Design, synthesis, and biological evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathway
Cheng, Heng, Chong, Youhoon, Hwang, Inkyu, Tavassoli, Ali, Zhang, Yan, Wilson, Ian A., Benkovic, Stephen J. and Boger, Dale L. (2005) Design, synthesis, and biological evaluation of 10-methanesulfonyl-DDACTHF, 10-methanesulfonyl-5-DACTHF, and 10-methylthio-DDACTHF as potent inhibitors of GAR Tfase and the de novo purine biosynthetic pathway. Bioorganic & Medicinal Chemistry, 13, (10), 3577-3585. (doi:10.1016/j.bmc.2004.12.004).
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Description/Abstract
The synthesis and evaluation of 10-methanesulfonyl-DDACTHF (1), 10-methanesulfonyl-5-DACTHF (2), and 10-methylthio-DDACTHF (3) as potential inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) are reported. The compounds 10-methanesulfonyl-DDACTHF (1, K(i) = 0.23 microM), 10-methanesulfonyl-5-DACTHF (2, K(i) = 0.58 microM), and 10-methylthio-DDACTHF (3, K(i) = 0.25 microM) were found to be selective and potent inhibitors of recombinant human GAR Tfase. Of these, 3 exhibited exceptionally potent, purine sensitive growth inhibition activity (3, IC50 = 100 nM) against the CCRF-CEM cell line being 3-fold more potent than Lometrexol and 30-fold more potent than the parent, unsubstituted DDACTHF, whereas 1 and 2 exhibited more modest growth inhibition activity (1, IC50 = 1.0 microM and 2, IC50 = 2.0 microM).
| Item Type: | Article |
|---|---|
| ISSNs: | 0968-0896 (print) |
| Related URLs: | |
| Keywords: | antineoplastic agents, chemical synthesis, pharmacology cell survival/drug effects *drug design enzyme inhibitors/chemical synthesis/chemistry/pharmacology evaluation studies humans hydroxymethyl and formyl transferases, antagonists & inhibitors inhibitory concentration 50 phosphoribosylaminoimidazolecarboxamide formyltransferase phosphoribosylglycinamide formyltransferase purines/antagonists & inhibitors/metabolism structure-activity relationship tetrahydrofolates, chemical synthesis/chemistry, pharmacology tumor cells, cultured |
| Subjects: | Q Science > QD Chemistry Q Science > QH Natural history > QH301 Biology |
| Divisions: | University Structure - Pre August 2011 > School of Electronics and Computer Science University Structure - Pre August 2011 > School of Chemistry |
| Item ID: | 45308 |
| Date Deposited: | 20 Mar 2007 |
| Last Modified: | 01 Jun 2011 04:41 |
| Contributors: | Cheng, Heng (Author) Chong, Youhoon (Author) Hwang, Inkyu (Author) Tavassoli, Ali (Author) Zhang, Yan (Author) Wilson, Ian A. (Author) Benkovic, Stephen J. (Author) Boger, Dale L. (Author) |
| Date: | 2005 |
| Status: | Published |
| URI: | http://eprints.soton.ac.uk/id/eprint/45308 |
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