Linked Life Data

15089091

Source:http://linkedlifedata.com/resource/pubmed/id/15089091

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2004-4-19
pubmed:abstractText
Two widely used biological buffers [tris(hydroxymethyl)aminomethane (TRIS) and phosphate] covalently react with the topoisomerase II inhibitor clerocidin, affecting the drug's reactivity profile. Comprehensive analytical and structural analysis obtained by LC/MS, MS/MS, NMR, and IR techniques shows that these buffers form reversible and irreversible adducts through reactions with chemical groups, such as carbonyls, aldehydes, and epoxide. Analysis of the kinetic data on adducts formation suggests two parallel mechanisms for the inhibition of drug activity. The first involves modulation of the reactivity of the epoxide group obtained by elimination of the spiro system and relief of ring strain. This effect does not abolish epoxide reactivity and is more evident for the TRIS adduct, which can count on intramolecular stabilization of the form devoid of the spiro system. The second mechanism involves the slow nucleophilic attack to the epoxide ring, which results in permanent deactivation of the functional group responsible for topoisomerase II inhibition. This effect is predominant in phosphate buffer and is more evident for longer reaction times. These results provide a compelling reminder that the activity of chemically complex drugs in biological systems can be severely altered by buffer interactions, which may not be immediately predictable from the identity of the active group(s) and may require a more detailed knowledge of the subtle effects induced by vicinal groups.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0893-228X
pubmed:author
pubmed:issnType
Print
pubmed:volume
17
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
492-501
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2004
pubmed:articleTitle
Effects of common buffer systems on drug activity: the case of clerocidin.
pubmed:affiliation
Department of Pharmaceutical Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't