Linked Life Data

11900865

Source:http://linkedlifedata.com/resource/pubmed/id/11900865

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2002-3-19
pubmed:abstractText
Thiols are the most reactive nucleophilic reagents among the biological models investigated. The reactivity of butenolides 1a-c, 2-4, and 6-8 toward L-cysteine, a model biological nucleophile, was studied spectrophotometrically. The rates of the reactions were measured and correlated with antitumour activity of these molecules. N-Acetylcysteine addition product 5, resulting from the treatment of butenolide 4 with glutathione precursor, N-acetyl-L-cysteine, was isolated. Unlike purine-containing gamma-(Z)-ethylidene-2,3-dimethoxybutenolides 1a-c, 4, 6, and 7, adduct 5 and butenolides 10-12 did not exhibit inhibitory activity against murine leukemias (L1210 and P388), breast carcinoma (MCF7), and human T-lymphoblasts (Molt4/C8 and CEM/0) cell lines. As such, the biological activity of purine-containing butenolides can be attributed to their adenine moiety as a recognition site as well as their reactivity towards the cysteine residues of functional proteins forming covalent bond via reverse Michael type addition. Adenine-containing phosphonothioanhydride derivative 8 was also synthesised. Its reaction with N-acetyl-L-cysteine produced N,S-diacetylcysteine and thiophosphonate 9. Compound 9 did not exhibit anticancer activity; yet its precursor 8 displayed the most pronounced inhibition on all the examined malignant tumour cell lines. In the presence of L-cysteine, cytotoxicity of 4 and 8 was decreased, whereas glutathione addition more influenced on the cytotoxicity of 8. It was found that adenine-containing phosphonothioanhydride 8 functions as a significant irreversible inactivator of the Escherichia coli ribonucleoside diphosphate reductase. After treatment of MCF7 cells with compound 8, fluorescence microscopy demonstrated the presence of nucleus shrinkage or segmentation. This apoptotic morphology, however, was not pronounced in the presence of glutathione or dithiotheritol.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0223-5234
pubmed:author
pubmed:issnType
Print
pubmed:volume
37
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
207-17
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:11900865-4-Butyrolactone, pubmed-meshheading:11900865-Acetylcysteine, pubmed-meshheading:11900865-Animals, pubmed-meshheading:11900865-Antineoplastic Agents, pubmed-meshheading:11900865-Apoptosis, pubmed-meshheading:11900865-Cell Division, pubmed-meshheading:11900865-Cell Line, pubmed-meshheading:11900865-Cysteine, pubmed-meshheading:11900865-Cytarabine, pubmed-meshheading:11900865-Dose-Response Relationship, Drug, pubmed-meshheading:11900865-Escherichia coli, pubmed-meshheading:11900865-Fibroblasts, pubmed-meshheading:11900865-Furans, pubmed-meshheading:11900865-Humans, pubmed-meshheading:11900865-Mice, pubmed-meshheading:11900865-Molecular Structure, pubmed-meshheading:11900865-Purines, pubmed-meshheading:11900865-Ribonucleotide Reductases, pubmed-meshheading:11900865-Sulfhydryl Compounds, pubmed-meshheading:11900865-Tumor Cells, Cultured
pubmed:year
2002
pubmed:articleTitle
Reactions of purines-containing butenolides with L-cysteine or N-acetyl-L-cysteine as model biological nucleophiles: a potent mechanism-based inhibitor of ribonucleotide reductase caused apoptosis in breast carcinoma MCF7 cells.
pubmed:affiliation
Institute of Chemistry, Academia Sinica, 115 Taipei, Taiwan, ROC. hosein@chem.sinica.edu.tw
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't