Imidazole Catalysis. I. The Catalysis of the Hydrolysis of Phenyl Acetates by Imidazole

Bruice, Thomas C.; Schmir, Gaston L.

doi:10.1021/ja01564a036

Cited by 163 publications

(82 citation statements)

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“…To demonstrate the feasibility of nucleic acid-triggered catalytic drug release, we designed a model system (Fig. 2) based on the well known ability of imidazole to catalyze the release of p-nitrophenol from p-nitrophenyl esters (22)(23)(24). Release of a substituted o-or p-nitrophenol is also the key step in the activation of a recently reported class of prodrugs of the chemotherapeutic drugs daunorubicin, phenol nitrogen mustard, and 5-fluorouracil (25)(26)(27).…”

Section: Resultsmentioning

confidence: 99%

Nucleic acid-triggered catalytic drug release

Taylor

2000

Proc. Natl. Acad. Sci. U.S.A.

138

105

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We propose a concept for the rational design and synthesis of highly selective chemotherapeutic agents that makes direct use of genetic information about the disease state. The key idea is to use the mRNA or DNA specific to the disease state to trigger the catalytic release of a cytotoxic drug by promoting the association of a prodrug with a catalyst capable of releasing the drug. We demonstrate the feasibility of such an approach in vitro with a model system that is based on the hydrolysis of p-nitrophenyl esters by imidazole. In our model system, the catalytic component consists of an imidazole group linked to the 5 end of a 15-mer that is complementary to the 5 end of the triggering oligodeoxynucleotide. The corresponding prodrug component consists of a pnitrophenol ester linked to the 3 end of an 8-mer oligodeoxynucleotide that is complementary to the 3 end of the triggering sequence. We show that this system efficiently releases p-nitrophenol in the presence of all three components and that the reaction is catalytic and undergoes multiple turnovers. We also show that the complex between the catalytic component and the triggering oligodeoxynucleotide behaves like an enzyme and follows Michaelis-Menten kinetics, with a KM of 22 M and a kcat of 0.018 min ؊1 . Most importantly, we show that catalytic release of p-nitrophenol is sensitive to the presence of a single base-pair mismatch.

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Section: Resultsmentioning

confidence: 99%

Nucleic acid-triggered catalytic drug release

Taylor

2000

Proc. Natl. Acad. Sci. U.S.A.

138

105

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“…Enthalpic effects have also been shown to predominate in systems in which catalysis is much less pronounced, including general base catalysis of the bromination of acetoacetate by glycolate (16), in the covalent catalysis of the hydrolysis of 4-nitrophenyl acetate by imidazole (17), in general base catalysis of the aminolysis of carboxylic esters by alkylamines (18), and in the Mg II -catalyzed methanolysis of ATP (19).…”

Section: Do Primitive Catalysts Act By Lowering δH ‡ ? a Testmentioning

confidence: 99%

Impact of temperature on the time required for the establishment of primordial biochemistry, and for the evolution of enzymes

Stockbridge

Lewis

Yuan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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All reactions are accelerated by an increase in temperature, but the magnitude of that effect on very slow reactions does not seem to have been fully appreciated. The hydrolysis of polysaccharides, for example, is accelerated 190,000-fold when the temperature is raised from 25 to 100°C, while the rate of hydrolysis of phosphate monoester dianions increases 10,300,000-fold. Moreover, the slowest reactions tend to be the most heat-sensitive. These tendencies collapse, by as many as five orders of magnitude, the time that would have been required for early chemical evolution in a warm environment. We propose, further, that if the catalytic effect of a "proto-enzyme"-like that of modern enzymes-were mainly enthalpic, then the resulting rate enhancement would have increased automatically as the environment became cooler. Several powerful nonenzymatic catalysts of very slow biological reactions, notably pyridoxal phosphate and the ceric ion, are shown to meet that criterion. Taken together, these findings greatly reduce the time that would have been required for early chemical evolution, countering the view that not enough time has passed for life to have evolved to its present level of complexity.activation energy | thermophilic organisms | pyridoxal phosphate | phosphate ester hydrolysis | amino acid decarboxylation W hereas enzyme reactions ordinarily occur in a matter of milliseconds, the same reactions proceed with half-lives of hundreds, thousands, or millions of years in the absence of a catalyst ( Fig. 1) (1). Yet life is believed to have taken hold within the first 25% of Earth's history (2). How could cellular chemistry, and the enzymes that make life possible, have arisen so quickly? Here, we show that because of an extraordinarily sensitive relationship between temperature and the rates of very slow reactions, the time required for early evolution on a warm earth was very much shorter than it might appear. That sensitivity also suggests some likely properties of an evolvable catalyst, and a testable mechanism by which its ability to enhance rates might have been expected to increase as the environment cooled.Rapid substrate turnover is necessary to support the metabolism of an organism at the enzyme concentrations found in cells, but the same reactions, in the absence of enzymes, proceed vastly more slowly (Fig. 1). For example, the decarboxylation of orotidine 5′-phosphate (OMP), the final step in the biosynthesis of pyrimidines-and thus nucleic acids-proceeds with a half-life of 0.017 s at the active site of OMP decarboxylase. In neutral solution in the absence of the enzyme, the same reaction proceeds with a half-life of 78 million years (1). It is natural to ask how enzymes arose to meet so formidable a challenge. The Time Required for Primordial Chemistry to Become EstablishedThe rates of simple reactions, even if they are immeasurably slow at ordinary temperatures, can often be estimated by first determining their rates at elevated temperatures. Plots of the logarithm of the observed rate constants a...

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“…The same sort of effect was observed for the hydrolysis of phenyl acetates by imidazole. 14 As to the leaving group ability, as pH increases the amount of protonation on the benzimidazole moiety decreases significantly and this moiety is no longer a good leaving group.…”

Section: Hydrolysis In Intermediate Mediamentioning

confidence: 99%

“…A solid-liquid extraction was performed and the organic phase was dried with Na 2 SO 4 , filtered off and evaporated to dryness. The presence of compound 3 was detected by TLC (AcOEt) and identified by HR-MS (ESI) 258.14732 (258.147512 M + for C 14 H 18 N 4 O).…”

Section: -Phenyl 2-(methylamino)-1h-benzimidazole-1-carboxylate (2)mentioning

confidence: 99%

Kinetics and mechanism of hydrolysis of benzimidazolylcarbamates

Norberto¹,

Santos²,

Iley³

et al. 2007

J. Braz. Chem. Soc.

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Através da carbamoilação do 2-aminobenzimidazole com diferentes cloroformatos substituídos, sintetizaram-se novos N- [1-(2-amino)benzimidazolil]carbamatos. Estudouse a hidrólise em meio aquoso destes carbamatos numa gama de pH compreendida entre 1 e 13, a uma temperatura de 25 ºC. Os parâmetros cinéticos avaliados levaram a concluir que até pH 4 a reação se processa por mecanismo que envolve o ataque bimolecular da água ao substrato N-protonado. Esta é a primeira vez que este comportamento é observado em carbamatos, sendo muito provavelmente devido à diferença de basicidade entre um dos azotos do anel de benzimidazolilo e o oxigênio da função carbamato. Para valores mais elevados de pH, os resultados são consistentes com um mecanismo B Ac 2, atuando a água como nucleófilo entre pH 4 e 7 enquanto que em pH superior o íon hidróxido é o nucleófilo.Synthesis of new 2-aminobenzimidazole-1-carbamates was accomplished by carbamoylation of 2-aminobenzimidazole using different substituted phenyl chloroformates. The aqueous hydrolysis of the new compounds was examined in the pH range 1-13 at 25 o C. The evaluated kinetic parameters led to the conclusion that up to pH 4 reaction proceeds by a bimolecular attack of water to the N-protonated substrate. This is the first time this behavior is described for carbamates, and can be ascribed to the higher basicity of the benzimidazolyl moiety when compared with the carbonyl oxygen. For higher values of pH, the results are consistent with a B Ac 2 mechanism with nucleophilic catalysis, but while between pH 4 and pH 7 water acts as the nucleophile, for pH> 7 the hydroxide ion is the acting species.

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Imidazole Catalysis. I. The Catalysis of the Hydrolysis of Phenyl Acetates by Imidazole

Cited by 163 publications

References 1 publication

Nucleic acid-triggered catalytic drug release

Nucleic acid-triggered catalytic drug release

Impact of temperature on the time required for the establishment of primordial biochemistry, and for the evolution of enzymes

Kinetics and mechanism of hydrolysis of benzimidazolylcarbamates

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