Linked Life Data

15615536

Source:http://linkedlifedata.com/resource/pubmed/id/15615536

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
27
pubmed:dateCreated
2004-12-23
pubmed:abstractText
Active resistance of tumor cells against DNA alkylating agents arises by the production of high levels of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT). This resistance during treatment with, for example, the anticancer agent temozolomide can be reversed by administration of O(6)-benzylguanine, a purine that transfers its benzyl group to AGT and irreversibly inactivates it. Stimulated by the favorable therapeutic properties of temozolomide we designed and synthesized DNA-methylating triazenes built on the antiresistance benzylguanine ring system. The condensation reaction between 2-nitrosopurines and acylhydrazines proved to be very suitable to prepare acylated methyltriazenes. Fine-tuning of the release rate of both the methylating agent (diazomethane) and of O(6)-benzylguanine was accomplished by variation of the hydrolysis-sensitive acyl substituent in 5. Hydrolysis studies were performed with (1)H NMR and revealed that the p-nitrophenyl substituted triazene 26 showed an optimal hydrolysis rate (t(1/2) = 23 min) and almost 100% selectivity for the desired fragmentation route. In vitro antitumor studies in the 60 human tumor cell line panel of the National Cancer Institute confirmed the superior properties of p-nitrophenyl-protected methyl triazene 26, showing mean IC(50) values of 10 microM compared to 100 microM for temozolomide. In analogy with temozolomide, triazene 26 showed however low preference for each of the cancer subpanels, with IC(50) values between 8 and 14 microM.
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
30
pubmed:volume
47
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
6875-83
pubmed:meshHeading
pubmed:year
2004
pubmed:articleTitle
Synthesis and antitumor activity of methyltriazene prodrugs simultaneously releasing DNA-methylating agents and the antiresistance drug O(6)-benzylguanine.
pubmed:affiliation
Laboratory of Bioorganic Chemistry, Van't Hoff Institute of Molecular Sciences, University of Amsterdam, Nieuwe Achtergracht 129, NL-1018 WS Amsterdam.
pubmed:publicationType
Journal Article