- Evaluation of benzoic acid derivatives as sirtuin inhibitors
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Employing a genetically modified yeast strain as a screening tool, 4-dimethylaminobenzoic acid (5) was isolated from the marine sediment-derived Streptomyces sp. CP27-53 as a weak yeast sirtuin (Sir2p) inhibitor. Using this compound as a scaffold, a series of disubstituted benzene derivatives were evaluated to elucidate the structure activity relationships for Sir2p inhibition. The results suggested that 4-alkyl or 4-alkylaminobenzoic acid is the key structure motif for Sir2p inhibitory activity. The most potent Sir2p inhibitor, 4-tert-butylbenzoic acid (20), among the tested compounds in this study turned out to be a weak but selective SIRT1 inhibitor. The calculated binding free energies between the selected compounds and the catalytic domain of SIRT1 were well correlated to their measured SIRT1 inhibitory activities.
- Chen, Yi-Pei,Catbagan, Chad C.,Bowler, Jeannette T.,Gokey, Trevor,Goodwin, Natalie D.M.,Guliaev, Anton B.,Wu, Weiming,Amagata, Taro
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- Evaluation of benzoic acid derivatives as sirtuin inhibitors
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Employing a genetically modified yeast strain as a screening tool, 4-dimethylaminobenzoic acid (5) was isolated from the marine sediment-derived Streptomyces sp. CP27-53 as a weak yeast sirtuin (Sir2p) inhibitor. Using this compound as a scaffold, a series of disubstituted benzene derivatives were evaluated to elucidate the structure activity relationships for Sir2p inhibition. The results suggested that 4-alkyl or 4-alkylaminobenzoic acid is the key structure motif for Sir2p inhibitory activity. The most potent Sir2p inhibitor, 4-tert-butylbenzoic acid (20), among the tested compounds in this study turned out to be a weak but selective SIRT1 inhibitor. The calculated binding free energies between the selected compounds and the catalytic domain of SIRT1 were well correlated to their measured SIRT1 inhibitory activities.
- Chen, Yi-Pei,Catbagan, Chad C.,Bowler, Jeannette T.,Gokey, Trevor,Goodwin, Natalie D.M.,Guliaev, Anton B.,Wu, Weiming,Amagata, Taro
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supporting information
p. 349 - 352
(2015/05/12)
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- BORON-CONTAINING SMALL MOLECULES
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This invention relates to, among other items, 6-substituted benzoxaborole compounds and their use for treating bacterial infections.
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Page/Page column 134
(2012/06/05)
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- 4' SUBSTITUTED COMPOUNDS HAVING 5-HT6 RECEPTOR AFFINITY
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The present disclosure provides compounds having affinity for the 5-HT6 receptor which are of the formula (I): wherein R1, R2, R5, R6, B, D, E, G, Q, x and n are as defined herein. The disclosure also relates to methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
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Page/Page column 37
(2009/01/24)
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- 6' SUBSTITUTED COMPOUNDS HAVING 5-HT6 RECEPTOR AFFINITY
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The present disclosure provides compounds having affinity for the 5-HT6 receptor which are of the formula (I): wherein R1—R4 A, B, D, E, and G are as defined herein. The disclosure also relates to methods of preparing such compounds, compositions containing such compounds, and methods of use thereof.
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Page/Page column 60
(2008/12/08)
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- Structure-activity relationships in platelet-activating factor (PAF). 11-From PAF-antagonism to phospholipase A2 inhibition: Syntheses and structure-activity relationships in 1-arylsulfamido-2-alkylpiperazines
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1-Benzoyl-2-alkyl piperazines are strong inhibitors of Group I and II secreted PLA2s. An improvement of their activity was obtained by replacing the amide function by a sulfamide and by introduction of electrodonor substituents on the para position of the benzenesulfonyl moiety. Neither the position on one of the carbon of the piperazine ring nor the absolute configuration of this carbon have an effect on the affinity for one or the other group of PLA2, but the lipophilicity remains for these series an essential parameter. In addition structure-activity relationships allow new hypothesis on interaction of these piperazine derivatives with the catalytic site of PLA2s.
- Binisti, Carine,Assogba, Leon,Touboul, Estera,Mounier, Carine,Huet, Jack,Ombetta, Jean-Edouard,Dong, Chang Zhi,Redeuilh, Catherine,Heymans, Francoise,Godfroid, Jean-Jacques
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p. 809 - 828
(2007/10/03)
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- Effect of Microwave Heating on Organic Reactions of Different Types
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Sulfonation of N,N-dimethylaniline, dehydration of succinic acid, and synthesis of 3′,6′-dihydroxyspiro(isobenzofuran-1,9′-xanthen)-3-one occur in the same or similar way under both microwave and convection heating.
- Tselinskii,Brykov,Astrat'ev
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p. 1653 - 1655
(2007/10/03)
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- New classes of antimuscarinic agents endowed with selective antispasmodic properties. 1-Arylsulfonyl pyrrolidin-2-ones and 2-thiones, 1-arylsulfonyl piperidin-2-ones and 2-thiones and 1-arylsulfonyl hexahydro-2H-azepin-2-one
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A series of 1-arylsulfonylpyrrolidin-2-ones (and 2-thiones), 1-aryl sulfonylpiperidin-2-ones (and 2-thiones) and 1-arylsulfonyl hexahydro-2H-azepin-2-one were synthesized and submitted to a battery of binding assays. The compounds showed little or no affinity for the receptors tested other than muscarinic receptors labelled either with [3H]pirenzepine or with [3H]quinuclidinyl benzilate. When tested in the isolated guinea pig ileum, they antagonized the contractions induced by acetylcholine and behaved as competitive muscarinic antagonists. After parenteral administration in mice, most compounds inhibited carbachol-induced diarrhoea but were less effective in counteracting salivation and lacrimation and showed little or no mydriatic action, thus displaying selectivity at the intestinal level. The reference drugs tested, atropine, butyl scopolamine and cimetropium bromide were far less selective. Maximal in vivo activity was obtained by introducing diethylamino or 1-piperidino or 1-hexahydroazepinyl groups in the 4-position of the phenyl ring while the enlargement of a 5- to a 6-membered lactam ring or its conversion into a thiolactam had a less marked effect. The most interesting compounds were further evaluated for their ability to antagonize carbachol-induced colonic hypermotility in the rat and arecoline-induced analgesia in mice. The effect on gastric acid secretion in the rat was also investigated. The overall in vivo data showed that compounds 14, 15, 26 and 27, i.e. those bearing a 1-hexahydroazepinyl group in the 4-position of the phenyl ring, were the most potent and selective compounds. Unlike the reference drugs, they antagonized carbachol-induced diarrhoea and colonic hypermotility at doses (0.6-4 mg/kg i.p.) 1-2 orders of magnitude lower than those needed to counteract carbachol-induced salivation and lacrimation or to induce mydriatic and antisecretory effects. The novelty of these structures and their selectivity of action on smooth muscle are the two key features of this class of antimuscarinics.
- Toja,Parini,Bonetti,Hunt,Fortin,Barzaghi,Cesana,Maggioni,Nencioni,Galliani
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p. 501 - 509
(2007/10/02)
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- ISOMERIC TRANSFORMATIONS OF AMINOSULFONIC ACIDS OF THE BENZENE SERIES IN MIXTURES OF SULFURIC AND ACETIC ACIDS
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The isomerization rate of aminosulfonic acids in anhydrous binary mixtures of sulfuric and acetic acids is lower than in aqueous sulfuric acid solutions but higher than in 100percent sulfuric acid.This is explained by the differences in the structure and activity of the proton carriers during desulfonation.The rate of transformation of the labile isomers into the meta isomers increases with increase in the acidity of the medium, and this is due to the increase in the resulfonation rate of the protonating molecules of the amines formed during the desulfonation of the aminosulfonic acids.The effect of mercuric sulfate on the isomeric transformations of aminosulfonic acids is explained by the mercuration of the protonated molecules of the amines, which takes place at higher rates than their sulfonation and leads to the formation of the meta-mercury derivatives of the amines.The latter are than converted into the m-aminosulfonic acids by the action of concentrated sulfuric acid.
- Khelevin, R. N.
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p. 132 - 137
(2007/10/02)
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- KINETICS OF SULFONATION OF AMINES OF THE BENZENE SERIES WITH SULFUR TRIOXIDE
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The sulfonation of amines of the benzene series with sulfur trioxide in dichloroethane is described by a third-order kinetic equation for an irreversible process, and first order is observed with respect to the compound being sulfonated and second with respect to the sulfur trioxide.The unprotonated molecules of the amines undergo sulfonation, and this leads to the production of the para-aminosulfonic acids with small amounts of the ortho isomers.The reaction mechanism involves electrophilic reaction of the unprotonated amine molecule with the sulfur trioxide dimer S2O6 and subsequent dissociation of the obtained pyrosulfonate with the production of the amino sulfonic acid and sulfur trioxide.
- Khelevin, R. N.
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p. 535 - 539
(2007/10/02)
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- KINETICS OF THE SULFONATION OF AMINES OF THE BENZENE SERIES BY CHLOROSULFONIC ACID
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The kinetics of the sulfonation of amines of the benzene series by an equimolar amount of chlorosulfonic acid in o-dichlorobenzene were studied.It was shown that the sulfonation of aniline and N-alkylanilines is described by a second-order kinetic equation for irreversible reactions.The sulfonation of N,N-dialkylanilines by chlorosulfonic acid is described by a first-order kinetic equation for irreversible reactions.The observed relationships are explained by different mechanism for the sulfonation of amines of the benzene series by chlorosulfonic acid.The sulfonation of aniline and N-alkalynilines takes place by direct reaction between the unprotonated molecules of the amines and the HSO3(1+) ion, whereas in the reaction of chlorosulfonic acid with N,N-dialkylanilines complexes of the N,N-dialkylanilines with sulfur trioxide (dialkylanilinesulfotrioxides) are formed initially and then rearrange to the corresponding para-aminosulfonic acids.
- Khelevin, R. N.
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p. 1709 - 1713
(2007/10/02)
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- Kinetics of hydrolysis of aromatic mono- and disulfonyl chlorides
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A continuous polarografic method of recording instantaneous concentrations of - SO2Cl groups in an aqueous acetic acid system containing CH3CO2Na has been elaborated.Ten model monosulfonyl chlorides underwent hydrolysis according to pseudo-first order kinetics (20percent H2O, 80percent v.v.CH3CO2H, 0.5 mol/dm3 CH3CO2Na).Plots of hydrolysis for seven disulfonyl dichlorides with different number of - CH3 groups have been determined.Pseudo-first order rate constants for two consecutive reactions of hydrolysis (k1 and k2) have been computed and the influence of -SO2Cl and -SO3- groups on the reactivity of the second group - SO2Cl has been discussed.The mechanism of nucleophilic substitution has also been discussed.
- Sanecki, Przemyslaw,Rokaszewski, Edward
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p. 2263 - 2267
(2007/10/02)
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- REARRANGEMENT OF PHENYL- AND N-ALKYLPHENYLAMMONIUM HYDROGEN SULFATES IN ORGANIC SOLVENTS
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The kinetics of the rearrangement of phenyl- and N-alkylphenylammonium hydrogen sulfates in halogen-containing organic solvents were investigated in closed systems and with the removal of the water produced in the reaction.The isomeric composition of the obtained aminobenzenesulfonic acids was also studied.The rearrangement is described by a second-order kinetic equation.The reaction mechanism involves thermal dissociation of the phenyl- and N-alkylphenylammonium hydrogen sulfates at high temperatures to amines (bases) and sulfuric acid, followed by direct sulfonation of the amines (bases) by the sulfuric acid with the formation mostly of para-aminosulfonic acids of the benzene series.
- Khelevin, R. N.
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p. 1906 - 1911
(2007/10/02)
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- KINETIC OF THE SULFONATION OF AMINES OF THE BENZENE SERIES WITH SULFURIC ACID
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The kinetics of the sulfonation of primary, secondary, and tertiary amines of the benzene series with 80-99.7percent sulfuric acid were investigated.It was shown that the unprotonated and protonated forms of the amines, which are present in equilibrium, undergo sulfonation.The effective reaction rate constants and the activation energies for the sulfonation of the unprotonated and protonated molecules of the amines were calculated.The reaction mechanism and the structure of the transition state are discussed.
- Khelevin, R. N.
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p. 339 - 347
(2007/10/02)
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- MECHANISM OF THE SULFONATION OF AROMATIC AMINES BY SULFURIC ACID AT HIGH TEMPERATURES
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The kinetics of the rearrangement of unsubstituted and N-substituted phenylammonium hydrogen sulfates to the corresponding aminosulfonic acids of the benzene series were studied.The isomeric composition of the reaction products formed during the sulfonation of amines of the benzene series by various amounts of 100percent H2SO4 was also studied.The rearrangement is described by a second-order kinetic equation.Its effective rate constant at various temperatures and the activation energies were calculated.It is suggested that the sulfonation of aromatic amines by an equimolar amount of sulfuric acid at high temperatures takes place through the dissociation of the arylammonium hydrogen sulfates with the formation of arylamines and sulfuric acid and subsequent direct sulfonation of the arylamines by the sulfuric acid.
- Khelevin, R. N.
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p. 1173 - 1178
(2007/10/02)
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- KINETICS OF THE SULFONATION OF AMINES OF THE BENZENE SERIES BY OLEUM IN THE PRESENCE OF MERCURIC SULFATE
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Sulfonated mixtures with increased contents of the meta isomers are formed during the sulfonation of amine sulfates of the benzene series with oleum containing mercuric sulfate.The following mechanism is proposed for the sulfonation of the amines by oleum in the presence of mercuric sulfate.Two fast reactions take place initially, i.e., sulfonation of the unprotonated molecules of the amines of the benzene series and electrophilic mercuration of the protonated molecules of the amines with the formation of the meta-mercurio derivatives.Electrophilic substitution of the mercury by the sulfo group with formation of the meta-mercuric derivatives then occurs under the influence of the oleum.
- Khelevin, R. N.
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p. 1723 - 1726
(2007/10/02)
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- ISOMERIZATION OF AMINOSULFONIC ACIDS OF THE BENZENE SERIES IN THE PRESENCE OF MERCURIC SULFATE
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The isomerization of aminosulfonic acids of the benzene series in 85, 90, and 95percent sulfuric acid at 180, 190, and 200 deg C in the presence of mercuric sulfate was investigated.Mercuric sulfate accelerates the isomerization of ortho- and para-aminosulfonic acids of the benzene series to the meta isomers.Here the para aminosulfonic acids are converted irreversibly into the meta-aminosulfonic acids.The ortho isomers initially form a mixture of the meta and para isomers.Subsequently the para isomers are converted into the kintically more stable meta isomers.The effective rate constants for the isomerization of the aminosulfonic acids and also the activation energies were calculated.The effect of mercuric sulfate on the isomerization of the aminosulfonic acid is explained by the mercuration of the protonated arylamines, which takes place at higher rates compared with the sulfonation rates.The meta-mercurated derivatives are converted by the action of concentrated sulfuric acid into meta-aminobenzenesulfonic acids.
- Khelevin, R.N.
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p. 720 - 725
(2007/10/02)
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- ISOMERIZATION OF AMINOSULFONIC ACIDS OF THE BENZENE SERIES
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The isomerization of aminosulfonic acids of the benzene series was investigated in 85, 90, and 95percent sulfuric acid at 180, 190, and 200 deg C.It was established that the transformation of the ortho and para isomers into the meta isomers takes place almost irreversibly.The effective rate constants for the isomerisation of the aminosulfonic acids and the activation energies of the reactions were calculated.It was shown that in 85-95percent sulfuric acid the protonated molecules of the aminosulfonic acids undergo hydrolysis in addition to the unprotonated molecules.
- Khelevin, R. N.
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p. 1651 - 1656
(2007/10/02)
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