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Design, synthesis and biological evaluation of 10-CF3CO-DDACTHF analogues and derivatives as inhibitors of GAR Tfase and the de novo purine biosynthetic pathway

Design, synthesis and biological evaluation of 10-CF3CO-DDACTHF analogues and derivatives as inhibitors of GAR Tfase and the de novo purine biosynthetic pathway
Design, synthesis and biological evaluation of 10-CF3CO-DDACTHF analogues and derivatives as inhibitors of GAR Tfase and the de novo purine biosynthetic pathway
The synthesis and evaluation of analogues and key derivatives of 10-CF3CO-DDACTHF as inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide transformylase (AICAR Tfase) are reported. Polyglutamate analogues of 1 were evaluated as inhibitors of Escherichia coli and recombinant human (rh) GAR Tfase, and AICAR Tfase. Although the pentaglutamate 6 was found to be the most active inhibitor of the series tested against rhGAR Tfase (Ki=0.004 ?M), little distinction between the mono-pentaglutamate derivatives was observed (Ki=0.02-0.004 microM), suggesting that the principal role of the required polyglutamation of 1 is intracellular retention. In contrast, 1 and its defined polyglutamates 3-6 were much less inactive when tested against rhAICAR Tfase (Ki=65-0.120 ?M) and very selective (? or =100-fold) for rh versus E. coli GAR Tfase. Additional key analogues of 1 were examined (7 and 8) and found to be much less active (1000-fold) highlighting the exceptional characteristics of 1.
drug design, enzyme inhibitors, chemical synthesis, pharmacology, folic acid, analogs & derivatives, humans, hydroxymethyl and formyl transferases, antagonists & inhibitors, phosphoribosylaminoimidazolecarboxamide formyltransferase, phosphoribosylglycinamide formyltransferase, purines, biosynthesis, structure-activity relationship, tetrahydrofolates, chemistry/pharmacology
0968-0896
4511-4521
Desharnais, Joel
f4d5b1db-e99b-4487-b37a-f64f24c7914a
Hwang, Inkyu
8ade2adf-15cf-4366-bac8-608048102ff0
Zhang, Yan
8552a39d-0c4d-4712-8ad8-d0d5cc9d1779
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2
Baboval, Justin
24afa059-282a-4431-9a4d-3511524c8ecd
Benkovic, Stephen J.
f85498a5-27fc-4a22-9069-ff61a4297520
Wilson, Ian A.
7865d500-d638-4a67-ad6d-fefad0ae83bb
Boger, Dale L.
d81e0270-0561-47df-8904-85718bd462ff
Desharnais, Joel
f4d5b1db-e99b-4487-b37a-f64f24c7914a
Hwang, Inkyu
8ade2adf-15cf-4366-bac8-608048102ff0
Zhang, Yan
8552a39d-0c4d-4712-8ad8-d0d5cc9d1779
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2
Baboval, Justin
24afa059-282a-4431-9a4d-3511524c8ecd
Benkovic, Stephen J.
f85498a5-27fc-4a22-9069-ff61a4297520
Wilson, Ian A.
7865d500-d638-4a67-ad6d-fefad0ae83bb
Boger, Dale L.
d81e0270-0561-47df-8904-85718bd462ff

Desharnais, Joel, Hwang, Inkyu, Zhang, Yan, Tavassoli, Ali, Baboval, Justin, Benkovic, Stephen J., Wilson, Ian A. and Boger, Dale L. (2003) Design, synthesis and biological evaluation of 10-CF3CO-DDACTHF analogues and derivatives as inhibitors of GAR Tfase and the de novo purine biosynthetic pathway. Bioorganic & Medicinal Chemistry, 11 (20), 4511-4521. (doi:10.1016/S0968-0896(03)00458-9).

Record type: Article

Abstract

The synthesis and evaluation of analogues and key derivatives of 10-CF3CO-DDACTHF as inhibitors of glycinamide ribonucleotide transformylase (GAR Tfase) and aminoimidazole carboxamide transformylase (AICAR Tfase) are reported. Polyglutamate analogues of 1 were evaluated as inhibitors of Escherichia coli and recombinant human (rh) GAR Tfase, and AICAR Tfase. Although the pentaglutamate 6 was found to be the most active inhibitor of the series tested against rhGAR Tfase (Ki=0.004 ?M), little distinction between the mono-pentaglutamate derivatives was observed (Ki=0.02-0.004 microM), suggesting that the principal role of the required polyglutamation of 1 is intracellular retention. In contrast, 1 and its defined polyglutamates 3-6 were much less inactive when tested against rhAICAR Tfase (Ki=65-0.120 ?M) and very selective (? or =100-fold) for rh versus E. coli GAR Tfase. Additional key analogues of 1 were examined (7 and 8) and found to be much less active (1000-fold) highlighting the exceptional characteristics of 1.

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More information

Published date: 2003
Keywords: drug design, enzyme inhibitors, chemical synthesis, pharmacology, folic acid, analogs & derivatives, humans, hydroxymethyl and formyl transferases, antagonists & inhibitors, phosphoribosylaminoimidazolecarboxamide formyltransferase, phosphoribosylglycinamide formyltransferase, purines, biosynthesis, structure-activity relationship, tetrahydrofolates, chemistry/pharmacology

Identifiers

Local EPrints ID: 45313
URI: http://eprints.soton.ac.uk/id/eprint/45313
ISSN: 0968-0896
PURE UUID: ebbe6908-dbeb-4485-be76-b6037cabcda5
ORCID for Ali Tavassoli: ORCID iD orcid.org/0000-0002-7420-5063

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Date deposited: 20 Mar 2007
Last modified: 09 Jan 2022 03:22

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Contributors

Author: Joel Desharnais
Author: Inkyu Hwang
Author: Yan Zhang
Author: Ali Tavassoli ORCID iD
Author: Justin Baboval
Author: Stephen J. Benkovic
Author: Ian A. Wilson
Author: Dale L. Boger

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