Syntheses, Structures, and Enzymic Evaluations of Conformationally Constrained, Analog Inhibitors of Carnitine Acetyltransferase: (2R,6R)-, (2S,6S)-, (2R,6S)-, and (2S,6R)-6-(Carboxylatomethyl)-2-(hydroxymethyl)-2,4,4-trimethylmorpholinium

Sun, Guobin; Savle, Prashant S.; Gandour, Richard D.; Bhaird, Noirin Nic A; Ramsay, Rona R.; Fronczek, Frank R.

doi:10.1021/jo00126a018

Cited by 21 publications

(6 citation statements)

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“…The configuration of the tetrahedral intermediate in the reaction of chloramphenicol acetyltransferase has also been predicted to be that indicated by 3a , by computer modeling of the reaction based on the known crystal structure of the enzyme . Extensive work with carnitine acetyltransferase has demonstrated the value of knowledge of the stereochemistry of the tetrahedral intermediate in inhibitor design, and these studies have provided further support for the predicted stereochemistry of this intermediate . Similar observations have been made in the design of hydroxyethylene isosteres as inhibitors of proteases, with the configuration at a chiral secondary alcohol center corresponding to the site of hydrolysis being important for optimum inhibition. , As part of our program in the synthesis and applications of CoA analogs as mechanistic tools in enzymology, we have designed a pair of secondary alcohol analogs of acetyl-CoA 6 as stereochemical probes of the tetrahedral intermediate in reactions catalyzed by the acetyl-CoA dependent acetyltransferases.…”

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confidence: 58%

A Stereochemical Probe of the Tetrahedral Intermediate in the Reactions of Acetyl-Coenzyme A Dependent Acetyltransferases

Schwartz

Drueckhammer

1996

J. Am. Chem. Soc.

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A pair of isomeric acetyl-coenzyme A (acetyl-CoA) analogs have been prepared in which the thioester group is replaced with a secondary alcohol. The two isomers differ in stereoconfiguration of the secondary alcohol and were designed to mimic the two possible configurations of the tetrahedral intermediate or transition state in the reactions of acetyl-CoA dependent acetyltransferases. These two isomers were tested as inhibitors of chloramphenicol acetyltransferase and carnitine acetyltransferase, both of which have previously been predicted to form a tetrahedral intermediate which matches the configuration of the (S)-alcohol. The (S)-isomer was the more potent inhibitor of both enzymes, with K i values 12-fold and 6-fold lower than the K i values for the (R)-isomer. The (S)-isomer was also the more potent inhibitor of phosphate acetyltransferase, acetyl-CoA synthetase, and arylamine acetyltransferase, for which the stereochemistry of the tetrahedral intermediate was previously unknown. These results suggest a common stereoconfiguration of the tetrahedral intermediate among acetyl-CoA dependent acetyltransferases.

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confidence: 58%

A Stereochemical Probe of the Tetrahedral Intermediate in the Reactions of Acetyl-Coenzyme A Dependent Acetyltransferases

Schwartz

Drueckhammer

1996

J. Am. Chem. Soc.

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“…[47] MS: Thioesterification of 4-Bromocrotonic Acid [48] In a round-bottom flask equipped with stirring bar under a N 2 atmosphere, 4-bromocrotonic acid (3.47 g, 21.0 mmol), EtSH (1.55 mL, 21.0 mmol) and DMAP (0.26 g, 2.10 mmol) were dissolved in CH 2 Cl 2 (120 mL), the solution was cooled to 0 8C and DCC (4.76 g, 23.1 mmol) was added. After addition the reaction mixture was stirred for 16 h at room temperature.…”

Section: General Procedures For the Esterification Of 4-bromocrotonic mentioning

confidence: 99%

Copper‐Catalyzed Asymmetric Allylic Alkylation of Halocrotonates: Efficient Synthesis of Versatile Chiral Multifunctional Building Blocks

et al. 2010

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Abstract:The highly enantioselective synthesis of amethyl-substituted esters is reported in up to 90% yield and up to 99% ee using copper-TaniaPhos as chiral catalyst. The transformation proved scalable to at least 6.6 mmol (1.7 g scale). The products of this transformation have been further elaborated to multifunctional building blocks with a single (branched esters and acids) or multiple stereogenic centers (vicinal dimethyl esters, as well as, hydroxy-or iodosubstituted lactones).

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“…Acid side metathesis precursor 14 was available from a single esterification reaction from acid 13 (72 % yield). [19] Owing to the large difference of steric hindrance between the two metathesis precursors 12 and 14, it was possible to favor the formation of the desired unsymmetrical alkene during their cross-coupling metathesis reaction. [20] Thus, compound 15 was formed in yield of 58 % by using a 20 % excess of 14 over 12.…”

Section: Resultsmentioning

confidence: 99%

Cyclic Peptide–Polymer Complexes and Their Self‐Assembly

Bélanger

Tong

Soumaré

et al. 2009

Chemistry A European J

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The efficient synthesis of novel chiral cyclic peptides cyclo[NHCHX-CH=CHCH(2)CO(NHCH(2)CH=CHCH(2)CO)(2)] designed to develop hydrogen-bonding interactions with suitable polymers is described. Complexation of a carboxylic acid derivatized cyclic peptide 2 (X = CH(2)OCOCH(2)CH(2)CO(2)H) capable of self-assembling as "endless" tubes, with poly(vinyl alcohol) (PVA) led to a vast weak-interaction network, in which the cyclopeptide developed extensive hydrogen-bonding interactions with the hydroxyl groups of PVA through not only the carboxylic acid, but also its ester carbonyl and amide groups. In aqueous solution, the peptide/PVA complexes self-assemble into long-grain ricelike aggregates compatible with the stacking of cyclic peptides through intercycle hydrogen bonds. Upon casting on silicon wafer, the anisotropic aggregates can coalesce to form filaments tens of micrometers long. The study demonstrates that complexing functionalized cyclic peptides with polymers through hydrogen bonding is a useful approach for using polymers to mediate the self-assembly and self-organization of cyclic peptides.

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Syntheses, Structures, and Enzymic Evaluations of Conformationally Constrained, Analog Inhibitors of Carnitine Acetyltransferase: (2R,6R)-, (2S,6S)-, (2R,6S)-, and (2S,6R)-6-(Carboxylatomethyl)-2-(hydroxymethyl)-2,4,4-trimethylmorpholinium

Cited by 21 publications

References 0 publications

A Stereochemical Probe of the Tetrahedral Intermediate in the Reactions of Acetyl-Coenzyme A Dependent Acetyltransferases

A Stereochemical Probe of the Tetrahedral Intermediate in the Reactions of Acetyl-Coenzyme A Dependent Acetyltransferases

Copper‐Catalyzed Asymmetric Allylic Alkylation of Halocrotonates: Efficient Synthesis of Versatile Chiral Multifunctional Building Blocks

Cyclic Peptide–Polymer Complexes and Their Self‐Assembly

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