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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

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
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
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).
*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
0968-0896
3593-3599
Cheng, Heng
d5528f70-6754-4bbd-a8fd-701c34350c33
Hwang, Inkyu
8ade2adf-15cf-4366-bac8-608048102ff0
Chong, Youhoon
e2730d88-537c-456c-ad50-38889c38cafc
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2
Webb, Michael E.
b708fbe4-2f5a-43c9-8c0b-ffa1ccb9b2be
Zhang, Yan
8552a39d-0c4d-4712-8ad8-d0d5cc9d1779
Wilson, Ian A.
7865d500-d638-4a67-ad6d-fefad0ae83bb
Benkovic, Stephen J.
f85498a5-27fc-4a22-9069-ff61a4297520
Boger, Dale L.
d81e0270-0561-47df-8904-85718bd462ff
Cheng, Heng
d5528f70-6754-4bbd-a8fd-701c34350c33
Hwang, Inkyu
8ade2adf-15cf-4366-bac8-608048102ff0
Chong, Youhoon
e2730d88-537c-456c-ad50-38889c38cafc
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2
Webb, Michael E.
b708fbe4-2f5a-43c9-8c0b-ffa1ccb9b2be
Zhang, Yan
8552a39d-0c4d-4712-8ad8-d0d5cc9d1779
Wilson, Ian A.
7865d500-d638-4a67-ad6d-fefad0ae83bb
Benkovic, Stephen J.
f85498a5-27fc-4a22-9069-ff61a4297520
Boger, Dale L.
d81e0270-0561-47df-8904-85718bd462ff

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).

Record type: Article

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).

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Published date: 2005
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
Organisations: Chemistry

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Local EPrints ID: 45307
URI: https://eprints.soton.ac.uk/id/eprint/45307
ISSN: 0968-0896
PURE UUID: b1147da6-cb1c-4b8f-9f43-6a16a214325a
ORCID for Ali Tavassoli: ORCID iD orcid.org/0000-0002-7420-5063

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Date deposited: 20 Mar 2007
Last modified: 14 Mar 2019 01:41

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Contributors

Author: Heng Cheng
Author: Inkyu Hwang
Author: Youhoon Chong
Author: Ali Tavassoli ORCID iD
Author: Michael E. Webb
Author: Yan Zhang
Author: Ian A. Wilson
Author: Stephen J. Benkovic
Author: Dale L. Boger

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