کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2487195 1114408 2009 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Breakdown Kinetics of C-Hydroxymethyl β-Dicarbonyl Derivatives of Carbon Acids: Implications in the Bioconversion Rate of C-Phosphoryloxymethyl Prodrugs of Carbon Acids
کلمات کلیدی
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی اکتشاف دارویی
پیش نمایش صفحه اول مقاله
Breakdown Kinetics of C-Hydroxymethyl β-Dicarbonyl Derivatives of Carbon Acids: Implications in the Bioconversion Rate of C-Phosphoryloxymethyl Prodrugs of Carbon Acids
چکیده انگلیسی
The kinetics of conversion of C-hydroxymethyl derivatives of pharmaceutically relevant β-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 °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 pKa of the corresponding carbon acid with a shorter conversion/dehydroxymethylation half-life (at all given pH values) with decreasing pKa 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 β-dicarbonyl carbon acid.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 98, Issue 5, May 2009, Pages 1804-1812
نویسندگان
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