Document Detail


Breakdown kinetics of C-hydroxymethyl beta-dicarbonyl derivatives of carbon acids: implications in the bioconversion rate of C-phosphoryloxymethyl prodrugs of carbon acids.
MedLine Citation:
PMID:  18781645     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The kinetics of conversion of C-hydroxymethyl derivatives of pharmaceutically relevant beta-dicarbonyl carbon acids of two series, pyrazolidin-3,5-diones and inden-1,3-diones, and a model carbon acid back to the respective carbon acids were studied as a function of pH at 25 degrees C and an ionic strength of 0.15 M. This is a somewhat surprising reaction since it involves the facile breakdown of a carbon-carbon bond. The slopes of the pH-rate profiles for the dehydroxymethylation were approximately unity, which along with the lack of buffer catalysis, indicates a specific-base mechanism involving spontaneous breakdown of the oxymethyl anion. This breakdown generates the conjugate base of the respective carbon acids. Thus within a series, there exists a correlation between the second-order rate constant for dehydroxymethylation and the pK(a) of the corresponding carbon acid with a shorter conversion/dehydroxymethylation half-life (at all given pH values) with decreasing pK(a) of the parent carbon acid. The increasing acidity of the carbon acid affords an increase in the leaving group ability of the carbanion, and therefore facilitation of the rate-determining unimolecular carbon-carbon bond cleavage. Since the hydroxymethyl derivative is an intermediate in the bioconversion of C-phosphoryloxymethyl prodrugs of carbon acids, also under study, the relationship allows one to reasonably predict how facile the dehydroxymethylation would be for any new beta-dicarbonyl carbon acid.
Authors:
Sundeep S Dhareshwar; Valentino J Stella
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of pharmaceutical sciences     Volume:  98     ISSN:  1520-6017     ISO Abbreviation:  J Pharm Sci     Publication Date:  2009 May 
Date Detail:
Created Date:  2009-03-30     Completed Date:  2009-06-19     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985195R     Medline TA:  J Pharm Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1804-12     Citation Subset:  IM    
Affiliation:
Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, Kansas 66047, USA.
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MeSH Terms
Descriptor/Qualifier:
Alkaline Phosphatase / chemistry
Buffers
Half-Life
Hydrogen-Ion Concentration
Indicators and Reagents
Ketones / chemistry*
Kinetics
Prodrugs / chemistry*
Pyrazoles / chemistry*
Spectrophotometry, Ultraviolet
Chemical
Reg. No./Substance:
0/Buffers; 0/Indicators and Reagents; 0/Ketones; 0/Prodrugs; 0/Pyrazoles; EC 3.1.3.1/Alkaline Phosphatase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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