Synthesis and biological evaluation of N-[4-[5-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroac etyl)pentyl]benzoyl]-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway
Cheng, Heng, Hwang, Inkyu, Chong, Youhoon, Tavassoli, Ali, Webb, Michael E., Zhang, Yan, Wilson, Ian A., Benkovic, Stephen J. and Boger, Dale L. (2005) Synthesis and biological evaluation of N-[4-[5-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroac etyl)pentyl]benzoyl]-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway. Bioorganic & Medicinal Chemistry, 13, (10), 3593-3599. (doi:10.1016/j.bmc.2004.11.049).
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Description/Abstract
The synthesis and evaluation of N-[4-[5-(2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroac etyl)pentyl]benzoyl]-L-glutamic acid (2) as an inhibitor of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The inhibitor 2 was prepared in a convergent synthesis involving C-alkylation of methyl 4-(4,4,4-trifluoro-3-dimethylhydrazonobutyl)benzoate with 1-chloro-3-iodopropane followed by construction of the pyrimidinone ring. Compound 2 was found to be an effective inhibitor of recombinant human GAR Tfase (K(i) = 0.50 microM), whereas it was inactive (K(i) > 100 microM) against E. coli GAR Tfase as well as recombinant human AICAR Tfase. Compound 2 exhibited modest, purine-sensitive growth inhibitory activity against the CCRF-CEM cell line (IC50 = 6.0 microM).
| Item Type: | Article |
|---|---|
| ISSNs: | 0968-0896 (print) |
| Related URLs: | |
| Keywords: | *antineoplastic agents/chemical synthesis/pharmacology *enzyme inhibitors/chemical synthesis/pharmacology glutamic acid, analogs & derivatives/chemical synthesis/pharmacology humans hydroxymethyl and formyl transferases, antagonists & inhibitors leukemia, lymphocytic, acute/metabolism/pathology molecular structure phosphoribosylaminoimidazolecarboxamide formyltransferase phosphoribosylglycinamide formyltransferase purines/antagonists & inhibitors, biosynthesis pyrimidines, chemical synthesis, pharmacology structure-activity relationship tumor cells, cultured |
| Subjects: | Q Science > QD Chemistry Q Science > QH Natural history > QH301 Biology |
| Divisions: | University Structure - Pre August 2011 > School of Chemistry |
| Item ID: | 45307 |
| Date Deposited: | 20 Mar 2007 |
| Last Modified: | 02 Mar 2012 11:49 |
| Contributors: | Cheng, Heng (Author) Hwang, Inkyu (Author) Chong, Youhoon (Author) Tavassoli, Ali (Author) Webb, Michael E. (Author) Zhang, Yan (Author) Wilson, Ian A. (Author) Benkovic, Stephen J. (Author) Boger, Dale L. (Author) |
| Date: | 2005 |
| Status: | Published |
| Contact Email Address: | boger@scripps.edu |
| URI: | http://eprints.soton.ac.uk/id/eprint/45307 |
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