Linked Life Data

9822544

Source:http://linkedlifedata.com/resource/pubmed/id/9822544

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
24
pubmed:dateCreated
1998-12-17
pubmed:abstractText
7-Benzylamino-6-chloro-2-piperazino-4-pyrrolidinopteridine (7a) is a potent inhibitor of the cAMP-specific phosphodiesterase isoenzyme family PDE4 and induces growth inhibition in a panel of tumor cell lines. In this study, we describe a synthesis that yields 7a and novel derivatives free of positional isomers. The synthesis of alkylamino substituted pteridines is based on the successive nucleophilic aromatic substitution of the chlorine atoms of 2,4,6, 7-tetrachloropteridine. For the reaction with secondary amines, the positional order of reactivity was found to be C4 > C7 > C2 > C6. Final structural proof is given by X-ray crystallography. To unravel structural elements of 7a crucial for the interaction with the target enzyme, the compound was modified systematically. The impact of the modifications on activity was tested by evaluating the ability of the compounds to inhibit cAMP hydrolysis by cAMP-specific phosphodiesterase (PDE4) purified from the solid human large cell lung tumor xenograft LXFL529. Growth inhibitory properties were determined by in vitro treatment of the respective cell line LXFL529L using the sulforhodamine B assay (SRB). The results show that for high activity, the heterocyclic substituent in position 2 of the pteridine ring system requires the presence of a basic nitrogen in 4'-position, as represented by piperazine.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
19
pubmed:volume
41
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
4733-43
pubmed:dateRevised
2007-11-15
pubmed:meshHeading
pubmed-meshheading:9822544-3',5'-Cyclic-AMP Phosphodiesterases, pubmed-meshheading:9822544-Animals, pubmed-meshheading:9822544-Antineoplastic Agents, pubmed-meshheading:9822544-Cell Division, pubmed-meshheading:9822544-Crystallography, X-Ray, pubmed-meshheading:9822544-Cyclic AMP, pubmed-meshheading:9822544-Cyclic Nucleotide Phosphodiesterases, Type 4, pubmed-meshheading:9822544-Drug Screening Assays, Antitumor, pubmed-meshheading:9822544-Humans, pubmed-meshheading:9822544-Hydrolysis, pubmed-meshheading:9822544-Inhibitory Concentration 50, pubmed-meshheading:9822544-Isoenzymes, pubmed-meshheading:9822544-Lung Neoplasms, pubmed-meshheading:9822544-Mice, pubmed-meshheading:9822544-Mice, Nude, pubmed-meshheading:9822544-Phosphodiesterase Inhibitors, pubmed-meshheading:9822544-Piperazines, pubmed-meshheading:9822544-Pteridines, pubmed-meshheading:9822544-Rhodamines, pubmed-meshheading:9822544-Structure-Activity Relationship, pubmed-meshheading:9822544-Transplantation, Heterologous, pubmed-meshheading:9822544-Tumor Cells, Cultured
pubmed:year
1998
pubmed:articleTitle
Synthesis of 7-benzylamino-6-chloro-2-piperazino-4-pyrrolidinopteridine and novel derivatives free of positional isomers. Potent inhibitors of cAMP-specific phosphodiesterase and of malignant tumor cell growth.
pubmed:affiliation
Departments of Chemistry, Division of Food Chemistry and Environmental Toxicology and Division of Inorganic Chemistry, University of Kaiserslautern, Germany.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't