Linked Life Data

15624927

Source:http://linkedlifedata.com/resource/pubmed/id/15624927

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2004-12-30
pubmed:abstractText
Epoxides, aziridines, and thiiranes are electrophilic building blocks that are widely used in synthetic organic chemistry. As a result of their reactivity against nucleophiles they are also used as electrophilic "warheads" for irreversible peptidic or peptidomimetic cysteine protease inhibitors. A general feature of these inhibitors is the remarkable higher inhibition potency of derivatives containing a free carboxylic acid in comparison to corresponding esters. In contrast, experimental investigations about the reaction of methyl thiolate with substituted epoxides revealed a contrary reactivity pattern. These studies also gave information about the regioselectivity of such reactions; however, mechanistic studies were not performed. By analyzing the computed energy profiles of the corresponding reactions we investigate the substituent effects (H vs ester vs carboxylic acid) on the kinetics and thermodynamics of the ring opening by the nucleophile methyl thiolate. Our model computations nicely explain experimental results concerning variations in the reactivities and the regioselectivities and indicate different reasons for the increased inhibition potency of three-membered heterocycles containing an acidic substituent. For aziridines an intramolecular water-mediated acid catalysis seems to be the main reason for the high activity of these inhibitors in acidic media. For epoxides and thiiranes this catalysis is not found, confirming the hypothesis that an ionic interaction between negatively charged carboxylate and the histidinium ion of the active site of the proteases mainly causes the high inhibitory activity of the acids compared to the esters.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0022-3263
pubmed:author
pubmed:issnType
Print
pubmed:day
7
pubmed:volume
70
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
233-7
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
Theoretical studies about the influence of different ring substituents on the nucleophilic ring opening of three-membered heterocycles and possible implications for the mechanisms of cysteine protease inhibitors.
pubmed:affiliation
Institut für Organische Chemie and Institut für Pharmazie und Lebensmittelchemie, Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't