Document Detail


Zn2+-chelating motif-tethered short-chain fatty acids as a novel class of histone deacetylase inhibitors.
MedLine Citation:
PMID:  14711316     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Among various classes of histone deacetylase (HDAC) inhibitors, short-chain fatty acids exhibit the least potency, with IC(50) in the millimolar range. We rationalized that this weak potency was, in part, attributable to their inability to access the zinc cation in the HDAC active-site pocket, which is pivotal to the deacetylation catalysis. We thus explored the structural optimization of valproate, butyrate, phenylacetate, and phenylbutyrate by coupling them with Zn(2+)-chelating motifs (hydroxamic acid and o-phenylenediamine) through aromatic omega-amino acid linkers. This strategy has led to a novel class of Zn(2+)-chelating, motif-tethered, short-chain fatty acids that exhibited varying degrees of HDAC inhibitory potency. One hydroxamate-tethered phenylbutyrate compound, N-hydroxy-4-(4-phenylbutyrylamino)benzamide (HTPB), displayed nanomolar potency in inhibiting HDAC activity. Exposure of several cancer cell lines to HTPB at the submicromolar level showed reduced cell proliferation accompanied by histone hyperacetylation and elevated p21(WAF/CIP1) expression, which are hallmark features associated with intracellular HDAC inhibition.
Authors:
Qiang Lu; Ya-Ting Yang; Chang-Shi Chen; Melanie Davis; John C Byrd; Mark R Etherton; Asad Umar; Ching-Shih Chen
Related Documents :
22417496 - Physical changes in white and brown rice during simulated gastric digestion.
6876086 - 5-sulfamoylorthanilic acids, a sulfonamide series with salidiuretic activity.
22733776 - Intestinal synthesis and secretion of bile salts as an adaptation to developmental bili...
15128026 - Abscisic acid and jasmonic acid affect proteinase inhibitor activities in barley leaves.
19868376 - Streptolysin production in carbohydrate media.
9268176 - Chronic alcoholism decreases polyunsaturated fatty acid levels in human plasma, erythro...
Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  47     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2004 Jan 
Date Detail:
Created Date:  2004-01-08     Completed Date:  2004-03-05     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  467-74     Citation Subset:  IM    
Affiliation:
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Acetylation
Antineoplastic Agents / chemical synthesis*,  chemistry,  pharmacology
Benzamides / chemical synthesis*,  chemistry,  pharmacology
Cell Division / drug effects
Cell Line, Tumor
Chelating Agents / chemical synthesis*,  chemistry,  pharmacology
Cyclin-Dependent Kinase Inhibitor p21
Cyclins / biosynthesis
Fatty Acids / chemical synthesis*,  chemistry,  pharmacology
Histone Deacetylase Inhibitors*
Histones / metabolism
Humans
Male
Valproic Acid / analogs & derivatives,  chemical synthesis,  chemistry,  pharmacology
Zinc / chemistry*
Grant Support
ID/Acronym/Agency:
CA94829/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Benzamides; 0/CDKN1A protein, human; 0/Chelating Agents; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/Fatty Acids; 0/Histone Deacetylase Inhibitors; 0/Histones; 0/N-hydroxy-4-(4-phenylbutyrylamino)benzamide; 7440-66-6/Zinc; 99-66-1/Valproic Acid

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


Previous Document:  (2S,1'S,2'R,3'R)-2-(2'-Carboxy-3'-hydroxymethylcyclopropyl) glycine is a highly potent group 2 and 3...
Next Document:  DNA-targeted 1,2,4-benzotriazine 1,4-dioxides: potent analogues of the hypoxia-selective cytotoxin t...