10-Formyl-5,10-dideaza-acyclic-5,6,7,8-tetrahydrofolic acid (10-formyl-DDACTHF): a potent cytotoxic agent acting by selective inhibition of human GAR Tfase and the de novo purine biosynthetic pathway
Marsilje, Thomas H., Labroli, Marc A., Hedrick, Michael P., Jin, Qing, Desharnais, Joel, Baker, Stephen J., Gooljarsingh, Lata T., Ramcharan, Joseph, Tavassoli, Ali, Zhang, Yan, Wilson, Ian A., Beardsley, G. Peter, Benkovic, Stephen J. and Boger, Dale L. (2002) 10-Formyl-5,10-dideaza-acyclic-5,6,7,8-tetrahydrofolic acid (10-formyl-DDACTHF): a potent cytotoxic agent acting by selective inhibition of human GAR Tfase and the de novo purine biosynthetic pathway. Bioorganic & Medicinal Chemistry, 10, (8), 2739-2749. (doi:10.1016/S0968-0896(02)00102-5).
Download
Full text not available from this repository.
Description/Abstract
The synthesis of 10-formyl-DDACTHF (3) as a potential inhibitor of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide ribonucleotide transformylase (AICAR Tfase) is reported. Aldehyde 3, the corresponding gamma- and alpha-pentaglutamates 21 and 25 and related agents were evaluated for inhibition of folate-dependent enzymes including GAR Tfase and AICAR Tfase. The inhibitors were found to exhibit potent cytotoxic activity (CCRF-CEM IC(50) for 3=60nM) that exceeded their enzyme inhibition potency [K(i) (3)=6 and 1 microM for Escherichia coli GAR and human AICAR Tfase, respectively]. Cytotoxicity rescue by medium purines, but not pyrimidines, indicated that the potent cytotoxic activity is derived from selective purine biosynthesis inhibition and rescue by AICAR monophosphate established that the activity is derived preferentially from GAR versus AICAR Tfase inhibition. The potent cytotoxic compounds including aldehyde 3 lost activity against CCRF-CEM cell lines deficient in the reduced folate carrier (CCRF-CEM/MTX) or folylpolyglutamate synthase (CCRF-CEM/FPGS(-)) establishing that their potent activity requires both reduced folate carrier transport and polyglutamation. Unexpectedly, the pentaglutamates displayed surprisingly similar K(i)'s versus E. coli GAR Tfase and only modestly enhanced K(i)'s versus human AICAR Tfase. On the surface this initially suggested that the potent cytotoxic activity of 3 and related compounds might be due simply to preferential intracellular accumulation of the inhibitors derived from effective transport and polyglutamation (i.e., ca. 100-fold higher intracellular concentrations). However, a subsequent examination of the inhibitors against recombinant human GAR Tfase revealed they and the corresponding gamma-pentaglutamates were unexpectedly much more potent against the human versus E. coli enzyme (K(i) for 3, 14nM against rhGAR Tfase versus 6 microM against E. coli GAR Tfase) which also accounts for their exceptional cytotoxic potency.
| Item Type: | Article |
|---|---|
| ISSNs: | 0968-0896 (print) |
| Related URLs: | |
| Keywords: | antineoplastic agents, chemical synthesis/pharmacology carrier proteins/physiology cell division/drug effects enzyme inhibitors/chemical synthesis/pharmacology humans hydroxymethyl and formyl transferases, antagonists & inhibitors peptide synthases/physiology phosphoribosylaminoimidazolecarboxamide formyltransferase phosphoribosylglycinamide formyltransferase purines/antagonists & inhibitors, biosynthesis *receptors, cell surface structure-activity relationship tetrahydrofolates, chemical synthesis 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: | 45316 |
| Date Deposited: | 21 Mar 2007 |
| Last Modified: | 01 Jun 2011 04:40 |
| Contributors: | Marsilje, Thomas H. (Author) Labroli, Marc A. (Author) Hedrick, Michael P. (Author) Jin, Qing (Author) Desharnais, Joel (Author) Baker, Stephen J. (Author) Gooljarsingh, Lata T. (Author) Ramcharan, Joseph (Author) Tavassoli, Ali (Author) Zhang, Yan (Author) Wilson, Ian A. (Author) Beardsley, G. Peter (Author) Benkovic, Stephen J. (Author) Boger, Dale L. (Author) |
| Date: | 2002 |
| Status: | Published |
| Contact Email Address: | boger@scripps.edu |
| URI: | http://eprints.soton.ac.uk/id/eprint/45316 |
Actions (login required)
 |
View Item |
