- PABA/NO lead optimization: Improved targeting of cytotoxicity to glutathione S-transferase P1-overexpressing cancer cells
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PABA/NO [O2-{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N-dimethylamino) diazen-1-ium-1,2-diolate] is a nitric oxide (NO)-releasing arylating agent designed to be selectively activated by reaction with glutathione (GSH) on catalysis by glutathione S-transferase P1 (GSTP1), an enzyme frequently overexpressed in cancer cells. PABA/NO has proven active in several cancer models in vitro and in vivo, but its tendency to be metabolized via a variety of pathways, some that generate inactive metabolites and hydrolysis products, limits its potential as a drug. Here we show that a simple replacement of cyano for nitro at the 4 position to give compound 4b ('p-cyano-PABA/NO') has the dual effect of slowing the undesired side reactions while enhancing the proportion of NO release and arylating activity on catalysis by GSTP1. Compound 4b showed increased resistance to hydrolysis and uncatalyzed reaction with GSH, along with a more favorable product distribution in the presence of GSTP1. It also showed significant proapoptotic activity. The data suggest p-cyano-PABA/NO to be a more promising prodrug than PABA/NO, with better selectivity toward cancer cells.
- Kim, Youseung,Maciag, Anna E.,Cao, Zhao,Deschamps, Jeffrey R.,Saavedra, Joseph E.,Keefer, Larry K.,Holland, Ryan J.
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Read Online
- Acetic Acid Accelerated Visible-Light Photoredox Catalyzed N-Demethylation of N,N-Dimethylaminophenyl Derivatives
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N,N-Dimethylaminophenyl moiety is a common fragment in medicinal chemistry as several pharmaceuticals bearing this privileged motif are on the market and under clinical evaluation. Oxidative N-demethylation is generally regarded as the major metabolic pathway. However, pharmacokinetics, metabolites studies as well as the further structural modification are precluded by the impracticality of chemical synthesis. Here we report that acetic acid can significantly accelerate visible-light photoredox catalyzed N-demethylation of N,N-dimethylaminophenyl derivatives. This approach is easy for large scale reaction and even for potential industrial manufacture. (Figure presented.).
- Wu, Guolin,Li, Yazhen,Yu, Xuemei,Gao, Yu,Chen, Haijun
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supporting information
p. 687 - 692
(2017/02/23)
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- A facile and practical copper powder-catalyzed, organic solvent-and ligand-free ullmann amination of aryl halides
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A facile and practical method that the copper powder-catalyzed Ullmann amination of aryl halides with aqueous methylamine under organic solvent-and ligand-free condition at 100 °C and in air gave N-arylamines as sole products in good to excellent yields. The presence of a small amount of air is essential. Other aliphatic primary amines show good to very high reactivity. Secondary amines and aniline are not reactive. Sensitive substituents (i.e., CHO, MeCO, CN and Cl) are tolerable in the reaction.
- Jiao, Jiao,Zhang, Xi-Ru,Chang, Ning-Hui,Wang, Jie,Wei, Jun-Fa,Shi, Xian-Ying,Chen, Zhan-Guo
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supporting information; experimental part
p. 1180 - 1183
(2011/04/24)
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- N-THIAZOL-2-YL-BENZAMIDE DERIVATIVES
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The invention relates to N-thiazol-2-yl-benzamide derivatives of the formula I in the description wherein the variables are as defined in the claims. The compounds are A2A-receptor ligands, such as antagonists, agonists, reverse agonists or partial agonists, and are useful in the treatment of neurological and psychiatric disorders where an A2A-receptor is implicated.
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Page/Page column 23
(2008/06/13)
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- Mono-N-methylation of functionalized anilines with alkyl methyl carbonates over NaY faujasites. 4. Kinetics and selectivity
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(Chemical Equation Presented) In the presence of NaY faujasite as the catalyst, the reaction of bifunctional anilines (1-4: XC6H 4-NH2; X = OH, CO2H, CH2OH, and CONH2) with methyl alkyl carbonates [MeOCO2R′: R′ = Me or MeO(CH2)2O(CH2)2] proceeds with a very high mono-N-methyl selectivity (XC6H 4NHMe up to 99%), and chemoselectivity as well, with other nucleophilic functions (OH, CO2H, CH2OH, CONH2) fully preserved from alkylation and/or transesterification reactions. Aromatic substituents, however, modify the relative reactivity of amines 1-4: good evidence suggests that, not only steric and electronic effects, but, importantly, direct acid-base interactions between substituents and the catalyst are involved. Weakly acidic groups (OH, CH2OH, CONH2, pKa ≥ 10) may help the reaction, while aminobenzoic acids (pK a of 4-5) are the least reactive substrates. The solvent polarity also affects the reaction, which is faster in xylene than in the more polar diglyme. The mono-N-methyl selectivity is explained by the adsorption pattern of reagents within the zeolite pores: a BAl2 displacement of the amine on methyl alkyl carbonate should occur aided by the geometric features of the NaY supercavities. Different factors account for the reaction chemoselectivity. Evidence proves that the polarizability of the two nucleophilic terms (NH 2 and X groups) of anilines is relevant, although adsorption and confinement phenomena of reagents promoted by the zeolite should also be considered.
- Selva, Maurizio,Tundo, Pietro,Foccardi, Tommaso
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p. 2476 - 2485
(2007/10/03)
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- Synthesis of mono-N-substituted functionalized anilines
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The present invention relates to a process for direct and selective synthesis of mono-N-substituted functionalized anilines by using alkylating agents selected from the class of organic carbonates, preferably of the dialkyl, dibenzyl and diallyl types, in the presence of suitable catalysts that are chemically related to the class of aluminosilicates.
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- Synthesis of mono-N-substituted functionalized anilines
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The present invention relates to a process for direct and selective synthesis of mono-N-substituted functionalized anilines by using alkylating agents selected from the class of organic carbonates, preferably of the dialkyl, dibenzyl and diallyl types, in the presence of suitable catalysts that are chemically related to the class of aluminosilicates.
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- Reaction of functionalized anilines with dimethyl carbonate over NaY faujasite. 3. Chemoselectivity toward mono-N-methylation
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In the presence of NaY faujasite, dimethyl carbonate (MeOCO2Me, DMC) is a highly chemoselective methylating agent of functionalized anilines such as aminophenols (1), aminobenzyl alcohols (2), aminobenzoic acids (3), and aminobenzamides (4). The reaction proceeds with the exclusive formation of N-methylanilines without any concurrent O-methylation or N-/O-methoxy carbonylation side processes. Particularly, only mono-N-methyl derivatives [XC6H4NHMe, X = o-, m-, and p-OH; o- and p-CH 2OH; o- and P-CO2H; o- and p-CONH2] are obtained with selectivity up to 99% and isolated yields of 74-99%. DMC, which usually promotes methylations only at T > 120 °C, is activated by the zeolite catalyst and it reacts with compounds 1, 2, and 4, at 90 °C. Aminobenzoic acids (3) require a higher reaction temperature (≥130 °C).
- Selva, Maurizio,Tundo, Pietro,Perosa, Alvise
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p. 7374 - 7378
(2007/10/03)
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- Supramolecular catalysis of ester and amide cleavage by a dinuclear barium(II) complex
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Five components spontaneously self-assemble to yield the productive complex 1, where one barium ion delivers and ethoxide to the carbonyl group of an amide substrate anchored by means of a distal carboxylate moiety to the other barium ion. High substrate specificity, fairly high reaction rates with catalytic turnover, and competitive inhibition by inert substrates are observed.
- Cacciapaglia, Roberta,Di Stefano, Stefano,Kelderman, Erik,Mandolini, Luigi
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p. 348 - 351
(2007/10/03)
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- Amine derivatives and process for producing the same
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An amine derivative having a liquid crystal property over a wide temperature range and a process for production thereof are disclosed, the amine derivative being represented by formula (I) STR1 wherein A represents STR2 X1 and X2, which may be the same or different, each represents STR3 Y represents --O-- or STR4 R1 and R3, which may be the same or different, each represents a straight chain or branched chain alkyl group having 1 to 18 carbon atoms; R2 represents a hydrogen atom or a methyl group; m and n each represents 0 or 1; and p and q each represents 1 or 2, provided that p and q are 1 when n is 0, and p and q are not 2 at the same time when n is 1.
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- KINETICS AND MECHANISM OF SOLVOLYSIS OF N-ARYL SULFURIC DIAMIDES
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The methanolysis and hydrolysis kinetics have been studied with the following sulfuric diamide derivatives: N-methyl-N-phenyl- (IIIa), N-methyl-N-(4-methoxycarbonylphenyl)- (IIIb), N-(4-methoxycarbonylphenyl)- (IIIc), N-methyl-N-(2-methoxycarbonylphenyl)- (IIId), N-(2-methoxycarbonylphenyl)- (IIIe), and N-methyl-N-(2,4-dibromophenyl)- (IIIf).The solvolyses of the neutral substrates IIIa and IIIb proceed by the addition-elimination mechanism.In the presence of the solvent lyate ions the solvolyses go by the E1cb mechanism.The solvolyses of the conjugated bases ofcompounds IIIa and IIIb are subject to general acid catalysis, the effects of the ring substituents being opposite to those in the addition-elimination mechanism.The solvolyses of compounds IIId and IIIf exhibit a distinct catalytic effect of neighbouring group; the reaction goes via a reactive intermediate, the transformation of the intermediate into the solvolysis product being subject to general acid and base catalysis.
- Kavalek, Jaromir,Kralikova, Ulrika,Machacek, Vladimir,Sedlak, Milos,Sterba, Vojeslav
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p. 202 - 222
(2007/10/02)
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- The Chemistry of N-Substituted Benzotriazoles. Part 4. A Novel and Versatile Method for the Mono-N-alkylation of Aromatic and Heteroaromatic Amines
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Mono-N-alkylation of aromatic and heteroaromatic amines is achieved in high yield by NaBH4 reduction of the adducts formed from benzotriazole, aliphatic aldehydes and the amines.Reaction of the same adducts with Grignard reagents gives N-(secondary alkyl)arylamines.Carboxy groups need no protection and nitro groups are unaffected.Adenine is mono-N-alkylated in high yield.
- Katritzky, Alan R.,Rachwal, Stanislaw,Rachwal, Bogumila
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p. 805 - 810
(2007/10/02)
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- Radiopharmaceutical composition based on technetium-99m and reagent for making it
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Radiopharmaceutical compositions containing complexes of technetium-99m with a complexing agent are prone to time and activity-related decomposition and formation of pertechnetate. Stabilizing agents for such complexes are organic compounds having an amine group and a carboxylic acid group attached to an aromatic ring. A preferred stabilizing agent is the sodium salt of 4-aminobenzoic acid. There are claims to a composition comprising a technetium 99-m complex stabilized by means of the said stabilizing agent; and to a reagent which forms, on addition of an aqueous solution of pertechnetate, a radiopharmaceutical composition, which reagent comprises a tin metal or stannous reducing agent for the pertechnetate, a complexing agent for the reduced technetium, for example a phosphorus-containing bone scanning agent, and a stabilizing agent as defined.
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