Source:http://linkedlifedata.com/resource/pubmed/id/11063604
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
22
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pubmed:dateCreated |
2000-11-20
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pubmed:abstractText |
A series of O(6)-allyl- and O(6)-(2-oxoalkyl)guanines were synthesized and evaluated, in comparison with the corresponding O(6)-alkylguanines, as potential inhibitors of the DNA-repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT). Simple O(6)-alkyl- and O(6)-cycloalkylguanines were weak AGT inactivators compared with O(6)-allylguanine (IC(50) = 8.5 +/- 0.6 microM) with IC(50) values ranging from 100 to 1000 microM. The introduction of substituents at C-2 of the allyl group of O(6)-allylguanine reduced activity compared with the parent compound, while analogous compounds in the O(6)-(2-oxoalkyl)guanine series exhibited very poor activity (150-1000 microM). O(6)-Cycloalkenylguanines proved to be excellent AGT inactivators, with 1-cyclobutenylmethylguanine (IC(50) = 0.55 +/- 0.02 microM) and 1-cyclopentenylmethylguanine (IC(50) = 0.39 +/- 0.04 microM) exhibiting potency approaching that of the benchmark AGT inhibitor O(6)-benzylguanine (IC(50) = 0.18 +/- 0.02 microM). 1-Cyclopentenylmethylguanine also inactivated AGT in intact HT29 human colorectal carcinoma cells (IC(50) = 0.20 +/- 0.07 microM) and potentiated the cytotoxicity of the monomethylating antitumor agent Temozolomide by approximately 3- and 10-fold, respectively, in the HT29 and Colo205 tumor cell lines. The observation that four mutant AGT enzymes resistant to O(6)-benzylguanine also proved strongly cross-resistant to 1-cyclopentenylmethylguanine indicates that the O(6)-substituent of each compound makes similar binding interactions within the active site of AGT.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, Alkylating,
http://linkedlifedata.com/resource/pubmed/chemical/Cell Extracts,
http://linkedlifedata.com/resource/pubmed/chemical/Dacarbazine,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Guanine,
http://linkedlifedata.com/resource/pubmed/chemical/O(6)-Methylguanine-DNA...,
http://linkedlifedata.com/resource/pubmed/chemical/temozolomide
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:ArrisC ECE,
pubmed-author:BleasdaleCC,
pubmed-author:BoyleF TFT,
pubmed-author:CalvertA HAH,
pubmed-author:CurtinN JNJ,
pubmed-author:DalbyCC,
pubmed-author:GoldingB TBT,
pubmed-author:GriffinR JRJ,
pubmed-author:KanugulaSS,
pubmed-author:LembiczN KNK,
pubmed-author:NewellD RDR,
pubmed-author:PeggA EAE
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pubmed:issnType |
Print
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pubmed:day |
2
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pubmed:volume |
43
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4071-83
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:11063604-Antineoplastic Agents, Alkylating,
pubmed-meshheading:11063604-Cell Extracts,
pubmed-meshheading:11063604-Dacarbazine,
pubmed-meshheading:11063604-Drug Resistance, Neoplasm,
pubmed-meshheading:11063604-Drug Screening Assays, Antitumor,
pubmed-meshheading:11063604-Drug Synergism,
pubmed-meshheading:11063604-Enzyme Inhibitors,
pubmed-meshheading:11063604-Guanine,
pubmed-meshheading:11063604-Humans,
pubmed-meshheading:11063604-Mutation,
pubmed-meshheading:11063604-O(6)-Methylguanine-DNA Methyltransferase,
pubmed-meshheading:11063604-Structure-Activity Relationship,
pubmed-meshheading:11063604-Tumor Cells, Cultured
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pubmed:year |
2000
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pubmed:articleTitle |
Resistance-modifying agents. 8. Inhibition of O(6)-alkylguanine-DNA alkyltransferase by O(6)-alkenyl-, O(6)-cycloalkenyl-, and O(6)-(2-oxoalkyl)guanines and potentiation of temozolomide cytotoxicity in vitro by O(6)-(1-cyclopentenylmethyl)guanine.
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pubmed:affiliation |
Department of Chemistry, Bedson Building, The University, Newcastle upon Tyne NE1 7RU, UK. r.j.griffin@ncl.ac.uk
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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