 3-thiazoline as two diastereomers.