Linked Life Data

17181155

Source:http://linkedlifedata.com/resource/pubmed/id/17181155

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
26
pubmed:dateCreated
2006-12-21
pubmed:abstractText
The structure-activity relationship studies of ethyl 2-amino-6-cyclopentyl-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (1, HA 14-1), an antagonist of the antiapoptotic Bcl-2 proteins, are reported. A series of analogues of 1 with varied functional groups at the 6-position of the chromene ring were synthesized. These candidates were evaluated for their binding interactions with three antiapoptotic proteins: Bcl-2, Bcl-XL, and Bcl-w. They were also assayed for their in vitro cytotoxicities against a set of Jurkat cells with varied levels of Bcl-2 and Bcl-XL proteins and a non-small-cell lung carcinoma cell line (NCI-H460). It was found that the 6-bromo of 1 was not essential for its bioactivity and the 6-position can accommodate a variety of alkyl groups. 1 and its analogues bind to all of the three antiapoptotic Bcl-2 proteins tested. Positive correlations were observed between the binding affinities of these candidates to the antiapoptotic Bcl-2 proteins and their in vitro cytotoxicities, suggesting that the antiapoptotic Bcl-2 proteins are likely to be the cellular targets of 1 and its analogues. (In this study, the binding interactions of the small molecules to antiapoptotic Bcl-2 proteins were studied by assaying their abilities to compete against a Bak peptide binding to the antiapoptotic Bcl-2 proteins. Inhibitory constants, instead of dissociation constants, were obtained in such assays. The term "binding affinity" is used in this article for simplicity.) The most active compound, 3g, had a >3-fold increase of binding affinity to the antiapoptotic Bcl-2 proteins and a >13-fold increase of in vitro cytotoxicity over 1. Though Jurkat cells with transgenic overexpression of Bcl-2 or Bcl-XL protein can develop resistance to standard cancer therapies, such cells failed to develop resistance to 1 based candidates. 1 also sensitizes Jurkat cells to cisplatin. These studies provide further support that 1 and its analogues function as antagonists for antiapoptotic Bcl-2 proteins and that they have the potential, either as a single agent or as a combination therapy with other anticancer agents, to treat cancers with the overexpression of antiapoptotic Bcl-2 proteins.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
28
pubmed:volume
49
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
7731-9
pubmed:dateRevised
2008-6-5
pubmed:meshHeading
pubmed:year
2006
pubmed:articleTitle
Structure-activity relationship studies of ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (HA 14-1), an antagonist for antiapoptotic Bcl-2 proteins to overcome drug resistance in cancer.
pubmed:affiliation
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, 308 Harvard Street SE, Minneapolis, MN 55455, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't