- Delineation and decomposition of energies involved in quaternary ammonium binding in the active site of acetylcholinesterase
-
The quaternary ammonium binding locus in the active site of mammalian acetylcholinesterase is subtended by the side chains of Trp86, Tyr133, Glu202, and Tyr337. Linear free-energy relationships define the interactions involved in molecular recognition by mouse acetylcholinesterase of the quaternary ammonium moiety of ligands. For substrates CH3C(=O)XCH2CH2Y [X = O, Y = CHMe2, or CH2CH3; X = S, Y = H, NH+Me2, or N+Me3] and trifluoroacetophenone transition state analogue inhibitors m-YC6H4C(=O)CF3 [Y = H, Me, Et, iPr, tBu, CF3, NH2, NO2, NMe2, or N+Me3], log(k(cat)/K(m)) and pK(i) depend linearly on the molar refractivity, but not the hydrophobicity, of the substituents Y. These correlations indicate that, in the acylation stage of catalysis, interactions in the quaternary ammonium binding locus stabilize the tetrahedral intermediate (as modeled by transition state analogue affinity) by (5 x 105)-fold (ΔΔG(TI) = -32.5 kJ mol-1) and the transition state by (2 x 104)-fold (ΔΔG(+) = -24.5 kJ mol-1). To evaluate the contribution of cation-π interactions, Trp86 was convened into Tyr, Phe, and Ala by site-specific mutagenesis. For this set of enzymes, a linear free-energy relationship is observed between the pK(i) values for inhibitions by the respective neutral and cationic transition state analogue inhibitors, m-tert-butyltrifluoroacetophenone and m-(N,N,N- trimethylammonio)-trifluoroacetophenone, which indicates that the free energy released on interaction of the quaternary, ammonium moiety with Trp86 arises about equally from cation-π and charge-independent interactions.
- Quinn, Daniel M.,Feaster, Shawn R.,Nair, Haridasan K.,Baker, Nathan A.,Radic, Zoran,Taylor, Palmer
-
-
Read Online
- Intramolecular Catalysis of Thiol Ester Hydrolysis by a Tertiary Amine and a Carboxylate
-
The syntheses of 4-nitro thiol benzoate esters of ethyl 2-mercaptoacetate, thioglycolic acid, 2-(dimethylamino)ethanethiol, and 2-(N,N,N-trimethylammono)ethanethiol iodide (10-13) have been carried out and their rates of hydrolysis at 50°C studied as a function of pH. Thiol esters 10 and 13 have linear pH-log kobs profiles indicative of an exclusive specific base attack of OH-. Thiol esters 11 and 12 exhibit a plateau in their pH/log kobs profiles due to the participation of pendant carboxylate and dimethylamino groups, respectively, most probably as intramolecular general bases. At higher pH, specific base catalysis becomes predominant for both 11 and 12. In the plateau region, the hydrolysis of 12 is subject to a solvent deuterium kinetic isotope effect of 2.2, consistent with the operation of a general base role for the pendant dimethylamino group. The hydrolysis of 12 in the presence of Ellman's reagent produces the Ellman's anion at a rate that is identical to that for disappearance of the thioester, consistent with a general base process where the thiolate anion product of hydrolysis is produced in the rate-limiting step.
- Brown,Aman, Ahmed
-
-
Read Online
- Lewis Acid Promoted Aerobic Oxidative Coupling of Thiols with Phosphonates by Simple Nickel(II) Catalyst: Substrate Scope and Mechanistic Studies
-
Exploring new catalysts for efficient organic synthesis is among the most attractive topics in chemistry. Here, using Ni(OAc)2/LA as catalyst (LA: Lewis acid), a novel catalyst strategy was developed for oxidative coupling of thiols and phosphonates to phosphorothioates with oxygen oxidant. The present study discloses that when Ni(OAc)2 alone was employed as the catalyst, the reaction proceeded very sluggishly with low yield, whereas adding non-redox-active metal ions such as Y3+ to Ni(OAc)2 dramatically promoted its catalytic efficiency. The promotional effect is highly Lewis acidity dependent on the added Lewis acid, and generally, a stronger Lewis acid provided a better promotional effect. The stopped-flow kinetics confirmed that adding Y(OTf)3 can obviously accelerate the activation of thiols by Ni(II) and next accelerate its reaction with phosphonate to generate the phosphorothioate product. ESI-MS characterizations of the catalyst disclosed the formation of the heterobimetallic Ni(II)/Y(III) species in the catalyst solution. Additionally, this Ni(II)/LA catalyst can be applied in the synthesis of a series of phosphorothioate compounds including several commercial bioactive compounds. This catalyst strategy has clearly supported that Lewis acid can significantly improve the catalytic efficiency of these traditional metal ions in organic synthesis, thus opening up new opportunities in their catalyst design.
- Xue, Jing-Wen,Zeng, Miao,Zhang, Sicheng,Chen, Zhuqi,Yin, Guochuan
-
supporting information
p. 4179 - 4190
(2019/04/30)
-
- Cs2CO3-Catalyzed Aerobic Oxidative Cross-Dehydrogenative Coupling of Thiols with Phosphonates and Arenes
-
An efficient Cs2CO3-catalyzed oxidative coupling of thiols with phosphonates and arenes that uses molecular oxygen as the oxidant is described. These reactions provide not only a novel alkali metal salt catalyzed aerobic oxidation, but also an efficient approach to thiophosphates and sulfenylarenes, which are ubiquitously found in pharmaceuticals and pesticides. The reaction proceeds under simple and mild reaction conditions, tolerates a wide range of functional groups, and is applicable to the late-stage synthesis and modification of bioactive molecules.
- Song, Song,Zhang, Yiqun,Yeerlan, Adeli,Zhu, Bencong,Liu, Jianzhong,Jiao, Ning
-
supporting information
p. 2487 - 2491
(2017/02/23)
-
- LIPOCATIONIC POLYMERS AND USES THEREOF
-
Polymers produced by ring opening polymerization which comprises an amino group that can be used in compositions to deliver a nucleic acid such as a miRNA or a siRNA. In some embodiments, compositions which comprise the polymers described herein and a nucleic acid are also provided herein. In some embodiments, these compositions are used to silence one or more genes in vivo or treat a disease or disorder.
- -
-
Page/Page column 46
(2016/07/05)
-
- Rapid Synthesis of a Lipocationic Polyester Library via Ring-Opening Polymerization of Functional Valerolactones for Efficacious siRNA Delivery
-
The ability to control chemical functionality is an exciting feature of modern polymer science that enables precise design of drug delivery systems. Ring-opening polymerization of functional monomers has emerged as a versatile method to prepare clinically translatable degradable polyesters.1 A variety of functional groups have been introduced into lactones; however, the direct polymerization of tertiary amine functionalized cyclic esters has remained elusive. We report a strategy that enabled the rapid synthesis of >130 lipocationic polyesters directly from functional monomers without protecting groups. These polymers are highly effective for siRNA delivery at low doses in vitro and in vivo.
- Hao, Jing,Kos, Petra,Zhou, Kejin,Miller, Jason B.,Xue, Lian,Yan, Yunfeng,Xiong, Hu,Elkassih, Sussana,Siegwart, Daniel J.
-
supporting information
p. 9206 - 9209
(2015/08/06)
-
- Stable-isotope dimethylation labeling combined with LC-ESI MS for quantification of amine-containing metabolites in biological samples
-
One of the challenges associated with metabolome profiling in complex biological samples is to generate quantitative information on the metabolites of interest. In this work, a targeted metabolome analysis strategy is presented for the quantification of amine-containing metabolites. A dimethylation reaction is used to introduce a stable isotopic tag onto amine-containing metabolites followed by LC-ESI MS analysis. This labeling reaction employs a common reagent, formaldehyde, to label globally the amine groups through reductive animation. The performance of this strategy was investigated in the analysis of 20 amino acids and 15 amines by LC-ESI MS. It is shown that the labeling chemistry is simple, fast (13C-dimethylation does not show any isotope effect on either RPLC or HILIC LC, indicating that 13C-labeling is a preferred approach for relative quantification of amine-containing metabolites in different samples. The isotopically labeled 35 amine-containing analogues were found to be stable and proved to be effective in overcoming matrix effects in both relative and absolute quantification of these analytes present in a complicated sample, human urine. Finally, the characteristic mass difference provides additional structural information that reveals the existence of primary or secondary amine functional groups in amine-containing metabolites. As an example, for a human urine sample, a total of 438 pairs of different amine-containing metabolites were detected, at signal-to-noise ratios of greater than 10, by using the labeling strategy in conjunction with RP LC-ESI Fourier-transform ion cyclotron resonance MS.
- Guo, Kevin,Ji, Chengjie,Li, Liang
-
p. 8631 - 8638
(2008/03/15)
-
- Benzothiazole derivatives with activity as adenosine receptor ligands
-
The present invention relates to substituted benzothiazole derivitives and to their pharmaceutically acceptable salts useful for the treatment of diseases related to the adenosine receptor.
- -
-
-
- Kinetics and Equilibria of Thiol/Disulfide Interchange Reactions of Selected Biological Thiols and Related Molecules with Oxidized Glutathione
-
Rate constants for reaction of coenzyme A and cysteine with oxidized glutathione (GSSG) and equilibrium constants for the reaction of coenzyme A, cysteine, homocysteine, cysteamine, and related thiols with GSSG by thiol/disulfide interchange were determined over a range of pD values by NMR spectroscopy.The rate constants for reaction of the thiolate anion forms of coenzyme A and cysteine with GSSG suggest that reduction of GSSG by coenzyme A and cysteine is a mechanistically uncomplicated SN2 reaction.Equilibrium constants for the thiol/disulfide interchange reactions show a strong dependence on the Bronsted basicity of the thiolate anion.In a similar way, ΔE0', the difference between the half-cell potentials for the RSSR/RSH and GSSG/GSH redox couples, is linearly dependent on the difference between the pKA values of RSH and glutathione: ΔE0' = 64ΔpKA - 7.7 where ΔE0' is in units of mV.The reducing strength at a given pH is also determined by the fraction of the thiol present in the reactive thiolate form.At pD 7, the half-cell potentials for coenzyme A, cysteine, homocysteine, and cysteamine are close to that of glutathione, the major intracellular thiol redox system, which suggests that small changes in the intracellular redox potential can cause significant changes in the intracellular distribution of these biological thiols between their reduced and oxidized forms.
- Keire, David A.,Strauss, Erin,Guo, Wei,Noszal, Bela,Rabenstein, Dallas L.
-
p. 123 - 127
(2007/10/02)
-
- REACTIONS OF AZIRINES WITH SULFUR NUCLEOPHILES. 4. TREATMENT OF 2H-AZIRINE WITH MERCAPTOSUBSTITUTED ACIDS. REACTIONS OF AZIRIDINYL ALKYL SULFIDES WITH CARBOXYLIC ACIDS AND ACYL CHLORIDE DERIVATIVES
-
Treatment of 2H-azirines with mercaptosubstituted acids and their derivatives leads to β-ketoamides and 2-aziridinyl alkyl sulfides, respectively. 2-Aziridinyl alkyl sulfides, in turn, react with carboxylic acids to give β-ketoamides and substituted ethanethiol derivatives.Acylation of 2-aziridinyl alkyl sulfides with acyl halides generates a variety of products, depending on the reaction conditions; either products derived from cleavage and isomerization of the aziridinyl ring or (1-acylaziridinyl-2) alkyl sulfides are obtained.
- El'kinson, R.S.,Eremeev, A.V.
-
p. 161 - 166
(2007/10/02)
-
