Document Detail

S-2-pentyl-4-pentynoic hydroxamic acid and its metabolite s-2-pentyl-4-pentynoic acid in the NMRI-exencephaly-mouse model: pharmacokinetic profiles, teratogenic effects, and histone deacetylase inhibition abilities of further valproic acid hydroxamates and amides.
MedLine Citation:
PMID:  16415118     Owner:  NLM     Status:  MEDLINE    
Structure-activity relationship studies of valproic acid (VPA) derivatives have revealed a quantitative correlation between histone deacetylase (HDAC) inhibition and induction of neural tube defects (NTDs) in the NMRI-exencephaly-mouse model, but this correlation has been, so far, limited to congeners with a carboxylic acid function. Whereas the classical HDAC inhibitor trichostatin A is active only as a hydroxamate but not as a carboxylic acid, we found that neither VPA amides nor hydroxamates inhibit HDACs, but can cause NTDs; e.g., 2-pentyl-4-pentynoic hydroxamic acid with its S-enantiomer being the potent teratogen. We therefore investigated the hypothesis that hydroxamic acid derivatives of VPA might be metabolized in vivo and may possibly be pro-teratogenic, as had been shown for valpromide but not valproic hydroxamic acid. We developed two stereoselective quantification methods based on chiral derivatization of VPA hydroxamates with (1R,2S,5R)-(-)-menthylchloroformate and carboxylic acid derivatives with (S)-(-)-1-naphthylethylamine, followed by gas chromatography-nitrogen phosphor detector analysis of biological samples. We then determined the pharmacokinetic profiles of S-2-pentyl-4-pentynoic hydroxamic acid and of S-2-pentyl-4-pentynoic acid in mice. S-2-Pentyl-4-pentynoic hydroxamic acid was found to be extensively metabolized to the corresponding carboxylic acid without affecting the stereochemistry at position C2. Furthermore, the metabolite S-2-pentyl-4-pentynoic acid was found to be very stable in vivo, with an extended half-life of 4.2 h compared with that of VPA, 1.4 h. Comparison of the individual HDAC inhibition abilities of additional VPA amides and hydroxamates, as measured by cellular and enzymatic assays, led us to the conclusion that both classes of VPA derivatives can be pro-teratogenic.
Daniel Eikel; Katrin Hoffmann; Karolin Zoll; Alfonso Lampen; Heinz Nau
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-01-13
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  34     ISSN:  0090-9556     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2006 Apr 
Date Detail:
Created Date:  2006-03-22     Completed Date:  2006-09-25     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  612-20     Citation Subset:  IM    
University of Veterinary Medicine Hannover-Foundation, Center for Systemic Neuroscience Hannover, Center for Food Science, Department of Food Toxicology and Chemical Analysis-Food Toxicology, Bischofsholer Damm 15, 30173 Hannover, Germany.
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MeSH Terms
Abnormalities, Drug-Induced / etiology*
Blood-Brain Barrier / metabolism
Disease Models, Animal
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis,  pharmacology
Fetus / drug effects*
Histone Deacetylase Inhibitors*
Neural Tube Defects / chemically induced
Protein Binding
Valproic Acid / analogs & derivatives,  chemical synthesis
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Histone Deacetylase Inhibitors; 0/S-2-pentyl-4-pentynoic hydroxamic acid; 0/pentyl-4-pentynoic acid; 99-66-1/Valproic Acid

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