Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway

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

doi:10.1016/j.bmc.2004.11.049

Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway

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

Chemistry

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

The synthesis and evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)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 μM), whereas it was inactive (K_i > 100 μM) 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 μM).

Original language	English (US)
Pages (from-to)	3593-3599
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry
Volume	13
Issue number	10
DOIs	https://doi.org/10.1016/j.bmc.2004.11.049
State	Published - May 15 2005

All Science Journal Classification (ASJC) codes

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Organic Chemistry
Clinical Biochemistry

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Cheng, H., Hwang, I., Chong, Y., Tavassoli, A., Webb, M. E., Zhang, Y., Wilson, I. A., Benkovic, S. J., & Boger, D. L. (2005). Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway. Bioorganic and Medicinal Chemistry, 13(10), 3593-3599. https://doi.org/10.1016/j.bmc.2004.11.049

@article{f820abc28e874a1d85ca120c51da96a4,

title = "Synthesis and biological evaluation of N-\{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl\}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway",

abstract = "The synthesis and evaluation of N-\{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)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 (Ki = 0.50 μM), whereas it was inactive (Ki > 100 μM) 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 μM).",

author = "Heng Cheng and Inkyu Hwang and Youhoon Chong and Ali Tavassoli and Webb, \{Michael E.\} and Yan Zhang and Wilson, \{Ian A.\} and Benkovic, \{Stephen J.\} and Boger, \{Dale L.\}",

note = "Funding Information: We gratefully acknowledge the financial support of the National Institute of Health (CA 63536, to D.L.B., I.A.W., and S.J.B.), and the Skaggs Institute for Chemical Biology. Y.Z. is a Skaggs Fellow.",

year = "2005",

month = may,

day = "15",

doi = "10.1016/j.bmc.2004.11.049",

language = "English (US)",

volume = "13",

pages = "3593--3599",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier Ltd",

number = "10",

}

Cheng, H, Hwang, I, Chong, Y, Tavassoli, A, Webb, ME, Zhang, Y, Wilson, IA, Benkovic, SJ & Boger, DL 2005, 'Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway', Bioorganic and Medicinal Chemistry, vol. 13, no. 10, pp. 3593-3599. https://doi.org/10.1016/j.bmc.2004.11.049

Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)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 et al.
In: Bioorganic and Medicinal Chemistry, Vol. 13, No. 10, 15.05.2005, p. 3593-3599.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway

AU - Cheng, Heng

AU - Hwang, Inkyu

AU - Chong, Youhoon

AU - Tavassoli, Ali

AU - Webb, Michael E.

AU - Zhang, Yan

AU - Wilson, Ian A.

AU - Benkovic, Stephen J.

AU - Boger, Dale L.

N1 - Funding Information: We gratefully acknowledge the financial support of the National Institute of Health (CA 63536, to D.L.B., I.A.W., and S.J.B.), and the Skaggs Institute for Chemical Biology. Y.Z. is a Skaggs Fellow.

PY - 2005/5/15

Y1 - 2005/5/15

N2 - The synthesis and evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)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 (Ki = 0.50 μM), whereas it was inactive (Ki > 100 μM) 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 μM).

AB - The synthesis and evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)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 (Ki = 0.50 μM), whereas it was inactive (Ki > 100 μM) 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 μM).

UR - https://www.scopus.com/pages/publications/17444418621

UR - https://www.scopus.com/pages/publications/17444418621#tab=citedBy

U2 - 10.1016/j.bmc.2004.11.049

DO - 10.1016/j.bmc.2004.11.049

M3 - Article

C2 - 15848772

AN - SCOPUS:17444418621

SN - 0968-0896

VL - 13

SP - 3593

EP - 3599

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 10

ER -

Cheng H, Hwang I, Chong Y, Tavassoli A, Webb ME, Zhang Y et al. Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway. Bioorganic and Medicinal Chemistry. 2005 May 15;13(10):3593-3599. doi: 10.1016/j.bmc.2004.11.049

Synthesis and biological evaluation of N-{4-[5-(2,4-diamino-6-oxo-1,6- dihydropyrimidin-5-yl)-2-(2,2,2-trifluoroacetyl)pentyl]benzoyl}-L-glutamic acid as a potential inhibitor of GAR Tfase and the de novo purine biosynthetic pathway

Abstract

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