Linked Life Data

20149665

Source:http://linkedlifedata.com/resource/pubmed/id/20149665

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2010-3-11
pubmed:abstractText
Imatinib (STI571) is the frontline targeted-therapeutic agent for patients with chronic myelogenous leukemia (CML). However, resistance to imatinib due to point mutations in Bcr-Abl kinase domain is an emerging problem. We recently reported that triptolide (compound 1) could effectively kill CML cells including those harboring T315I mutant Bcr-Abl. In the present study, we designed a series of C-14 triptolide derivatives with C-14-hydroxyl substituted by different amine esters (3-18): 3-6 and 13 (by aliphatic chain amine esters); 7-9, 11, 12 and 15-18 (by alicyclic amine esters with different size), and 10 and 14 (by aralkylamine esters).The compounds were examined for their antineoplastic activity against CML cells (including KBM5-T315I cells) in terms of proliferation inhibition, apoptosis and signal transduction. Nude mouse xenograft model was also used to evaluate the in vivo activity. Compounds 2-9, 11-14, 17 and 18 exhibited a potent inhibitory activity against KBM5 and KBM5-T315I cells. This series of derivatives down-regulated Bcr-Abl mRNA. Compounds 4, 5, 8 and 9 were further examined for their impact on signaling and apoptosis with immunoblotting. Compound 5 was chosen for evaluation in a nude mouse xenograft model. The stereo-hindrance of C-14 group appeared to be responsible for the antitumor effect. The computational small molecule-protein docking analysis illustrated the possible interaction between compound 9 and RNA polymerase II. Our results suggest that this series of derivatives may be promising agents to overcome imatinib-resistance caused by the Bcr-Abl-T315I mutation.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
1464-3391
pubmed:author
pubmed:copyrightInfo
Copyright 2010 Elsevier Ltd. All rights reserved.
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
18
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1806-15
pubmed:meshHeading
pubmed-meshheading:20149665-Amino Acid Substitution, pubmed-meshheading:20149665-Animals, pubmed-meshheading:20149665-Antineoplastic Agents, pubmed-meshheading:20149665-Apoptosis, pubmed-meshheading:20149665-Binding Sites, pubmed-meshheading:20149665-Cell Line, pubmed-meshheading:20149665-Computer Simulation, pubmed-meshheading:20149665-Diterpenes, pubmed-meshheading:20149665-Down-Regulation, pubmed-meshheading:20149665-Drug Design, pubmed-meshheading:20149665-Drug Resistance, Neoplasm, pubmed-meshheading:20149665-Epoxy Compounds, pubmed-meshheading:20149665-Fusion Proteins, bcr-abl, pubmed-meshheading:20149665-Humans, pubmed-meshheading:20149665-Leukemia, Myelogenous, Chronic, BCR-ABL Positive, pubmed-meshheading:20149665-Mice, pubmed-meshheading:20149665-Mice, Nude, pubmed-meshheading:20149665-Phenanthrenes, pubmed-meshheading:20149665-Piperazines, pubmed-meshheading:20149665-Pyrimidines, pubmed-meshheading:20149665-RNA, Messenger, pubmed-meshheading:20149665-Signal Transduction, pubmed-meshheading:20149665-Water, pubmed-meshheading:20149665-Xenograft Model Antitumor Assays
pubmed:year
2010
pubmed:articleTitle
Design, synthesis, and biological evaluation of novel water-soluble triptolide derivatives: Antineoplastic activity against imatinib-resistant CML cells bearing T315I mutant Bcr-Abl.
pubmed:affiliation
School of Chemistry and Chemical Engineering, Sun Yat-Sen University, 135 Xingangxi Road, Guangzhou 510275, People's Republic of China.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't