Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Benzaldehydes”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 577 records · Page 32Linked to original sources
PubMed2005

Ozonation of carbamazepine in drinking water: identification and kinetic study of major oxidation products.

Kinetics and product formation of the anti-epileptic drug carbamazepine (CBZ) were investigated in lab-scale experiments during reactions with ozone and OH radicals. Ozone reacts rapidly with the double bond in CBZ, yielding several ozonation products containing quinazoline-based functional groups. The structures for three new oxidation products were elucidated using a combination of mass spectrometric and NMR techniques. The three products were determined to be 1-(2-benzaldehyde)-4-hydro-(1H,3H)-quinazoline-2-one (BQM), 1-(2-benzaldehyde)-(1H,3H)-quinazoline-2,4-dione (BQD), and 1-(2-benzoic acid)-(1H,3H)-quinazoline-2,4-dione (BaQD). Additional kinetic studies of the ozonation products showed very slow subsequent oxidation kinetics with ozone (second-order rate constants, kO3 = approximately 7 M(-1)s(-1) and approximately 1 M(-1)s(-1) at pH = 6 for BQM and BQD, respectively). Rate constants for reactions with OH radicals, kOH, were determined as approximately 7 x 10(9) M(-1)s(-1) for BQM and approximately 5 x 10(9)M(-1)s(-1) for BQD. Thus, mainly reactions with OH radicals lead to their further oxidation. A kinetic model including ozone and OH radical reactions allows a prediction of the time-dependent product distribution during ozonation of natural waters. In Rhine River water, CBZ spiked at 500 ng/L was completely oxidized by ozone with applied doses > or =0.3 mg/L. To confirm that the two major ozonation products BQM and BQD are produced as a result of the ozonation of a CBZ-containing natural water, Lake Zurich water samples were spiked with CBZ (1 microM, 236 microg/L). The oxidation products were identified via LC-UV. Concentrations of 0.48 and 0.15 microM for BQM and BQD, respectively, were measured for an ozone dose of 1.9 mg/L. BQM and BQD were also identified in ozonated water from a German waterworks containing CBZ in its raw water with 0.07-0.20 microg/L. Currently, there are no data available on the biological effects of the formed oxidation products.

Carbamazepine↗
PubMed2002

Oxygen transfer reactions. 4. Reaction of high valent oxoruthenium compounds with sulfides.

The oxidation of methoxy substituted benzyl phenyl sulfides can be used to distinguish between oxidants that react by single electron transfer (followed by oxygen rebound) and those which react by direct oxygen atom transfer in a two-electron process. Transfer of a single electron results in the formation of an intermediate radical cation, which can undergo C-S bond cleavage and deprotonation reactions leading to the formation of methoxy substituted benzyl derivatives, methoxy substituted benzaldehydes, and diphenyl disulfide. The oxidation of 4-methoxybenzyl phenyl sulfide and 3,4,5-trimethoxybenzyl phenyl sulfide by oxidants known to participate in single electron transfers (Ce(4+), Mn(3+), and Cr(6+)) results in the formation of the corresponding benzaldehydes, benzyl alcohols, benzyl acetates, and benzyl nitrates in variable yields. However, the only products obtained from the oxidation of the same compounds with RuO(4), RuO(4-), and RuO(4)(2-) are sulfoxides and sulfones. Therefore, it is concluded that the oxidation of sulfides by oxoruthenium compounds likely proceeds by a concerted mechanism.

Journal Article↗
PubMed2003

Ruthenium complexes with chiral tetradentate imino-sulfoxide ligands.

Treatment of 2-(methylsulfinyl)benzaldehyde (1) with ethylenediamine or (1R,2R)-(-)-1,2-diaminocyclohexane afforded N,N'-bis[2-(methylsulfinyl)benzylidene]ethylenediamine (L(1)) or (1R,2R)-N,N'-bis[2-(methylsulfinyl)benzylidene]-1,2-cyclohexanedia mine (L(2)), respectively. Lithiation of 2-bromobenzaldehyde diethylacetal with n-BuLi/TMEDA followed by reaction with (1R,2S,5R)-(-)-menthyl-(S)-p-toluenesulfinate afforded 2-(S)-(p-tolylsulfinyl)benzaldehyde diethyl acetal (2). Deprotection of 2 with pyridinium tosylate followed by condensation with ethylenediamine, (1R,2R)-(-)-diaminocyclohexane, or (S,S)-(+)-diaminocyclohexane afforded N,N'-bis[2-(S)-(p-tolylsulfinyl)benzylidene]ethylenediamine (L(3)), (1R,2R)-N,N'-bis[2-(S)-(p-tolylsulfinyl)benzylidene]-1,2-cyclohexanediamine ((R,R)-L(4)), or (S,S)-N,N'-bis[2-(S)-(p-tolylsulfinyl)benzylidene]-1,2-cyclohexanediamine ((S,S)-L(4)), respectively. Treatment of [Ru(PPh(3))(3)Cl(2)] with L afforded trans-[Ru(L)Cl(2)] [L = L(1) (3), L(2) (4), L(3) (5), (R,R)-L(4) ((R,R)-6), (S,S)-L(4) ((S,S)-6)]. The X-ray structures of (S(S),R(S))-4, (R,R)-6, and (S,S)-6 have been determined. The average Ru-N, Ru-S, and Ru-Cl distances in (S(S),R(S))-4 are 2.063, 2.2301, and 2.4039 A, respectively. The corresponding distances in (R,R)-6 are 2.071, 2.256, and 2.411 A, and those in (S,S)-6, 2.058, 2.2275, and 2.3831 A. Compound 3 exhibited a reversible Ru(III/II) couple at 0.56 V vs Cp(2)Fe(+/0) in CH(2)Cl(2). Treatment of 3 with AgNO(3) in water afforded the aqua compound trans-[Ru(L(1))Cl(H(2)O)][PF(6)] (7), which has been characterized by X-ray crystallography. The Ru-Cl, Ru-O, average Ru-N, and average Ru-S distances in 7 are 2.3733(6), 2.1469(16), 2.071, and 2.2442 A, respectively. Treatment of 3 with AgNO(3) followed by reaction with PPh(3) afforded [Ru(L(1))(PPh(3))(2)][PF(6)](2) (8). Treatment of [Os(PPh(3))(3)Cl(2)] with L(1) resulted in deoxygenation of one sulfoxide group of L(1) and formation of [Os(L(5))Cl(2)(PPh(3))] (9) (L(5) = N-[2-(methylsulfinyl)benzylidene]-N'-[2-(methylthio)benzylididene]ethylenediamine), which has been characterized by X-ray crystallography. The average Os-S(O), Os-N(trans to P), Os-N(trans to S), Os-P, and Os-Cl distances are 2.1931, 2.085, 2.175, 2.3641, and 2.4266 A, respectively.

Journal Article↗
PubMed2004

Photochemical organic oxidations and dechlorinations with a mu-oxo bridged heme/non-heme diiron complex.

Steady state and laser flash photolysis studies of the heme/non-heme mu-oxo diiron complex [((6)L)Fe(III)-O-Fe(III)-Cl](+) (1) have been undertaken. The anaerobic photolysis of benzene solutions of 1 did not result in the buildup of any photoproduct. However, the addition of excess triphenylphosphine resulted in the quantitative photoreduction of 1 to [((6)L)Fe(II)...Fe(II)-Cl](+) (2), with concomitant production by oxo-transfer of 1 equiv of triphenylphosphine oxide. Under aerobic conditions and excess triphenylphosphine, the reaction produces multiple turnovers (approximately 28) before the diiron complex is degraded. The anaerobic photolysis of tetrahydrofuran (THF) or toluene solutions of 1 likewise results in the buildup of 2. The oxidation products from these reactions included gamma-butyrolactone (approximately 15%) for the reaction in THF and benzaldehyde (approximately 23%) from the reaction in toluene. In either case, the O-atom which is incorporated into the carbonyl product is derived from dioxygen present under workup or under aerobic photolysis conditions. Transient absorption measurements of low-temperature THF solutions of 1 revealed the presence of an (P)Fe(II)-like [P = tetraaryl porphyrinate dianion] species suggesting that the reactive species is a formal (heme)Fe(II)/Fe(IV)=O(non-heme) pair. The non-heme Fe(IV)=O is thus most likely responsible for C-H bond cleavage and subsequent radical chemistry. The photolysis of 1 in chlorobenzene or 1,2-dichlorobenzene resulted in C-Cl cleavage reactions and the formation of [[((6)L)Fe(III)-Cl...Fe(III)-Cl](2)O](2+) (3), with chloride ligands that are derived from solvent dehalogenation chemistry. The resulting organic products are biphenyl trichlorides or biphenyl monochlorides, derived from dichlorobenzene and chlorobenzene, respectively. Similarly, product 3 is obtained by the photolysis of benzene-benzyl chloride solutions of 1; the organic product is benzaldehyde (approximately 70%). A brief discussion of the dehalogenation chemistry, along with relevant environmental perspectives, is included.

Electron Spin Resonance Spectroscopy↗
PubMed2006

Alpha-monodeuterated benzyl alcohols and phosphobetaines from reactions of aromatic aldehydes with a water/D2O-soluble phosphine.

With the aim of learning more about the bleaching action of pulps by (hydroxymethyl)phosphines, we reacted several benzaldehydes, containing MeO, Me, OH, or halogen substituents, with tris(3-hydroxypropyl)phosphine, [HO(CH2)3]3P, in aqueous solution at 90 degrees C under argon. Effective reduction of the aldehydes to the corresponding benzyl alcohols with concomitant oxidation of the phosphine to the phosphine oxide takes place, the reaction proceeding via an initially formed phosphonium species. When the reactions are carried out in D2O, the benzyl alcohol product from 3,4-dimethoxybenzaldehyde contains one deuterium atom at the benzyl-carbon atom, consistent with the last step of the mechanism involving a carbanion intermediate. With syringaldehyde (3,5-dimethoxy-4-hydroxy-benzaldehyde), the reduction product (syringyl alcohol) is more reactive toward the phosphine than is the starting aldehyde, and a zwitterionic, phosphobetaine product is formed. In D2O, the zwitterion benzyl protons and protons of the hydroxypropyl-CH2 adjacent to the P atom undergo H/D exchange via presumed phosphorus ylide intermediates. Under the same aqueous reaction conditions, tris(3-hydroxypropyl)phosphine, [HO(CH2)3]3P (THPP), does not undergo redox reactions with aliphatic aldehydes but simply promotes a base-catalyzed self-condensation (aldol) reaction. THPP reduction of an aromatic ketone is sluggish, presumably because the carbonyl C-atom is less electrophilic than that present in an aromatic aldehyde.

Journal Article↗
PubMed1999

Oxidation of Benzyl Alcohol by a Dioxo Complex of Ruthenium(VI).

The kinetics and mechanism of reduction of trans-[Ru(VI)(tpy)(O)(2)(L)](2+) (L is H(2)O or CH(3)CN; tpy is 2,2':6',2' '-terpyridine) by benzyl alcohol have been studied in water and acetonitrile. The reactions are first order in alcohol and complex in both solvents and give benzaldehyde as the sole oxidation product. In acetonitrile, sequential Ru(VI) --> Ru(IV) and Ru(IV) --> Ru(II)(') steps occur. As shown by FTIR and UV-visible measurements, Ru(II)(') solvolyzes to give [Ru(II)(tpy)(CH(3)CN)(3)](2+) and benzaldehyde. With (18)O-labeled Ru(VI), approximately 50% of the label ends up in the aldehyde product for both the Ru(VI) --> Ru(IV) and Ru(IV) --> Ru(II) steps as shown by FTIR. In water, Ru(VI) --> Ru(IV) reduction is followed by rapid dimerization by &mgr;-oxo formation. Kinetic parameters for the individual redox steps in 0.1 M HClO(4) at 25 degrees C are k(VI)(-->)(IV) = 13.3 +/- 0.8 M(-)(1) s(-)(1) (DeltaH() = 11.4 +/- 0.2 kcal/mol, DeltaS() = -15.0 +/- 1 eu, k(H)/k(D) = 10.4 for alpha,alpha-d(2) benzyl alcohol). In CH(3)CN at 25 degrees C, k(VI)(-->)(IV) = 67 +/- 3 M(-)(1) s(-)(1) (DeltaH() = 7.5 +/- 0.3 kcal/mol, DeltaS() = -33 +/- 2 eu, k(H)/k(D) = 12.1) and k(IV)(-->)(II)(') = 2.4 +/- 0.1 (DeltaH() = 5.1 +/- 0.3 kcal/mol, DeltaS() = -47 +/- 2 eu, k(H)/k(D) = 61.5). On the basis of the (18)O labeling results in CH(3)CN, the O atom of the oxo group transfers to benzyl alcohol in both steps. Mechanisms are proposed involving prior coordination of the alcohol followed by O insertion into a benzylic C-H bond.

Journal Article↗
PubMed1999

Alcohol and Aldehyde Adducts of Zinc Thiolates: Structural Modeling of Alcoholdehydrogenase.

Bis(pentafluorothiophenolato)zinc (1) and bis(2,4,6-triisopropylthiophenolato)zinc (2) can be combined with nitrogen-containing derivatives of benzyl alcohol and benzaldehyde to form (N,O-chelate) zinc thiolates. 2-Pyridylmethanol as well as 2-quinolylmethanol (HetMeOH) yield [(HetMeO)Zn(SR)](4) (3, 4) having a cyclo-Zn(4)(&mgr;-O)(4) backbone and only terminal SR. Likewise, thiolate 1 and 2-(dimethylamino)benzyl alcohol form zwitterionic [(dimethylammoniobenzylato)Zn(SR)(2)](2) (5) with bridging alkoxide and terminal thiolate. In contrast, 6-picolylmethanol (PicMeOH) and thiolate 1 result in [(PicMeOH)Zn(SC(6)F(5))(2)] (6) containing zinc in a tetrahedral ZnNS(2)O, environment. Simple aromatic aldehydes form polymeric complexes [(RCHO)Zn(SC(6)F(5))(2)] (7: R = p-tolyl, 8: R = mesityl) with a [Zn-S](infinity) backbone. Chelating aldehydes (CA) yield mononuclear complexes with tetrahedral ZnNS(2)O coordination [(CA)Zn(SC(6)F(5))(2)] (9, CA = pyridine-2-carbaldehyde; 10, CA = 6-methylpyridine-2-carbaldehyde; 11, CA = 6-methoxypyridine-2-carbaldehyde; 12, CA = quinoline-2-carbaldehyde; 13, CA = 2-(dimethylamino)benzaldehyde). In contrast, N-methylimidazole-2-carbaldehyde (ImA) is coordinated twice in tetrahedral [(ImA)(2)Zn(SC(6)F(5))(2)] (14) lacking any Zn-O interactions. Pyridine-2,6-dicarbaldehyde (PDA) forms trigonal bipyramidal [(PDA)Zn(SC(6)F(5))(2)] (15) with ZnNO(2)S(2) ligation. The structures of 3, 4, 6, 8, 10, 11, 13, and 14 were determined crystallographically, and the structures of 5 and 15 were deduced from those of the corresponding ZnBr(2) complexes. The ZnNS(2)O coordination pattern observed for the enzyme has been reproduced to a very good approximation. In complexes 6 and 10, which are almost superimposable, it is realized for both the corresponding alcohol and aldehyde.

Journal Article↗
PubMed2002

Substituent effects in carbon-nitrogen cleavage of thiamin derivatives. Fragmentation pathways and enzymic avoidance of cofactor destruction.

The combination of thiamin and benzaldehyde can produce benzoin but also destroys thiamin. The destruction comes from fragmentation of the conjugate of thiamin and benzaldehyde undergoing a process that produces a phenyl thiazole ketone and pyrimidine. The key step in this process is cleavage of the C-N bond between the heterocycles, which occurs by an unknown mechanism. Enzymes that utilize similar intermediates do not fragment the cofactor although fragmentation is inherent to the structure. To analyze the nature of the C-N cleavage step, the rates of fragmentation of a series of phenyl-substituted N1'-methyl-2-(1-hydroxybenzyl)thiamin derivatives were determined under two sets of conditions: (1) where proton transfer in the step prior to C-N bond breaking is rate-determining and (2) where C-N bond breaking is rate-determining. The resulting rho values are 1.6 and 1.8, respectively, leading to the conclusion that C-N cleavage is insensitive to substituent effects. On the basis of these results, we conclude that cleavage occurs by a facile process that resembles the outcome of a [1,5] sigmatropic rearrangement. An enzyme may avoid the fragmentation by holding the intermediate in a conformation that prevents such a process, allowing the normal catalytic process to proceed.

Coumarins↗
PubMed2002

Reactivity of intermediates in benzoylformate decarboxylase: avoiding the path to destruction.

Benzoylformate decarboxylase forms a covalent intermediate from thiamin diphosphate (TDP) and benzoylformate, alpha-mandelylTDP. This loses carbon dioxide to form a carbanion (enamine). Protonation of the carbanion and elimination of benzaldehyde regenerate enzyme-bound TDP. We synthesized alpha-mandelylthiamin and found that the rate of the loss of carbon dioxide is one-millionth that of the enzymic reaction. Thus, the enzyme provides an environment that facilitates the unimolecular decarboxylation process. However, the resulting nonenzymic carbanion reacts very rapidly to give products that lead to the irreversible destruction of the cofactor. This contrasts with the normal process on the enzyme. Brønsted acids on the enzyme may divert the reaction to the benzaldehyde precursor, or the enzyme may block access to the pathway that leads to destruction of the cofactor.

Carboxy-Lyases↗
PubMed2003

Substantial (2)h-magnetic isotope effects on the diastereoselectivity of triplet photocycloaddition reactions.

Magnetic isotope effects (MIE) on the diastereoselectivity of the triplet [2+2]-photocycloaddition of benzaldehyde with 2,3-dihydrofuran are described for four substrate combinations. The MIE results from H/D exchange at the reactive carbons of either the aldehyde or the alkene, respectively, but also from deuteration of the aromatic positions of benzaldehyde. Weaker isotope effects on the diastereoselectivity were detected for the reaction of alpha-deuterated propionaldehyde.

Journal Article↗
PubMed2004

Mechanism of stereo- and regioselectivity in the Paternò-Büchi reaction of furan derivatives with aromatic carbonyl compounds: importance of the conformational distribution in the intermediary triplet 1,4-diradicals.

Temperature and substituent effects on the stereo- and regioselectivity have been investigated in the photochemical [2 + 2] cycloaddition reaction, the so-called Paternò-Büchi (PB) reaction, of unsymmetrically substituted furans 2a,b (2-methyl- and 3-methylfuran) with aromatic carbonyl compounds 1a,b (benzaldehyde and benzophenone). The regio-random but stereoselective (exo/endo > 97/3) formation of lower substituted oxetane 3a and higher substituted oxetane 4a is found in the reaction with benzaldehyde (1a). The exclusive stereoselectivity is not dependent on the position of methyl substituent on the furan ring and the reaction temperature. The double-bond selection (3a versus 4a) is slightly dependent on the reaction temperature (3a/4a = 55/45 to 40/60). The Eyring plots of the regioselectivity are linear. Contrastively, in the reaction with benzophenone (1b), the double-bond selection (3b versus 4b) largely depends on the reaction temperature. The Eyring plots are not linear, but the inflection points are observed. The transient absorption spectroscopic analyses (picosecond time scale) clarify the intervention of triplet 2-oxabutane-1,4-diyls in the photochemical processes. Computational studies reveal the equilibrium structures of the triplet diradicals, energy barriers between the conformers, and the equilibrium constants. A rational mechanism is herein proposed by the support of both experimental and computational investigations to account for not only the exclusive formation of the exo-configured oxetanes 3a and 4a but also the nonlinear Eyring plots observed in the reaction with 1b.

Journal Article↗
PubMed2002

Tyrosinase inhibitors of Pulsatilla cernua root-derived materials.

The inhibition of mushroom tyrosinase by Pulsatilla cernua root-derived materials was evaluated. The bioactive components of Pulsatilla cernua root were characterized by spectroscopic analyses as 3,4-dihydroxycinnamic acid and 4-hydroxy-3-methoxycinnamic acid, which exhibited potent antityrosinase activity. The ID50 values of 3,4-dihydroxycinnamic acid and 4-hydroxy-3-methoxycinnamic acid were 0.97 and 0.33 mM, respectively. The compounds isolated from Pulsatilla cernua roots exhibited noncompetitive inhibition against oxidation of L-DOPA by mushroom tyrosinase. This activity was compared with that of three cinnamic acid derivatives and four well-known tyrosinase inhibitors. The ID50 of 4-hydroxy-3-methoxycinnamic acid exhibited superior activity relative to anisaldehyde, anisic acid, benzoic acid, benzaldehyde, cinnamic acid, and cinnamaldehyde; but antityrosinase inhibitors and cinnamic acid derivatives, except for cinnamyl alcohol, were slightly more effective than 3,4-dihydroxycinnamic acid. In the case of benzaldehyde and cinnamaldehyde, the aldehyde group is, apparently, a key group in eliciting potent inhibitory activity, whereas anisaldehyde is more effective than anisic acid. Methoxy substitutions, such as 2-methoxycinnamic acid, 3-methoxycinnamic acid, and 4-methoxycinnamic acid, enhanced inhibition of tyrosinase activity. As a naturally occurring tyrosinase inhibitor, 3,4-dihydroxycinnamic acid and 4-hydroxy-3-methoxycinnamic acid may be useful as new agents to inhibit the oxidation of L-3,4-dihydroxyphenylalanine (L-DOPA) by mushroom tyrosinase.

Agaricales↗
PubMed2002

In vitro efficacy of plant volatiles for inhibiting the growth of fruit and vegetable decay microorganisms.

The effects of acetaldehyde, benzaldehyde, cinnamaldehyde, ethanol, benzyl alcohol, nerolidol, 2-nonanone, beta-ionone, and ethyl formate vapors on the growth of Rhizopus stolonifer, Penicillium digitatum, Colletotrichum musae, Erwinia carotovora, and Pseudomonas aeruginosa on agar medium were evaluated. The aldehydes were found to be the strongest growth inhibitors and the most lethal to the fungal spores and mycelia and bacterial cells. The average minimum inhibitory concentrations (MICs) of aldehydes that were germicidal to decay microorganisms were 0.28, 0.49, and 0.88 mmol per Petri dish, for cinnamaldehyde, benzaldehyde, and acetaldehyde, respectively. Ethanol also inhibited growth completely, but the MIC, which was 14.6 mmol per Petri dish, was significantly higher than those of the aldehydes. Ethanol can be considered germistatic because the alcohol does not inhibit germination of spores completely; it completely controlled only mycelial growth. The ketones tended to be effective only on P. digitatum and C. musae, whereas ethyl formate was not effective except on P. digitatum. The concentration of a volatile compound in the headspace of the Petri dish and its diffusion into the medium largely determined its efficacy against decay microorganisms.

Agar↗
PubMed2006

Amine degradation by 4,5-epoxy-2-decenal in model systems.

The reactions of 4,5-epoxy-2-decenal with octylamine, benzylamine, and 2-phenylglycine methyl ester were studied to investigate if amines may suffer a Strecker type degradation by epoxyalkenals analogously to amino acids. In addition to other reactions, the studied amines were converted into their corresponding Strecker aldehydes (octanal, benzaldehyde, and methyl 2-oxo-2-phenylacetate, respectively) to an extent that depended on the pH, the temperature, the amount of epoxyalkenal, and the amine involved. Each amine exhibited an optimum pH for the reaction, but the corresponding Strecker aldehydes were produced to a significant extent within a broad pH range. In addition, the temperature mostly influenced the reaction rate, which was increased between 6.5 and 9.5 times when the reaction was carried out at 60 degrees C than when it took place at 37 degrees C. Furthermore, Strecker aldehyde formation was linearly correlated with the amount of the epoxyalkenal present in the reaction mixture. Nevertheless, the reaction yield mostly depended on the amine involved. Thus, octylamine only produced trace amounts of octanal, benzylamine was converted into benzaldehyde with a yield of 4.3%, and 2-phenylglycine methyl ester was converted into methyl 2-oxo-2-phenylacetate with a reaction yield of 49%. All of these results suggest that suitable amines can be degraded by epoxyalkenals to their corresponding Strecker aldehydes to a significant extent.

Aldehydes↗
PubMed1993

Syntheses of 2,5- and 2,6-difluoronorepinephrine, 2,5-difluoroepinephrine, and 2,6-difluorophenylephrine: effect of disubstitution with fluorine on adrenergic activity.

Synthetic routes to difluorinated analogs of the adrenergic agonists, norepinephrine (NE), epinephrine (E), and phenylephrine (PE) have been developed. The syntheses were based on elaboration of the ethanolamine side chains from the appropriately polyfunctionalized benzaldehydes. The benzaldehydes were prepared from precursor difluorinated benzenes by sequential regioselective lithiations and reaction with electrophiles to introduce hydroxyl and carboxaldehyde functionalities. Binding and functional assay data demonstrate that the 2,6-difluorinated analogs are relatively inactive at both alpha- and beta-adrenergic receptors. These results are consistent with earlier observations that 2-fluoro substitution of adrenergic agonists decreases alpha-adrenergic activity whereas 6-fluoro substitution decreases beta-adrenergic activity.

Animals↗
PubMed1982

Catechol O-methyltransferase. 10. 5-Substituted 3-hydroxy-4-methoxybenzoic acids (isovanillic acids) and 5-substituted 3-hydroxy-4-methoxybenzaldehydes (isovanillins) as potential inhibitors.

A series of 5-substituted 3-hydroxy-4-methoxybenzoic acids (isovanillic acids) and -benzaldehydes (isovanillins) have been synthesized and evaluated as inhibitors of rat liver catechol O-methyltransferase. The compounds exhibited either noncompetitive or competitive patterns of inhibition when 3,4-dihydroxybenzoic acid was the variable substrate. The benzaldehydes were significantly more potent inhibitors than the corresponding benzoic acids, and electron-withdrawing substituents in the 5 position greatly enhanced their inhibitory activity.

Animals↗
PubMed2002

Inhibition of MIF bioactivity by rational design of pharmacological inhibitors of MIF tautomerase activity.

The pro-inflammatory mediator macrophage migration inhibitory factor (MIF) is produced by immune and endocrine cells and inhibits the antiinflammatory activities of glucocorticoids. MIF also catalyzes the tautomerization of the non-naturally occurring D-isomer of dopachrome, phenylpyruvate, and certain catecholamines, suggesting that MIF might exert its biological effects via enzymatic action on a substrate. However, no physiologically relevant substrate for MIF has been identified. Site-directed mutagenesis studies have not consistently supported a requirement for an intact, functional catalytic site as a prerequisite for MIF bioactivity. We hypothesized that the catalytically active site, but not the enzymatic activity per se, nevertheless plays a critical role in MIF pro-inflammatory activity. Accordingly, we designed small druglike molecules that bind at the catalytically active tautomerase site of MIF and tested the complex for MIF bioactivity. We describe herein the rational design and synthesis of a class of imine conjugates produced by coupling amino acids to a range of benzaldehyde derivatives that inhibit MIF tautomerase and biological activities. We found that aromatic amino acid Schiff bases were better inhibitors of MIF enzymatic and bioactivities compared to the aliphatic ones. For instance, the IC(50) inhibition of MIF tautomerase activity by aromatic amino acid Schiff base methyl esters was achieved at a concentration between 1.65 and 50 microM, suggesting a critical role for the additional binding of the aromatic residues within the vicinity of the active site. The most potent inhibitor of MIF tautomerase activity was 2-[(4-hydroxybenzylidene)amino]-3-(1H-indol-3-yl)propionic acid methyl ester (8), with an IC(50) of 1.65 microM. We found that compound 8 binding to MIF active site resulted in the inhibition of MIF bioactivity in three established bioassays: ERK-1/2 MAP kinase activation, p53-dependent apoptosis, and proliferation of serum-starved cells. Compound 8 inhibited MIF interaction with its as yet unidentified cognate cell surface receptor as shown by flow cytometry, concluding a critical role for the tautomerase active site in receptor binding. Thus the inhibitory effect of compound 8 on MIF bioactivities strongly correlated with the inhibition of MIF tautomerase activity, a connection not made previously through use of small-molecule MIF inhibitors. The inhibitory activity of amino acid-benzaldehyde Schiff base-type MIF antagonists is the first step toward a meaningful structure/function analysis of inhibitors of MIF cellular bioactivities.

Animals↗
PubMed1997

(E)- and (Z)-7-arylidenenaltrexones: synthesis and opioid receptor radioligand displacement assays.

The E-isomer of 7-benzylidenenaltrexone (BNTX, la) was reported by Portoghese as a highly selective delta-opioid antagonist. The corresponding Z-isomer 1b was not readily available through direct aldol condensation of naltrexone (6) with benzaldehyde. Using the photochemical methods employed by Lewis to isomerize cinnamamides, we have obtained Z-isomer 1b in good yield from E-isomer 1a. A series of (E)- and (Z)-7-arylidenenaltrexone derivatives was prepared to study the effect of larger arylidene groups on opioid receptor affinity in this series. By aldol condensation of naltrexone (6) with benzaldehyde, 1-naphthaldehyde, 2-naphthaldehyde, 4-phenylbenzaldehyde, and 9-anthracaldehyde, the (E)-arylidenes were readily obtained. Photochemical isomerization afforded the corresponding Z-isomers. These compounds were evaluated via opioid receptor radioligand displacement assays. In these assays, the Z-isomers generally had higher affinity and were more delta-selective than the corresponding E-isomers. The (Z)-7-(1-naphthylidene)naltrexone (3b) showed the greatest selectivity (delta:mu ratio of 15) and highest affinity delta-binding (Ki = 0.7 nM). PM3 semiempirical geometry optimizations suggest a significant role for the orientation of the arylidene substituent in the binding affinity and delta-receptor selectivity. This work demonstrates that larger groups may be incorporated into the arylidene portion of the molecule with opioid receptor affinity being retained.

Animals↗