Linked Life Data

7518523

Source:http://linkedlifedata.com/resource/pubmed/id/7518523

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
14
pubmed:dateCreated
1994-8-18
pubmed:abstractText
The plant-derived natural product ellagic acid (1) has recently been identified as a potent, though nonselective, inhibitor of the tyrosine-specific protein kinase pp60src. This report details efforts directed toward the identification of tricyclic structures related to ellagic acid, with enhanced specificity for inhibition of pp60src over other protein kinases. Phenanthridinone and carbazole core structures were selected for investigation, since N-functionalization allows for the synthesis of numerous analogs which can be utilized to probe enzyme-inhibitor interactions. These ring systems were prepared via a general sequence of biaryl bond formation followed by cyclization to form the desired tricyclic ring systems. N-Alkylation, -acylation, or -sulfonylation and deprotection with boron tribromide afford the target tetraphenolic phenanthridinones 5 and carbazoles 9. Several analogs from both of these series have potencies comparable to that of 1 and exhibit substantially enhanced selectivities for inhibition of pp60src relative to protein kinase A (PKA), a serine/threonine protein kinase. Carbazole-based analogs 9j,m,p are submicromolar inhibitors of pp60src, with potency for the target tyrosine kinase comparable to that of ellagic acid (1), however with 2 orders of magnitude greater selectivity versus that for PKA. As seen for ellagic acid, members of the phenanthridinone-based series (e.g., 5a) exhibited inhibition of pp60src in a manner which is partial mixed noncompetitive with respect to ATP, while analogs in the carbazole series (e.g., 9a) inhibit pp60src in an ATP competitive manner.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
8
pubmed:volume
37
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2224-31
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed:year
1994
pubmed:articleTitle
Identification of tricyclic analogs related to ellagic acid as potent/selective tyrosine protein kinase inhibitors.
pubmed:affiliation
Central Research Division, Pfizer Inc., Groton, Connecticut 06340.
pubmed:publicationType
Journal Article